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A Matter of Record
(301) 890-4188
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FOOD AND DRUG ADMINISTRATION 1
CENTER FOR DRUG EVALUATION AND RESEARCH 2
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ONCOLOGIC DRUGS ADVISORY COMMITTEE (ODAC) MEETING 6
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Tuesday, April 12, 2016 13
8:30 a.m. to 12:25 p.m. 14
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FDA White Oak Campus 19
Building 31, The Great Room 20
White Oak Conference Center 21
Silver Spring, Maryland 22
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Meeting Roster 1
ACTING DESIGNATED FEDERAL OFFICER (Non-Voting) 2
LCDR Jennifer A. Shepherd, RPh 3
Division of Advisory Committee and Consultant Management 4
Office of Executive Programs, CDER, FDA 5
Silver Spring, Maryland 6
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ONCOLOGIC DRUGS ADVISORY COMMITTEE MEMBERS (Voting) 8
Deborah K. Armstrong, MD 9
(Chairperson) 10
Professor of Oncology 11
The Sidney Kimmel Comprehensive Cancer Center at 12
Johns Hopkins 13
The Johns Hopkins University School of Medicine 14
Baltimore, Maryland 15
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Bernard F. Cole, PhD 17
Professor 18
Department of Mathematics and Statistics 19
University of Vermont 20
Burlington, Vermont 21
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Tito Fojo, MD, PhD 1
Professor of Medicine 2
Division of Medical Oncology 3
Department of Medicine 4
Columbia University 5
New York, New York 6
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Michael E. Menefee, MD 8
Assistant Professor of Medicine 9
Mayo Clinic Jacksonville 10
Jacksonville, Florida 11
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Grzegorz S. Nowakowski, MD 13
Assistant Professor of Medicine 14
Mayo Clinic Rochester 15
Rochester, Minnesota 16
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Brian I. Rini, MD, FACP 18
Professor of Medicine 19
Cleveland Clinic Taussig Cancer Institute 20
Glickman Urological and Kidney Institute 21
Cleveland, Ohio 22
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Bruce J. Roth, MD 1
Professor of Medicine 2
Division of Oncology 3
Washington University School of Medicine 4
St. Louis, Missouri 5
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ONCOLOGIC DRUGS ADVISORY COMMITTEE MEMBER (Non-Voting) 7
Phuong Khanh (P.K.) Morrow, MD, FACP 8
Executive Medical Director, Amgen Oncology 9
Therapeutic Area Head, US Medical Organization 10
Thousand Oaks, California 11
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TEMPORARY MEMBERS (Voting) 1
William Douglas Figg, Sr., PharmD, MBA 2
Senior Investigator and Head of the Clinical Pharmacology 3
Program in the Office of the Clinical Director, Center 4
for Cancer Research (CCR) 5
National Cancer Institute (NCI) 6
National Institutes of Health (NIH) 7
Head of Molecular Pharmacology Section 8
Deputy Branch Chief in the Genitourinary 9
Malignancies Branch, CCR, NCI, NIH 10
Bethesda, Maryland 11
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Terry Gillespie 13
(Patient Representative) 14
Westmont, Illinois 15
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Donald E. Mager, PharmD, PhD 17
Associate Professor of Pharmaceutical Sciences 18
Department of Pharmaceutical Sciences 19
University at Buffalo, State University of New York 20
Buffalo, New York 21
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Michele Orza, ScD 1
(Acting Consumer Representative) 2
Senior Advisor to the Executive Director 3
Patient-Centered Outcomes Research Institute (PCORI) 4
Washington, District of Columbia 5
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Arun Rajan, MD 7
Associate Research Physician 8
Thoracic and GI Oncology Branch 9
CCR, NCI, NIH 10
Bethesda, Maryland 11
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Eva Szabo, MD 13
Chief 14
Lung & Upper Aerodigestive Cancer Research Group 15
Division of Cancer Prevention, NCI, NIH 16
Bethesda, Maryland 17
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FDA PARTICIPANTS (Non-Voting) 1
Richard Pazdur, MD 2
Director 3
Office of Hematology and Oncology Products 4
(OHOP) 5
Office of New Drugs (OND), CDER, FDA 6
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Patricia Keegan, MD 8
Director 9
Division of Oncology Products 2 (DOP2) 10
OHOP, OND, CDER, FDA 11
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Gideon Blumenthal, MD 13
Medical Team Leader 14
Thoracic/Head & Neck Cancer Team 15
DOP2, OHOP, OND, CDER, FDA 16
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Lola Fashoyin-Aje, MD, MPH 18
Medical Officer 19
Thoracic/Head & Neck Cancer Team 20
DOP2, OHOP, OND, CDER, FDA 21
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Chao Liu, PhD 1
Pharmacometrics Reviewer 2
Division of Pharmacometrics (DPM) 3
Office of Clinical Pharmacology (OCP) 4
Office of Translational Sciences (OTS) 5
CDER, FDA 6
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C O N T E N T S 1
AGENDA ITEM PAGE 2
Call to Order and Introduction of Committee 3
Deborah Armstrong, MD 11 4
Conflict of Interest Statement 5
Jennifer Shepherd, RPh 14 6
Opening Remarks 7
Gideon Blumenthal, MD 18 8
Applicant Presentations – Clovis Oncology 9
Introduction 10
Lindsey Rolfe, MBCHB, MRCP 23 11
Unmet Need in EGFR Mutant NSCLC 12
David Carbone, MD, PhD 27 13
Efficacy 14
Sergey Yurasov, MD, PhD 32 15
Safety and Dose Selection 16
Lindsey Rolfe, MBCHB, MRCP 40 17
Clinical Perspective and Benefit-Risk 18
Ross Camidge, MD, PhD 52 19
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C O N T E N T S (continued) 1
AGENDA ITEM PAGE 2
FDA Presentations 3
NDA 208542- Rociletinib 4
Lola Fashoyin-Aje, MD, MPH 59 5
Chao Liu, PhD 69 6
Lola Fashoyin-Aje, MD, MPH 76 7
Clarifying Questions to the Presenters 94 8
Open Public Hearing 140 9
Questions to the Committee and Discussion 173 10
Adjournment 202 11
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P R O C E E D I N G S 1
(8:30 a.m.) 2
Call to Order 3
Introduction of Committee 4
DR. ARMSTRONG: Good morning. I'd first 5
like to remind everyone to please silence your cell 6
phones, smartphones, and any other devices you have 7
if you've not already done so. I'd also like to 8
identify the FDA press contact, Angela Stark. If 9
you're here, please stand up. There she is. Thank 10
you, Angela. 11
Now, I'd like to have the members of the 12
committee introduce themselves. We'll start with 13
P.K. Morrow. 14
DR. MORROW: P.K. Morrow, Amgen. 15
DR. MAGER: Don Mager, associate professor 16
at the University of Buffalo. 17
DR. SZABO: Eva Szabo, National Cancer 18
Institute. 19
MS. GILLESPIE: Terry Gillespie, advocate. 20
DR. ORZA: Michelle Orza, Patient-Centered 21
Outcomes Research Institute. I'm the acting 22
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consumer representative today. 1
DR. FIGG: William Figg, National Cancer 2
Institute. 3
DR. NOWAKOWSKI: Grzegorz Nowakowski, Mayo 4
Clinic, Rochester. 5
DR. FOJO: Tito Fojo, medical oncology at 6
Columbia University. 7
DR. ARMSTRONG: Deb Armstrong, medical 8
oncology, Johns Hopkins and ODAC chair. 9
LCDR SHEPHERD: Jennifer Shepherd, 10
designated federal officer. 11
DR. ROTH: Bruce Roth, Washington University 12
in St. Louis. 13
DR. MENEFEE: Michael Menefee, medical 14
oncology, Mayo Clinic, Florida. 15
DR. RINI: Brian Rini. I'm a medical 16
oncologist at Cleveland Clinic. 17
DR. COLE: Bernard Cole, biostatistics at 18
University of Vermont. 19
DR. LIU: Chao Liu, pharmacometrics, FDA. 20
DR. FASHOYIN-AJE: Lola Fashoyin-Aje, the 21
clinical reviewer for this application, FDA. 22
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DR. BLUMENTHAL: Gideon Blumenthal, 1
clinical, FDA. 2
DR. KEEGAN: Patricia Keegan, division 3
director, Division of Oncology Products 2, FDA. 4
DR. PAZDUR: Richard Pazdur, director, 5
Office of Hematology, Oncology Products. 6
DR. ARMSTRONG: Thank you. For topics such 7
as those being discussed at today's meeting, there 8
are often a variety of opinions, some of which are 9
quite strongly held. Our goal is that today's 10
meeting will be a fair and open forum for 11
discussion of these issues and that individuals can 12
express their views without interruption. Thus, as 13
a gentle reminder, individuals will be allowed to 14
speak into the record only if recognized by the 15
chairperson, and we look forward to a productive 16
meeting. 17
In the spirit of the Federal Advisory 18
Committee Act and the Government in the Sunshine 19
Act, we ask that the advisory committee members 20
take care that their conversations about the topic 21
at hand take place in the open forum of the 22
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meeting. We are also aware that members of the 1
media are anxious to speak with the FDA about these 2
proceedings, however, FDA will refrain from 3
discussing the details of this meeting with the 4
media until its conclusion. Also, the committee is 5
reminded to please refrain from discussing the 6
meeting topic during breaks or lunch. Thank you. 7
I'll now pass it on to Jennifer Shepherd, 8
who is replacing Lauren Tesh, who's on jury duty 9
today, who will read the Conflict of Interest 10
Statement. Life goes on. 11
Conflict of Interest Statement 12
LCDR SHEPHERD: Good morning. The Food and 13
Drug Administration is convening today's meeting of 14
the Oncologic Drugs Advisory Committee under the 15
authority of the Federal Advisory Committee Act of 16
1972. With the exception of the industry 17
representative, all members and temporary voting 18
members of the committee are special government 19
employees or regular federal employees from other 20
agencies and are subject to federal conflict of 21
interest laws and regulations. 22
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The following information on the status of 1
this committee's compliance with federal ethics and 2
conflict of interest laws, covered by but not 3
limited to those found at 18 U.S.C. Section 208, is 4
being provided to participants in today's meeting 5
and to the public. FDA has determined that members 6
and temporary voting members of this committee are 7
in compliance with Federal Ethics and Conflict of 8
Interest laws. 9
Under 18 U.S.C. Section 208, Congress has 10
authorized FDA to grant waivers to special 11
government employees and regular federal employees 12
who have potential financial conflicts when it is 13
determined that the agency's need for a special 14
government employee's services outweighs his or her 15
potential financial conflict of interest, or when 16
the interest of a regular federal employee is not 17
so substantial as to be deemed likely to affect the 18
integrity of the services, which the government may 19
expect from the employee. 20
Related to the discussion of today's 21
meetings, members and temporary voting members of 22
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this committee have been screened for potential 1
financial conflicts of interest of their own as 2
well as those imputed to them, including those of 3
their spouses or minor children, and for purposes 4
of 18 U.S.C. Section 208, their employers. These 5
interests may include investments, consulting, 6
expert witness testimony, contracts, grants, 7
CRADAs, teaching, speaking, writing, patents and 8
royalties, and primary employment. 9
Today's agenda involves new drug application 10
208542, rociletinib tablets, application submitted 11
by Clovis Oncology Incorporated. The proposed 12
indication for this product is for the treatment of 13
patients with mutant epidermal growth factor 14
receptor, or EGFRs, non-small cell lung cancer, who 15
have been previously treated with an EGFR-targeted 16
therapy and had the EGFR T790M mutation as detected 17
by an FDA approved test. This is a particular 18
matters meeting during which specific matters 19
related to Clovis Oncology's NDA will be discussed. 20
Based on the agenda for today's meeting and 21
all financial interests reported by the committee 22
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members and temporary voting members, no conflict 1
of interest waivers have been issued in connection 2
with this meeting. To ensure transparency, we 3
encourage all standing committee members and 4
temporary voting members to disclose any public 5
statements that they have made concerning the 6
product at issue. 7
With respect to FDA's invited industry 8
representative, we would like to disclose that 9
Dr. P.K. Morrow is participating in this meeting as 10
a non-voting industry representative acting on 11
behalf of regulated industry. Dr. Morrow's role at 12
this meeting is to represent industry in general 13
and not any particular company. Dr. Morrow is 14
employed by Amgen. 15
We would like to remind members and 16
temporary voting members that if the discussions 17
involve any other products or firms not already on 18
the agenda for which an FDA participant has a 19
personal or imputed financial interest, the 20
participants need to exclude themselves from such 21
involvement, and their exclusion will be noted for 22
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the record. FDA encourages all other participants 1
to advise the committee of any financial 2
relationships that they may have with the firm at 3
issue. Thank you. 4
DR. ARMSTRONG: Thank you. We'll now 5
proceed with the opening remarks from 6
Dr. Blumenthal. 7
Opening Remarks 8
DR. BLUMENTHAL: Good morning, Chairperson 9
Armstrong, members of the ODAC. We are here to 10
discuss the rociletinib New Drug Application 208542 11
for proposed indication for the treatment of 12
patients with EGFR mutation positive metastatic 13
non-small cell lung cancer, who have been 14
previously treated with an EGFR tyrosine kinase 15
inhibitor and whose tumors harbor an EGFR T790M 16
mutation as detected by an FDA approved test. 17
The applicant, Clovis Oncology, has 18
requested accelerated approval for rociletinib 19
based on the results of two non-randomized studies 20
conducted in patients with EGFR mutation positive 21
metastatic non-small cell lung cancer. The 22
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companion diagnostic test to detect EGFR T790M 1
mutations is also under review. 2
EGFR T790M mutation positive non-small cell 3
lung cancer is a serious and life-threatening 4
disease with unmet medical need. Safe and 5
effective therapies to treat this disease are 6
needed for patients who have progressed on 7
first-line EGFR TKI and often platinum doublet 8
chemotherapy. 9
Treatment options include docetaxel with or 10
without ramucirumab, pemetrexed, or nivolumab, with 11
response rates roughly 10 to 20 percent and median 12
survivals of 1 to 2 years. Recently, FDA granted 13
osimertinib accelerated approval for patients with 14
T790M mutation positive non-small cell lung cancer 15
based on a confirmed objective response rate of 59 16
percent by independent radiologic review in 411 17
patients. 18
Responses appear to be durable with a median 19
duration of response of 12 months. In addition, 20
osimertinib was well tolerated with no grade 3 or 4 21
toxicities occurring in more than 3 percent of 22
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patients. 1
During the review of the rociletinib 2
application, a number of issues arose and several 3
uncertainties remain. With respect to efficacy, 4
FDA disagreed with the applicant's inclusion of 5
unconfirmed responses when reporting ORR. FDA's 6
pooled analysis revealed an ORR of 30 percent with 7
a median duration of response of 9 months. 8
A key point to discuss is whether the ORR 9
and durability observed with rociletinib is better 10
than available therapies for second-line lung 11
cancer, which have demonstrated survival benefits. 12
Superiority to available therapy is necessary for 13
accelerated approval. 14
The main uncertainties with respect to 15
safety are the serious and life-threatening risks 16
associated with rociletinib and its toxic 17
metabolites M502 and M460. These toxicities 18
include serious hyperglycemia, which occurred in a 19
third of patients. 20
Furthermore, rociletinib is 21
pro-arrhythmogenic with cases of ventricular 22
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tachyarrhythmias and sudden deaths. The true 1
incidence of deaths due to arrhythmia may be 2
underestimated given that rociletinib was evaluated 3
in single-arm trials. 4
A major source of variability and exposure 5
to the metabolites M502 and M460 is a patient's 6
NAT2 genotype. Patients who are NAT2 slow 7
acetylators are at increased risk for serious 8
hyperglycemia and QTc prolongation leading to 9
ventricular arrhythmia, and uncertainty remains 10
with respect to how best to risk stratify patients 11
based on acetylator status. 12
With respect to dose, the applicant's 13
proposed dose of 625 milligrams twice daily is not 14
supported by the available clinical, clinical 15
pharmacology, or pharmacometric data submitted in 16
the application. 17
Today, we will discuss these issues and the 18
residual uncertainties. The discussion will focus 19
on the overall benefit-risk profile of rociletinib 20
for the proposed patient population and whether 21
more information is needed from the results of the 22
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randomized control trial of rociletinib versus 1
single-agent chemotherapy prior to making a 2
regulatory decision on this application. Thank 3
you. 4
DR. ARMSTRONG: Both the Food and Drug 5
Administration and the public believe in a 6
transparent process for information gathering and 7
decision making. To ensure such transparency at 8
the advisory committee meeting, FDA believes that 9
it is important to understand the context of an 10
individual's presentation. 11
For this reason, FDA encourages all 12
participants, including the sponsor's non-employee 13
presenters, to advise the committee of any 14
financial relationships they may have with the firm 15
at issue, such as consulting fees, travel expenses, 16
honoraria, and interests in the sponsor, including 17
equity interests and those based on the outcome of 18
the meeting. 19
Likewise, FDA encourages you at the 20
beginning of your presentation to advise the 21
committee if you do not have such financial 22
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relationships. If you choose not to address this 1
issue of financial relationships at the beginning 2
of your presentation, it will not preclude you from 3
speaking. We'll now proceed with the applicant's 4
presentation. 5
Applicant Presentation – Lindsey Rolfe 6
DR. ROLFE: Good morning. I am Lindsey 7
Rolfe, chief medical officer at Clovis Oncology. 8
We are pleased to be here to present our candidate, 9
rociletinib, for accelerated approval for the 10
treatment of T790M positive non-small cell lung 11
cancer patients. 12
Lung cancer is the second most common 13
serious cancer in the U.S. with over 200,000 new 14
cases each year and is the leading cause of cancer-15
related death in the U.S. Non-small cell lung 16
cancer accounts for almost 85 percent of lung 17
cancers and is associated with high mortality. By 18
the time of detection, most non-small cell lung 19
cancer patients have metastatic disease for which 20
there is no cure. Thus, treatment is focused on 21
reducing tumor burden, controlling disease, and 22
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managing symptoms. 1
Major recent advances in treating non-small 2
cell lung cancer have come from understanding the 3
underlying molecular abnormalities that drive the 4
disease. We now know that approximately 15 percent 5
of non-small cell lung cancer patients in the U.S. 6
have epidermal growth factor receptor, or EGFR, 7
activating mutations in their tumor, the majority 8
of whom will respond to a first or second 9
generation EGFR targeted tyrosine kinase inhibitor, 10
or TKI. However, almost all patients will develop 11
acquired resistance to therapy predominately due to 12
a second EGFR mutation, T790M. 13
Rociletinib was specifically designed to 14
inhibit T790M. Rociletinib is a novel, potent, 15
third generation EGFR targeting TKI. It 16
irreversibly inhibits both the initial activating 17
EGFR mutations and the T790M resistance mutation 18
without the dose limiting skin and GI effects that 19
are clinically observed with the first and second 20
generation inhibitors. 21
The proposed indication for rociletinib is 22
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for the treatment of patients with mutant EGFR 1
non-small cell lung cancer who have been previously 2
treated with an EGFR targeted therapy and have the 3
EGFR T790M mutation as detected by an FDA approved 4
test. 5
We are seeking accelerated approval and will 6
show that rociletinib meets the criteria outlined 7
by FDA. First, rociletinib treats a serious 8
condition in a subgroup of patients with advanced 9
EGFR mutant non-small cell lung cancer. 10
Second, rociletinib provides an advantage 11
over available therapy, which includes single agent 12
chemotherapy and immunotherapy. 13
Third, objective response rate is an 14
endpoint that reasonably predicts meaningful 15
clinical benefit in lung cancer. In addition, our 16
confirmatory randomized, controlled phase 3 study 17
is ongoing. 18
I would like to take a moment to discuss why 19
we are seeking approval for a different dose than 20
the recommended dose in the NDA. We studied a 21
number of doses in our phase 2 program, and all 22
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doses were active. At the time of our NDA 1
submission, we recommended 500 milligrams BID 2
because we anticipated that the response rate at 3
500 milligrams BID would increase as the data 4
matured. 5
As agreed previously with FDA, we submitted 6
a more mature efficacy update following our initial 7
submission, which also included a new analysis of 8
the data at FDA's request. Based on these data, we 9
revised our recommended dose to 625 milligrams as 10
the objective response rate is higher at 11
625 milligrams than at 500 milligrams, with similar 12
toxicity. 13
Due to the observed activity of both doses, 14
however, we are studying both the 500-milligram and 15
the 625-milligram doses in the randomized 16
confirmatory study. 17
For our agenda for the rest of the 18
presentation, Dr. David Carbone from the Ohio State 19
University will present the need for new treatment 20
options. Then, Dr. Sergey Yurasov from Clovis 21
Oncology will review the rociletinib efficacy data. 22
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I will return to the lectern to present the 1
safety data and our dose selection rationale. And 2
then Dr. Ross Camidge from the University of 3
Colorado will provide his clinical perspective on 4
the benefit-risk of rociletinib. I will then 5
return to answer your questions. 6
Additionally, we have some external experts 7
with us today to help answer your questions. All 8
have been compensated for their time. And now I 9
would like to invite Dr. Carbone to the lectern. 10
Applicant Presentation – David Carbone 11
DR. CARBONE: Good morning. I am David 12
Carbone, professor of medicine and director of the 13
James Thoracic Center at the Ohio State University. 14
I also serve as the president of the International 15
Association for the Study of Lung Cancer. 16
My research interests have been focused on 17
the development of new targeted therapies on lung 18
cancer genetics and immunotherapy of lung cancer. 19
I'm pleased to be here to discuss the need for new 20
effective treatments for patients with EGFR mutant 21
non-small cell lung cancer. 22
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Because we're not able to cure advanced EGFR 1
mutant lung cancer, the goal of treatment is to 2
achieve and maintain disease control while 3
minimizing treatment related toxicities. The 4
optimal therapy for newly diagnosed patients with 5
advanced or metastatic EGFR mutant non-small cell 6
lung cancer is to receive an EGFR targeted TKI as 7
their first-line therapy. 8
The vast majority of these patients 9
experience clinical benefit from this with an 10
overall response rate of 50 to 70 percent and a 11
duration of response that ranges between 6 and 12.5 12
months, with progression-free survival ranging from 13
10 to 14 months. 14
As patients can remain on treatment for many 15
months, even low-grade treatment related toxicities 16
that are present continuously can become important 17
to patients. Particularly relevant to patients 18
receiving EGFR inhibitors are skin effects, nail 19
changes, and diarrhea. While they sound innocent, 20
they can be difficult for patients to tolerate for 21
long periods of time. 22
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Regardless of treatment and toxicities, all 1
patients will eventually progress. In 2
approximately 60 percent of patients, progression 3
is due to a second EGFR mutation T790M, which 4
renders first and second generation EGFR inhibitors 5
ineffective. So how do we treat these patients? 6
Since it is generally considered optimal to 7
maintain well-tolerated oral TKI therapy for as 8
long as possible before transitioning to 9
chemotherapy, strategies include local therapy for 10
oligoprogressive disease and third generation TKIs 11
targeting the T790M resistance mechanism. 12
After exhaustion of TKI options, fit 13
patients may be appropriate for a platinum-based 14
doublet. There are now FDA approved second-line 15
therapies for treatment of metastatic non-small 16
cell. These include single agent chemotherapies 17
pemetrexed and docetaxel, immunotherapy with 18
nivolumab, and anti-VEGFR2 ramucirumab used in 19
combination with docetaxel. 20
Let me describe what can be expected with 21
the approved second-line agents. Single agent 22
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chemotherapy offers little clinical benefit as 1
second-line therapy with response rates in the 2
single digits and a median duration of response 3
between 4 and 9 months. 4
These patients also experience significant 5
clinically evident toxicities, including nausea, 6
fatigue, hair loss, and neuropathy. Neutropenia is 7
frequent with these agents and increases the risk 8
for symptomatic infection and may require 9
hospitalization with a substantial negative impact 10
on their lifestyle and can also lead to treatment 11
discontinuation. 12
There are two other approved treatments for 13
patients with non-small cell lung cancer. 14
Immunotherapy has shown activity in unselected 15
patients receiving second-line therapy. There's 16
insufficient data in patients with EGFR mutant lung 17
cancer. 18
It should be emphasized that all of these 19
options are available to EGFR mutant patients after 20
exhaustion of TKI options. In addition to having a 21
low response rate in these patients, the side 22
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effect profile of nivolumab is benign in the 1
majority of patients, but a small number of 2
patients do experience severe adverse events, like 3
colitis, hepatitis, pneumonitis, and rash. The 4
combination of ramucirumab plus docetaxel has all 5
the side effects of single-agent docetaxel plus 6
those associated with VEGFR2 inhibition. 7
While this is an exciting time for research 8
and development in an area of high unmet need, 9
there is still a need for more EGFR targeted 10
treatment options. I've been treating patients 11
with lung cancer throughout my career for the past 12
25 years, and it's hard to overemphasize how awful 13
a disease lung cancer is. 14
With over 220,000 cases a year, the majority 15
of these cases diagnosed at stage 4, where the 16
global median survival is only 6 months from 17
diagnosis to death. Thus, the goal of treatment is 18
to control patient symptoms as effectively as 19
possible for as long as possible, and I believe 20
this is achieved by maximizing time on TKIs. 21
Each of the current therapies I discuss has 22
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a unique risk-benefit profile enabling oncologists 1
to tailor therapy to individual patients. As a 2
clinical oncologist who has worked with lung cancer 3
patients, what's absolutely clear to me is that no 4
single therapy is appropriate for all patients. 5
There is a clear clinical need for new therapeutic 6
options for patients with EGFR T790M mutant 7
non-small cell. 8
Now, I will turn the lectern over to 9
Dr. Yurasov. 10
Applicant Presentation – Sergey Yurasov 11
DR. YURASOV: Thank you, Dr. Carbone. My 12
name is Sergey Yurasov, and I will present the 13
efficacy data for rociletinib. The evidence 14
support an accelerated approval comes from two 15
phase 2 trials, study 008 and study 019. Both 16
studies were ongoing at the time of the data 17
cutoff. 18
These studies have similar design and 19
patient populations, and data that we'll present 20
today is combined from the two studies. Results 21
were similar across trials. 22
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Study 008 was an open-label phase 1-2 study 1
to assess safety and efficacy of rociletinib in 2
patients with EGFR mutant non-small cell lung 3
cancer who have progressive disease after one or 4
more prior EGFR TKI therapies. Tumor responses 5
were seen at several dose levels during dose 6
escalation in phase 1. 7
In phase 2, T790M status was confirmed by 8
central lab. We started with a 750 milligram twice 9
daily dose, however investigators commented that 10
lower doses might have better tolerability while 11
maintaining the overall response rate. We expanded 12
the study to include 500- and 625-milligram BID 13
doses. 14
In study 008, tumor assessments were 15
performed every 6 weeks. Treatment continued until 16
disease progression or death. The end of study 17
evaluation was conducted 28 days after the last 18
dose. Patients were then followed every 2 months 19
to capture subsequent therapy as well as survival 20
data. 21
Based on the emergent data from study 008, 22
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the 625-milligram dose was chosen for further 1
evaluation in study 019. Study 019 was a phase 2, 2
open-label, single-arm study to evaluate the safety 3
and efficacy of rociletinib 625-milligram BID dose 4
in patients with centrally confirmed T790M positive 5
EGFR mutant lung cancer who had progression after 6
one prior EGFR TKI therapy. Tumor assessments were 7
performed every 8 weeks. Treatment continued until 8
disease progression or death. 9
Overall, 457 patients were enrolled in 10
study 008 and 019 across different dose levels. 11
Free-base formulation was discontinued early in 12
development and will not be presented. Our 13
clinical analyses are based on hydrobromide 14
formulation, which has a better PK profile. 15
Overall, 400 patients received rociletinib at 500, 16
625-, 750-, and 1000-milligram doses. This is our 17
safety population. 18
The T790M efficacy population contains only 19
patients who were treated with rociletinib and had 20
evidence of T790M positive tumors confirmed by 21
central lab and who had scans submitted for 22
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independent review; 325 patients matched these 1
criteria. This is our efficacy population. 2
Key inclusion criteria was similar for both 3
studies. Adult patients with ECOG performance 4
status 0 or 1 with confirmed EGFR mutation positive 5
lung cancer were enrolled. These were patients who 6
had recurrent disease after prior therapy with an 7
approved EGFR TKI. T790M mutation status was 8
centrally confirmed using tumor tissue. 9
For study 008, patients could have received 10
one or more prior lines of treatment. For 11
study 019, only patients who received one prior 12
EGFR TKI were enrolled. Key exclusion criteria 13
were also similar and excluded use of medications 14
that prolonged the QT interval, prior treatment 15
with T790M targeted agents, and unstable CNS 16
metastatic disease. 17
Demographics for the T790M positive patients 18
was typical of EGFR mutant lung cancer and 19
consistent across all doses. Most patients were 20
recruited from the United States. At least 21
two-thirds of patients had ECOG performance 22
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status 1. 1
Disease characteristics were typical of 2
patients with recurrent progressive lung cancer. 3
Median time since initial diagnosis ranged from 23 4
to 33 months. The vast majority of these patients 5
had distant metastases with two or more organs 6
affected, including approximately one-third of 7
patients with liver lesions or bone disease. More 8
than 40 percent of patients had a history of CNS 9
disease, which typically has a worse prognosis. 10
Patients progressed after multiple prior 11
therapies with a median of 2 to 3 prior therapies 12
for lung cancer. Fifty-seven to 73 percent of 13
patients received more than two prior lines of 14
therapy. Fifty-two to 68 percent of patients 15
received at least one chemotherapy regimen with 16
almost all of these patients having received a 17
platinum-containing chemotherapy. 18
Approximately one-third of patients received 19
two or more treatments with an EGFR TKI prior to 20
rociletinib. Patient disposition was generally 21
consistent across doses. Between 35 and 42 percent 22
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of patients continued to receive therapy at the 1
time of data cutoff. 2
The main reason for treatment 3
discontinuation across all doses was disease 4
progression followed by adverse events. Death as 5
the reason for treatment discontinuation was a rare 6
event. 7
Now, let's look at the efficacy results. 8
The primary endpoint was objective response rate, 9
or ORR, based on RECIST 1.1 criteria. While ORR 10
was evaluated by both independent physiological 11
review and investigator assessment, I will present 12
the IRR results. Investigator assessment results 13
are similar and included in your briefing book. 14
The key secondary endpoint was the duration 15
of response measured from the first observation of 16
response until radiographic evidence of disease 17
progression. 18
Now, turning to the primary efficacy 19
endpoint, consistent with the FDA approach of 20
pooling data across all doses for efficacy 21
analysis, the confirmed objective response rate 22
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overall was 30 percent. The response rates were 1
similar for 625- and 750-milligram doses. 2
Confirmed ORR at 500-milligram dose was slightly 3
below the lower boundary of 95 percentile 4
confidence interval for overall ORR. 5
Now, on to the duration of response. 6
Responses were durable for all rociletinib dose 7
levels combined. The median duration of response 8
was 8.9 months. At the 625-milligram dose, which 9
represents 51 percent of patients and is shown on 10
the graph in blue, the duration of response was 11
8.8 months. 12
Let's look at the target lesion reduction in 13
patients who have measurable disease at baseline. 14
Clinically meaningful benefit in patients receiving 15
rociletinib 625-milligram dose is supported by 16
significant target lesion reduction as demonstrated 17
on this waterfall plot with 93 percent of patients 18
who experienced target lesion reduction when 19
compared to baseline. 20
We also looked at efficacy across a number 21
of subgroups. At the top of this graph, the 22
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overall response rate of 30 percent seen across all 1
doses combined is shown. Overall, the response 2
rate was consistent across all major clinically 3
relevant subgroups as shown on this forest plot. 4
For all doses combined, substantial tumor 5
response was observed in patients with poor 6
prognostic factors, such as age above 65, ECOG 7
performance status 1, patients with liver and bone 8
disease, and history of CNS disease. 9
For patients who received two prior lines of 10
therapy, which is similar to the patient population 11
in our confirmatory phase 3 study, the response 12
rate was 33 percent. 13
In conclusion, rociletinib demonstrates 14
clinically meaningful and durable responses in 15
patients with T790M positive lung cancer. For all 16
doses combined, the objective response rate is 17
30 percent with a median duration of response of 18
approximately 9 months. 19
The 625-milligram BID dose with a response 20
rate of 32 percent and duration of response close 21
to 9 months is the appropriate dose to treat these 22
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patients, especially when compared to approved 1
chemotherapy-based regimens for recurrent lung 2
cancer. Similar response rates were observed 3
across all major clinical subgroups, including 4
patients with poor prognostic factors. 5
Now, I will turn the lectern over to Dr. 6
Lindsey Rolfe. 7
Applicant Presentation – Lindsey Rolfe 8
DR. ROLFE: Thank you, Dr. Yurasov. 9
Next, I will review the safety data set from 10
the combined 008 and 019 studies. The safety 11
population includes all patients treated at each 12
dose, including patients with or without the T790M 13
mutation. 14
The median duration of treatment ranged from 15
18 to 25 weeks across all three doses. 16
Thirty-seven percent of patients on the 17
500-milligram and 625-milligram doses were treated 18
for longer than 6 months with a higher percentage 19
on the 750-milligram dose. The analysis we present 20
is the most conservative, including events of 21
disease progression. Almost all patients reported 22
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one or more adverse events. 1
As we will show, AE frequencies tended to be 2
very similar between the 500-milligram and 3
625-milligram doses and higher at the 750-milligram 4
dose. Approximately 57 percent of patients had an 5
AE of grade 3 or 4 severity at the 500-and 6
625-milligram dose, and 65 percent at 7
750 milligrams. More patients on the 750-milligram 8
dose had an AE that led to dose modification. 9
Approximately 20 percent of patients had an 10
AE that led to discontinuation across all the 11
doses. About 46 percent of patients had a serious 12
AE and approximately 15 percent of patients had a 13
fatal AE. 14
Almost all of the deaths were related to 15
disease progression in line with the advanced 16
disease state under study. The most common adverse 17
events were diarrhea, nausea, hyperglycemia, and 18
fatigue across all doses. 19
Now, looking at grade 3 and 4 adverse 20
events, the most common were hyperglycemia, QT 21
prolongation, fatigue, and anemia. The large 22
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majority of these were grade 3 events. 1
We investigated AE preferred terms related 2
to diarrhea and cutaneous adverse events. These 3
AEs were generally mild across all doses. While 4
about half the patients experienced diarrhea, the 5
majority of the diarrhea events were grade 1 or 2. 6
We see a low rate of rash. When looking at 7
the combined terms of rash, the majority of events 8
were grade 1 or 2. Notably, very few events were 9
grade 3, and none was grade 4. This is important 10
because for other EGFR TKIs, rash can lead to 11
discontinuation. 12
The most common adverse events leading to 13
dose modification were hyperglycemia, QT 14
prolongation, nausea, diarrhea, and fatigue. I 15
should note that the protocol required a dose 16
interruption followed by a reduction for grades 3 17
QT prolongation. Almost all patients who had dose 18
modifications remained on study. 19
Approximately 22 percent of patients 20
discontinued treatment because of adverse events, 21
of which approximately half were events of disease 22
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progression. Discontinuation rates for other 1
events were low and similar across doses. 2
Now, moving to serious adverse events. 3
Approximately 46 percent of patients experienced a 4
serious adverse event. The most common serious 5
adverse event across all doses was tumor 6
progression. Except for hyperglycemia on the 7
500-milligram dose, all other serious adverse 8
events occurred in less than 10 percent of 9
patients. 10
Although 13 to 17 percent of adverse events 11
resulted in death, it is important to note that 12
86 percent of these events were events of disease 13
progression and judged unrelated to rociletinib by 14
the investigator. One patient died of pneumonia in 15
each of the arms, and 2 patients died with no cause 16
identified. 17
Now, I will review the adverse events of 18
special interest, starting with QT prolongation. 19
Using SMQ terms, approximately 34 percent of 20
patients experienced an adverse event in the QTc 21
prolongation category across all doses with 22
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8 percent, 13 percent, and 16 percent reported as 1
grade 3 or higher on the 500-, 625-and 2
750-milligram doses respectively. Approximately 3
12 percent of patients had dose modifications as 4
was required by the protocol. Very few patients 5
discontinued treatment. 6
Included in the serious adverse events were 7
3 events of ventricular tachyarrhythmia and 8
2 deaths where no cause of death was identified. 9
Detailed information related to these 5 events is 10
provided in the appendix of the briefing book. 11
A comprehensive ECG monitoring program was 12
included in the clinical trials and all ECGs were 13
collected and analyzed centrally by a specialist 14
vendor. The database, which comprises more than 15
25,000 individual tracings, has enabled us to 16
characterize the observed effect thoroughly. 17
This table shows the frequency of QTc 18
prolongation. QTc was greater than 19
500 milliseconds in 12 percent of the patients on 20
the 500-and 625-milligram doses and in 18 percent 21
in the 750-milligram dose. 22
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In the trials, we measured QTc on day 1, 1
day 15, and on the first day of each subsequent 2
cycle. No effect on QTc was observed on day 1. 3
The increases were observed by day 15, and then 4
remained stable throughout the duration of therapy. 5
While we recognize that QTc prolongation 6
occurs frequently, we do believe that these events 7
are manageable, and we have developed a 8
comprehensive risk management program. The 9
components and structure of the plan have been 10
agreed with FDA. 11
The risk minimization strategy has three key 12
elements. Firstly, a REMS program; secondly, a 13
black box warning on the prescribing information; 14
and thirdly, clear labeling statements on patient 15
selection, patient monitoring, and dose 16
modifications in case of QTc prolongation. 17
The goal of the REMS communication plan is 18
to mitigate the risks of prescribing rociletinib 19
and to inform the prescribers of the risk messages. 20
The risk messages are that rociletinib prolongs QTc 21
interval and that Torsades de pointes and sudden 22
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death have occurred. Also, that ECG and 1
electrolytes must be monitored, and rociletinib is 2
not recommended in patients with prolonged QT at 3
baseline. 4
Communication to healthcare professionals 5
and professional societies will be by letter, by 6
fact sheets, at congresses, and via a dedicated 7
website with an assessment plan. All new 8
prescribers will be identified on an ongoing basis 9
by Clovis and contacted in a timely manner in order 10
to receive documentation informing them of the 11
risks and of the risk mitigation plan. 12
The black box warning on the label will 13
provide clear information on which patients are not 14
suitable for rociletinib therapy based on baseline 15
risk factors that increase the risk of QT 16
complications. 17
The proposed label will also inform about 18
patient selection as well as provide information on 19
ECG monitoring during therapy. The ECG effect is 20
stable by day 15, and the proposed product labeling 21
will recommend ECG monitoring at day 8, day 15 and 22
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thereafter periodically. 1
There will also be a warning that 2
electrolytes should be checked and normalized 3
before starting therapy and if clinically 4
indicated. There will be information that drugs 5
causing QT prolongation should be avoided whilst 6
taking rociletinib. 7
Lastly, the proposed label will contain 8
clear guidance on when and how to dose reduce to 9
manage QT prolongation, and when to interrupt 10
rociletinib for prolonged QTc and when to restart. 11
Moving to hyperglycemia, as mentioned 12
earlier, approximately 55 percent of patients at 13
500 milligrams and 625 milligrams, and 66 percent 14
at 750 milligrams, reported an AE within the 15
hyperglycemia category. Grade 3 or 4 events were 16
similar between the 500-milligram and 625-milligram 17
doses, and higher at 750 milligrams. Most occurred 18
early in treatment. A similar number of patients 19
on 500-and 625-milligram doses had dose 20
modifications with substantially more on the 21
750-milligram dose. Overall, very few patients 22
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discontinued for hyperglycemia as there are a 1
number of measures to manage hyperglycemia. 2
Because most cases of grade 3 or higher 3
hyperglycemia occur early in treatments, regular 4
glucose monitoring in the initial weeks of therapy, 5
followed by periodic monitoring, is appropriate. 6
We know that hyperglycemia is caused by 7
rociletinib metabolites that inhibits insulin 8
receptor pathways. Therefore, it is appropriate to 9
manage the hyperglycemia using agents that target 10
insulin resistance. Dose reductions may be used if 11
hyperglycemia is not otherwise manageable. 12
Finally, hyperglycemia can be detected and 13
monitored by blood or urine testing, both of which 14
are widely available. 15
Additionally, there are some other special 16
interest AEs that we looked at. These include 17
pancreatitis and cataracts. Acute pancreatitis was 18
reported in 4 percent of patients. All patients 19
recovered and continued on rociletinib therapy. 20
After the data cutoff for the NDA, a report of 21
pancreatitis was received in a patient treated at 22
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625-milligrams BID with an outcome of death. 1
Cataract formation appears to be a late 2
effect of rociletinib, therefore we performed an 3
updated analysis of the NDA data set with a cutoff 4
in January 2016. At this time, there were 5
41 patients with treatment emergent cataracts 6
reported across all dose levels. We are continuing 7
to monitor this evolving signal to provide optimal 8
management guidance. 9
Overall, rociletinib has a well-defined, 10
manageable, and differentiated safety profile. 11
Thirty-seven percent of patients had treatment 12
duration greater than 6 months. The starting dose 13
of rociletinib may be reduced to manage adverse 14
events. Prescriber education will help manage the 15
events of QTc prolongation and hyperglycemia. 16
Awareness of these effects will enable 17
appropriate patient selection and implementation of 18
management strategies that reduce the risk of 19
potentially serious sequelae. 20
Lastly, the AE profile differs from other 21
AGFR TKIs in that it has higher rates of 22
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hyperglycemia and QTc prolongation. However, 1
cutaneous toxicities are minimal. These safety 2
data, together with the efficacy results, informed 3
our dosing recommendation. 4
An examination of the benefit-risk by dose 5
justifies our recommendation to use rociletinib 6
625-milligrams BID as the best dose. The point 7
estimate of the objective response rate was higher 8
in patients taking 625 milligrams than 500 9
milligrams, with no incremental increase at 10
750 milligrams. 11
Additionally, the safety profile between 12
rociletinib 625 milligrams and 500 milligrams are 13
generally similar with higher frequency of grade 3 14
and 4 adverse events at 750 milligrams. Overall, 15
we chose the most effective dose with an acceptable 16
and manageable safety profile. As such, 17
rociletinib 625 milligrams is the dose for which we 18
are seeking accelerated approval. 19
I would like to briefly describe our 20
confirmatory study. Our confirmatory study is a 21
phase 3, randomized, controlled trial of 22
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rociletinib compared to the investigators' choice 1
of single agent cytotoxic chemotherapy. To be 2
eligible patients, must have previously had at 3
least one line of EGFR inhibitor therapy and 4
cytotoxic chemotherapy comprising of platinum-5
containing doublet. 6
Patients' tumors will be assessed for T790M 7
but the mutation is not a requirement for 8
enrollment. The primary endpoint for this study is 9
progression-free survival in T790M positive 10
patients. Secondary endpoints include response 11
rate, duration of response, and overall survival. 12
Let me describe the study design. It is 13
important to note that this study began prior to 14
determining 625 milligrams as the recommended dose. 15
Thus, our confirmatory study currently randomizes 16
patients to open-label treatment with rociletinib 17
500 milligrams or investigator choice of 18
pemetrexed, gemcitabine, placlitaxel, or docetaxel. 19
We amended the protocol to add a 625-milligram BID 20
arm. 21
After randomization, treatment will be 22
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continued until disease progression or death. 1
Patients will be followed every 2 months to capture 2
subsequent therapy as well as survival data. The 3
confirmatory study is currently projected to 4
complete in the second half of 2018. 5
The study has enrolled 137 patients as of 6
April the 8th, 2016 and is tracking to enrollment 7
projections. We are opening more centers outside 8
of the U.S. to compensate for the availability of 9
third generation EGFR TKIs. This is giving us 10
confidence that the study will be completed in a 11
timely manner. 12
Thank you, and I will now turn the lectern 13
over to Dr. Ross Camidge to provide his clinical 14
perspective on the benefit-risk of rociletinib. 15
Applicant Presentation – Ross Camidge 16
DR. CAMIDGE: Thank you. I'm Ross Camidge, 17
the director of the thoracic oncology program at 18
the University of Colorado. Over the past several 19
years, I've treated many EGFR mutant lung cancer 20
patients with both licensed and investigational 21
agents, including rociletinib and osimertinib. 22
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Today, I'll provide my clinical perspective on the 1
benefit-risk profile of rociletinib 625 milligrams, 2
and why I believe it should be granted accelerated 3
approval. 4
With regard to dose, while there was no 5
statistically significant difference in the 6
response rate between 500, 625 and 750 milligrams, 7
the highest point estimates occurred at 625 and 8
750 milligrams; and the lower confidence interval, 9
the response rate at 500 milligrams, seems 10
disparate from those at the higher doses. 11
Could these rates actually be the same? Of 12
course. Equally, they may not truly be the same, 13
so why would we not give our patients the best 14
possible chance to respond? 15
While a 750-milligram dose was associated 16
with the highest incidence of adverse events, there 17
appears to be no significant difference in the side 18
effect profile between 500 and 625. In addition, 19
most side effects with this drug can be effectively 20
managed either through additional supportive 21
medications or through dose modification. 22
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In my own experience, patients with 1
symptomatic lung cancer feel better, often very 2
rapidly, when their cancer responds to rociletinib. 3
So aiming to get as many patients as possible to 4
respond, together with a tolerable side effect 5
profile, has to be the major goal of clinical 6
practice. 7
Given that a higher proportion of patients 8
responded at 625 than at 500, while the side effect 9
profiles were comparable, I believe 625 milligrams 10
should be the starting dose in order to give our 11
patients the best benefit-risk ratio possible. 12
While at first sight, a grade 3 or 4 adverse 13
event rate of 50 to 60 percent may seem worrisome, 14
I'd like to discuss two of the most common side 15
effects in detail to illustrate how all grade 3 or 16
4 events are not created equal in terms of their 17
impact on patients' lives. 18
As discussed by Dr. Rolfe, most of the 19
grade 3 and 4 adverse events were primarily related 20
to hyperglycemia or QT prolongation. It is 21
important to note that rociletinib associated 22
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hyperglycemia is often only a laboratory 1
observation. 2
Indeed, the grading system used focuses 3
primarily on blood values and not symptoms, with 4
grade 3 events representing glucose values between 5
251 to 500 milligrams per deciliter, and grade 4, 6
values greater than 500. 7
As the frequency of hyperglycemia SAEs was 8
significantly lower than the rate of grade 3 9
hyperglycemia, consistent with my own observations, 10
this supports the idea that most, although 11
admittedly not all, cases of rociletinib associated 12
hyperglycemia can be managed without serious 13
consequences, especially now that the underlying 14
mechanism is understood. 15
With regard to QTc prolongation, note that 16
the grading system doesn't specify symptoms until 17
grade 4 events occur. Grade 3 QTc represents EKG 18
values greater than 500 milliseconds. Grade 4 19
events use the same absolute QTc threshold but in 20
association with life-threatening signs or 21
symptoms. And such events occurred very rarely, 22
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both by grading and by SMQ-grouped SAEs, which 1
capture both unequivocal cardiac events and 2
potential ones, such as loss of consciousness or 3
sudden death. 4
While it is important not to minimize these 5
rare clinically significant cardiac events when 6
they do occur, it is also important to consider any 7
QTc risk in the context of an already established, 8
often heavily pretreated, life-threatening advanced 9
lung cancer. 10
In the data set you have seen, the patients' 11
treatment before rociletinib ranged from 1 to 13 12
prior lines of therapy with more than half of them 13
having received platinum chemotherapy and a third 14
having received at least two prior TKIs. Overall, 15
when we look at the alternatives for patients with 16
T790M positive tumors, rociletinib provides an 17
important therapeutic option very different from 18
the others currently available. 19
As you saw from Dr. Carbone, and from the 20
FDA briefing document on the proposed comparator 21
therapies, single agent docetaxel and pemetrexed 22
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are associated with response rates below 1
10 percent, together with the common toxicities and 2
inconveniences of intravenous chemotherapy. 3
The addition of ramucirumab to docetaxel can 4
increase the response rate to 23 percent but at the 5
expense of inflicting severe toxicities on nearly 6
80 percent of patients, and importantly these 7
toxicities, including neutropenia, nausea, 8
neuropathy, and hair loss, are not simple 9
laboratory or asymptomatic EKG changes, but 10
toxicities that often dramatically alter the 11
quality of patients' lives. 12
With regard to immunotherapy, early data 13
suggests that PD-1 inhibition may be less active in 14
patients with EGFR mutant disease than in the 15
general lung cancer population. Indeed, the latest 16
insight publication from the NCCN states that 17
currently immunotherapy in EGFR mutant lung cancer 18
can neither be recommended for or against based on 19
the available data. 20
To summarize, I believe the benefit-risk 21
profile of rociletinib at 625 milligrams is 22
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favorable. I have seen large masses shrink within 1
days of starting rociletinib, together with a 2
unique but manageable side effect profile, keeping 3
many patients alive, some of whom are sitting in 4
the audience today, when they had very few other 5
options to pursue. 6
Rociletinib allows patients with EGFR mutant 7
advanced lung cancer to maintain disease control 8
through oral therapy for longer and put off the 9
generally less effective, less proven, and/or less 10
attractive options of cytotoxic chemotherapy or 11
immunotherapy. 12
Beyond the fully approved options, there are 13
of course other third generation drugs being 14
developed, but rociletinib is not just a variant of 15
these. Each differs in its side effect profile, 16
and indeed we now know the common mechanisms of 17
acquired resistance to third generation drugs seems 18
to differ between these agents. 19
Consequently, the more options we have now, 20
the greater the chance is that we will not have to 21
deny patients access to safe and effective 22
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treatments simply because one size is never going 1
to fit all in the cancer therapy arena. Thus, I 2
believe the results we've seen today merit giving 3
patients immediate access to this drug via 4
accelerated approval. Thank you. 5
DR. ARMSTRONG: Thank you. We'll now 6
proceed with the presentation from FDA. 7
FDA Presentation – Lola Fashoyin-Aje 8
DR. FASHOYIN-AJE: Good morning. I'm Lola 9
Fashoyin-Aje, the clinical reviewer for NDA 208542, 10
rociletinib. I, along with Dr. Chao Liu, will 11
present the results of the efficacy, safety, and 12
clinical pharmacology evaluation of this 13
application. I would like to acknowledge the other 14
members of the review team whose collective effort 15
is represented in today's presentation. 16
During the review of this application, 17
several issues were identified. We will discuss 18
these issues highlighting areas of disagreement 19
with Clovis. The data demonstrate that rociletinib 20
is an active drug in the indicated population. 21
However, it is unclear whether the activity of this 22
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drug, specifically as measured by an overall 1
response rate of 30 percent and a median duration 2
of response of 9 months, demonstrates improvement 3
over available therapy. 4
The incidence of serious adverse reactions 5
is substantial. Up to one-third of patients 6
experienced grade 3 or grade 4 hyperglycemia. 7
Eleven percent of patients experienced grade 3 or 8
grade 4 QTc prolongation, and potentially fatal 9
ventricular tachyarrhythmias, including Torsades de 10
pointes, were observed. Two sudden and unexplained 11
deaths were also reported. 12
Single-arm trials are inadequate to 13
characterize the true extent of the incidence of 14
these serious and life-threatening adverse 15
reactions. 16
The clinical pharmacology evaluation 17
indicates that there is considerable variability in 18
the exposure to the rociletinib metabolites that 19
can contribute to the increased risk of 20
hyperglycemia and QTc prolongation. Factors 21
independent of dose may explain this variability 22
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and increased risk, including NAT2 acetylator 1
genotype status. 2
However, there is uncertainty regarding 3
whether and how to risk stratify patients according 4
to the NAT2 acetylator status to mitigate the 5
increased risks post by the rociletinib 6
metabolites. Finally, the data submitted to the 7
NDA do not support Clovis' proposed dose of 8
625 milligrams, and the uncertainty remains 9
regarding the optimal dose. 10
During the course of this presentation, I 11
will introduce the application, focusing on the 12
regulatory background and on the key issues in this 13
application. Dr. Liu will discuss the pertinent 14
clinical pharmacometric findings, focusing on 15
whether the data submitted in the NDA support 16
Clovis' proposed recommended dose. 17
I will then discuss the efficacy and safety 18
results with emphasis on the major safety concerns 19
and conclude the presentation by summarizing the 20
key issues relevant to our meeting today. 21
Rociletinib is a small molecule tyrosine 22
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kinase that irreversibly binds and inhibits the 1
common activating mutations Exon 21 L858R 2
substitution and Exon 19 deletion, and the EGFR 3
resistance mutation T790M. 4
The proposed indication for rociletinib is 5
for the treatment of patients with mutant epidermal 6
growth factor receptor non-small cell lung cancer 7
who have been previously treated with an EGFR 8
targeted therapy and have the EGFR T790M resistance 9
mutation as detected by an FDA approved test. 10
As described by Clovis, lung cancer is the 11
leading cause of cancer related mortality in the 12
United States and worldwide. Non-small cell lung 13
cancer accounts for nearly 85 percent of all cases. 14
Current treatment of non-small cell lung 15
cancer is guided by the presence of actionable 16
mutations, such as driver mutations in the kinase 17
domain of the EGFR gene, which occur in 10 to 15 18
percent of white patients, but more commonly in 19
Asian patients. The presence of these EGFR 20
mutations predicts for sensitivity to EGFR tyrosine 21
kinase inhibitors and improved outcomes in patients 22
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who receive these agents compared to patients who 1
are treated with chemotherapy. 2
Most patients who are treated with EGFR 3
tyrosine kinase inhibitors subsequently develop 4
acquired resistance. The T790M mutation is the 5
most common resistance mutation and is observed in 6
approximately 60 percent of patients. This 7
mutation renders the currently approved EGFR 8
tyrosine kinase inhibitors erlotinib, gefitinib, 9
and afatinib ineffective. 10
Following disease progression, patients are 11
managed in a similar fashion to unselected patients 12
with non-small cell lung cancer who have progressed 13
following doublet chemotherapy. 14
Shown here are the FDA approved treatment 15
options for these patients. These agents are 16
considered available therapy for the purposes of 17
this application. In the clinical trials that 18
supported the approval of these agents, the overall 19
response rate was not the primary efficacy 20
endpoint, and in most cases, the overall response 21
rate was assessed by the investigator. This is an 22
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additional limitation to consider when comparing 1
overall response rates between studies. 2
Available therapies for the treatment of 3
metastatic EGFR mutation positive non-small cell 4
lung cancer in the second-line setting have 5
demonstrated response rates ranging from 6 to 6
23 percent. There are limited data on duration of 7
response, however, nivolumab provides a 17-month 8
median duration of response. Importantly, all 9
available therapies have demonstrated definitive 10
clinical benefit as measured by improvements in 11
overall survival. 12
Another approved EGFR tyrosine kinase 13
inhibitor is osimertinib. Osimertinib received 14
accelerated approval in November 2015 for the 15
treatment of patients with metastatic EGFR T790M 16
mutation positive non-small cell lung cancer who 17
have progressed on or after EGFR TKI therapy. 18
Since osimertinib was approved under 19
accelerated approval, it is not considered 20
available therapy as described in FDA guidance 21
documents. However, given that the indication for 22
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which it is approved is similar to the indication 1
that is sought for rociletinib, I will briefly 2
review the basis for its approval. 3
The key efficacy endpoint for the 4
osimertinib application was overall response rate 5
according to RECIST and as assessed by central 6
independent radiology review. As highlighted in 7
the red box, the overall response rate was 8
59 percent with a median duration of response of 9
12.4 months. 10
The most common adverse reactions in 11
patients who received osimertinib were diarrhea, 12
rash, and nail toxicity. These adverse reactions 13
are similar to those caused by other EGFR targeted 14
therapies. The most common grade 3 or grade 4 15
adverse reactions were pneumonia and venous 16
thromboembolism. These adverse reactions occurred 17
in less than 3 percent of patients. 18
Other clinically important adverse reactions 19
are listed here. Relevant to our discussion today, 20
QTc prolongation occurred in patients who received 21
osimertinib. However, less than 3 percent of 22
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patients had serious QTc prolongation. 1
This table lists the regulatory milestones 2
for the rociletinib application. Rociletinib 3
received breakthrough therapy designation in 4
May 2014 on the basis of an overall response rate 5
of 54.5 percent in 33 patients who received 6
rociletinib across several doses. 7
In the NDA, Clovis has requested accelerated 8
approval for rociletinib based on the results of 9
two clinical studies, study 008 and study 019. 10
Clovis has presented the key elements necessary to 11
meet the requirement for accelerated approval, and 12
as such, I will not review them again. 13
Listed here are the two studies that support 14
the application. These have also been described in 15
detail by Clovis. To reiterate, the overall 16
response rate and duration of response were the 17
main efficacy endpoints. These outcomes were 18
assessed by the investigator and by an independent 19
radiology review in both studies. 20
Also described in Clovis' presentation is 21
the proposed confirmatory study, study 020. The 22
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rociletinib dose to be evaluated has been amended 1
several times, as you heard. In the most recent 2
amendment, Clovis stated that the two doses of 3
rociletinib, 500 milligrams and 625 milligrams, 4
will be evaluated in two study arms comparing each 5
rociletinib arm to the chemotherapy therapy arm. 6
FDA and Clovis held several meetings to 7
discuss the approach to the efficacy evaluation, as 8
well as to better understand our respective 9
interpretations of the clinical and clinical 10
pharmacology data. We disagree with Clovis' 11
approach to selecting the recommended dose for 12
rociletinib. 13
FDA's approach relies on the findings of the 14
clinical pharmacology data analysis, which will be 15
presented by my colleague. Another area of 16
disagreement with Clovis was the interpretation of 17
the efficacy results. I will discuss this in the 18
upcoming slides. 19
To provide context for the basis of our 20
disagreement with Clovis' proposed rociletinib 21
dose, I will provide a brief history of FDA's 22
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recent interactions with Clovis regarding this 1
issue. 2
In July 2015, Clovis submitted the clinical 3
component of the NDA, including draft labeling, 4
which indicated that 500 milligrams administered 5
twice daily was the dose for which Clovis sought 6
approval. 7
In December 2015, Clovis stated their 8
intention to amend the NDA to propose 9
625 milligrams. According to Clovis, this decision 10
was based on the observation of a numerically 11
higher point estimate for tumor response at that 12
dose compared to the 500-milligram dose. Clovis 13
submitted a revised draft label reflecting this 14
change in January 2016. 15
In February, FDA informed Clovis that the 16
available pharmacokinetic data submitted in the NDA 17
did not appear to support their proposal to change 18
the recommend dose to 625 milligrams. In March, 19
Clovis submitted a formal amendment to the proposed 20
confirmatory trial, study 020, to evaluate the 21
625 milligrams in a third study arm. 22
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Dr. Liu will now present the clinical 1
pharmacology findings as they pertain to the 2
applicant's proposed dose. 3
FDA Presentation – Chao Liu 4
DR. LIU: Good morning. My name is Chao 5
Liu, and I am the pharmacometric reviewer of this 6
application. On behalf of the FDA review team, 7
I'll be giving a brief summary of the 8
pharmacological property of this drug, and then 9
addressing if the rociletinib 625-milligram BID is 10
adequately supported by the available data. 11
Rociletinib exposure at steady state is 12
highly variable. When pH is greater than 2, 13
rociletinib is practically insoluble. Food affects 14
the drug absorption, and the rociletinib exposure 15
increases with a high fat meal. Therefore, in the 16
clinical trials, rociletinib was administered with 17
food to boost absorption. Rociletinib is mainly 18
metabolized by amide hydrolysis and N-acetylation. 19
The parent drug rociletinib is the moiety 20
associated with anti-tumor activity. Via amide 21
hydrolysis, rociletinib is converted to 2 major 22
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metabolites, M502 and M460. These two metabolites 1
are responsible for two major adverse reactions, 2
hyperglycemia and QT prolongation. Hyperglycemia 3
is primarily attributed to M502, and QT 4
prolongation is attributed to M460. 5
Here is the in vitro evidence for the 6
mechanism of action. The table shows the IC50 7
values of rociletinib M450 and M502 for different 8
targets. Lower values indicate stronger binding to 9
the receptors and a higher potency. 10
Rociletinib selectively binds to T790M EGF 11
receptor contributing to the anti-tumor activity. 12
Metabolites have limited activities against EGF 13
receptor, and thus are not contributing to the 14
efficacy. 15
M460 with high potency for hERG inhibition 16
leads to QT prolongation by inhibiting hERG related 17
potassium influx. M502 is primarily responsible 18
for hyperglycemia by inhibiting insulin-like growth 19
factor 1 receptor and insulin receptor. 20
Both M460 and M502 showed a similar potency 21
for IGF1 receptor and insulin receptor inhibition, 22
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but M502 exposure is 23-fold higher than M460 1
exposure. Therefore, M502 is mainly responsible 2
for the hypoglycemic effect of rociletinib. 3
To assess the proper dose of rociletinib, we 4
evaluated a dose exposure relationship over the 5
dose range from 500- to 1000-milligram BID. The 6
analysis was based on the intensive PK data 7
collected from a subset of the subjects in the 8
trial. 9
Non-compartmental analysis was employed to 10
derive the individual Cmax and a steady state AUC 11
on day 15 at cycle 1. Each dot represents one 12
individual patient data. The regression lines for 13
Cmax on the left and the steady state AUC on the 14
right are both flat, suggesting similar exposure 15
over the dose range from 500- to 1000-milligram 16
BID. 17
This slide shows the dose exposure 18
relationship based on the population PK analysis 19
from over 300 patients. Each dot represents the 20
steady state AUC from one individual patient. The 21
box plot represents the distribution of individual 22
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exposures. 1
Consistent with the results from intensive 2
PK data, subjects with 500-, 625-, 750-, and 3
1000-milligram BID doses showed similar rociletinib 4
exposure. Therefore, based on the intensive and 5
the population PK analysis, we concluded that the 6
dose exposure relationship is flat from 500-to 7
1000-milligram BID. 8
Exposure efficacy relationship between 9
rociletinib steady state AUC and objective response 10
rate was explored using data from patients who were 11
treated at various dose levels. Rociletinib steady 12
state AUC was derived from the population PK model. 13
The relationship was characterized by a saturable 14
model. 15
In the plot, the mean and a 95 percent 16
confidence interval of the observed response rate 17
of 4 quartiles based on the rociletinib exposure 18
are represented by the stars and the black vertical 19
bars. 20
The dashed black line and the green band 21
represent the model predicted ORR at the 95 percent 22
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73
confidence interval. The box plots at the bottom 1
represent the distribution of rociletinib steady 2
state AUC at each dose group. The vertical line 3
within the box represents the median sample value, 4
and the diamond represents the mean value. The end 5
of the box represents the 25th and the 75th 6
quartiles. 7
The plot shows that within the exposure 8
range between 500- to 750-milligram BID doses the 9
effect of drug exposure efficacy reaches a plateau. 10
Using this model, the predicted ORRs for the 500-, 11
625-, and the 750-milligram BID dose cohorts were 12
about 32 percent with overlapping 95 percent 13
confidence intervals. Other covariates were 14
screened, and no significant independent risk 15
factors were identified. Based on the exposure 16
efficacy analysis, the results predict comparable 17
efficacies at 500-, 625- and at 750-milligram BID. 18
Metabolite M502 is primarily responsible for 19
hyperglycemia. This slide represents exposure 20
safety relationship between M502 steady state AUC 21
and the incidence of grade 3 or 4 hyperglycemia 22
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evaluated by the FDA. The mean and 95 percent 1
confidence interval of the observed incidence of 2
grade 3 or 4 hyperglycemia of 4 quartiles, based on 3
M502 exposure, are represented by the stars and the 4
black vertical bars. 5
The dashed black line and the green band 6
represent the model predicted incidence of grade 3 7
or 4 hyperglycemia and its 95 percent confidence 8
interval. The box plot at the bottom represents 9
the distribution of M502 steady state AUC at each 10
dose group. 11
According to the exposure safety analysis, 12
there appeared to be a correlation between 13
increasing M502 exposure and the incidence of 14
grade 3 or 4 hyperglycemia suggesting that patients 15
with higher M502 exposure are at greater risk of 16
grades 3 or 4 hyperglycemia. 17
Metabolite M460 is responsible for QT 18
prolongation. A model to describe the relationship 19
between M460 exposure and a QT prolongation was 20
developed. The X-axis is the concentration of 21
M460, and the Y-axis is the change of QTcF from 22
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baseline. 1
The solid red line in the blue band 2
represent the predicted change from baseline in 3
QTcF and its 95 percent confidence interval across 4
the concentration ranges. The model showed a 5
correlation between prolongation of QTc interval 6
and the increasing M460 concentration. 7
Due to the similar exposure from 500- to 8
1000-milligram BID, the clinical pharmacological 9
data do not support a 625-milligram BID, and the 10
data could be pooled for efficacy and a safety 11
evaluation. In addition, based on the identified 12
exposure response relationship from 500- to 13
1000-milligram BID, patients with high rociletinib 14
exposure are unlikely to have further benefit. 15
However, subjects with higher concentration 16
of metabolite are at greater risk for QT 17
prolongation and hyperglycemia. Therefore, 18
625-milligram BID is not adequately supported by 19
the available data. 20
Next my clinical colleague, 21
Dr. Fashoyin-Aje, will continue the efficacy and 22
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the safety findings. Thank you. 1
FDA Presentation – Lola Fashoyin-Aje 2
DR. FASHOYIN-AJE: I will now discuss FDA's 3
approach to defining the primary efficacy endpoint 4
for this application. To reiterate, the clinical 5
pharmacology review concluded the following. The 6
dose exposure relationship appears to be flat 7
across doses ranging 500 to 1000 milligrams. The 8
exposure efficacy relationship also appears to be 9
flat. 10
On the basis of these findings, FDA 11
performed a pooled analysis of the efficacy data 12
across several dose groups. This approach may 13
provide a reasonable estimate of the effect of 14
rociletinib on tumor response. FDA discussed this 15
approach with Clovis. 16
You may recall from Clovis' presentation 17
that patients enrolled in the two clinical studies 18
that support this NDA received two different 19
formulations of rociletinib and were T790M mutation 20
positive or negative. 21
Shown here are the criteria upon which FDA 22
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based its selection of the efficacy analysis 1
population. The assessment of efficacy is based on 2
patients who received rociletinib hydrobromide salt 3
formulation, who were T790M mutation positive by 4
central testing, and whose scans were reviewed by 5
independent radiologic review. The table shows the 6
contribution of each of the 2 clinical studies to 7
the efficacy and safety populations by dose cohort. 8
I will now discuss the efficacy results. 9
These are the primary efficacy results as presented 10
by Clovis during the application orientation 11
meeting and in the NDA submission. Clovis claimed 12
that the overall response rate by investigator in 13
patients who received rociletinib 500 milligrams 14
was 42 percent as shown here. 15
This is the corresponding overall response 16
rate by central independent radiology review. 17
Clovis submitted an update to the efficacy results 18
as agreed upon during the pre-NDA meeting. The 19
main purpose of the update was to provide 20
additional data on durability of response. The 21
update was submitted to FDA in October 2015. 22
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During the review of the application, FDA 1
noted the following. The overall response rates 2
included patients with unconfirmed responses. The 3
denominator in the independent radiology review 4
assessment of the overall response rate did not 5
include all patients in the intent-to-treat 6
population. And, Clovis proposed investigator 7
assessed overall response rate as the primary 8
efficacy endpoint and the basis for the request for 9
rociletinib's approval. 10
FDA's position on these issues is as 11
follows. The assessment of overall response rates 12
will be based only on confirmed responses, 13
consistent with RECIST and as specified in the 14
study protocols for studies 008 and 019. 15
The denominator in the independent 16
radiologic review assessment should include all 17
patients in the intent-to-treat population also 18
consistent with RECIST. And, the overall response 19
rate as assessed by independent radiology review 20
will be the primary efficacy endpoint upon which a 21
regulatory decision is based. 22
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This position was conveyed to Clovis at the 1
time of the mid-cycle meeting in November 2015. 2
Subsequent amendments to the efficacy data was 3
submitted to the NDA and are the basis for FDA's 4
analysis of efficacy. 5
The overall response rates shown here are 6
based on the data submitted at the time of the 7
efficacy update with additional amendments as I 8
noted earlier. These are the overall response 9
rates by the assessment of the independent 10
radiology review. The following observations are 11
noteworthy. 12
The overall response rate for the 13
500-milligram dose cohort is 22.8 percent, which 14
represents a 15 percentage point decrement in the 15
overall response rate compared to the initial 16
submission. 17
Secondly, while the point estimates for 18
overall response rate differ across dose cohorts, 19
the confidence intervals are wide and they overlap. 20
Please note that the assignment to a particular 21
dose cohort was not random and, thus, important 22
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differences in patient characteristics between dose 1
cohorts may account for the numerically different 2
overall response rates seen here. 3
Notwithstanding this limitation, based upon 4
the analysis of the PK data, which were described 5
earlier by Dr. Liu, FDA conducted an analysis 6
pooling data across doses in an attempt to get a 7
more precise estimate of the effect of rociletinib 8
on overall response rate. 9
The overall response rate using this 10
approach is 30 percent, as shown in the red box. 11
The 95 percent confidence interval for this 12
estimate is narrower than that seen at the 500- and 13
625-milligram dose groups. The median duration of 14
response in the pooled analysis is 8.9 months. 15
I will now discuss the key safety findings. 16
Of note, single-arm studies are limited in 17
providing reliable information regarding the 18
incidence of fatal adverse reactions as these could 19
be erroneously attributed to disease progression, 20
particularly in patient population with advanced 21
cancer. Randomized controlled studies are much 22
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more reliable in providing this information. 1
As the applicant showed, overall, there were 2
no notable differences in the incidence of adverse 3
reactions in patients who received rociletinib 4
500 milligrams or 625 milligrams. 5
The information in this table has been 6
presented by Clovis. Almost all patients who 7
received rociletinib experienced one or more 8
adverse reaction, as highlighted in the pooled 9
safety population. Adverse reactions that occurred 10
in 30 percent or more or patients are listed here. 11
The salient points from this slide are the 12
following. The incidence of common adverse 13
reactions is similar between the 500-milligram and 14
625-milligram dose groups. The incidence in the 15
pooled population is shown in the red box. 16
Hyperglycemia and QTc prolongation are the 17
most common adverse reactions observed in patients 18
who received rociletinib, and a considerable 19
proportion of patients experienced these two 20
adverse reactions had grade 3 or grade 4 events. 21
This table provides an overview of the 22
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incidence of treatment interruptions, dose 1
reductions, and treatment discontinuations due to 2
adverse reactions. Over half of the patients who 3
received rociletinib had one or more dose 4
interruption or dose reduction. 5
Consistent with the incidence of common 6
adverse reactions, hyperglycemia and QTc 7
prolongation were the most common adverse reactions 8
leading to dose interruptions. A similar pattern 9
is observed with regards to adverse reactions 10
leading to dose reductions. 11
The previous two slides described the 12
incidence of adverse reactions leading to treatment 13
interruptions and dose reductions. FDA conducted 14
an analysis to determine the number of 15
inter-patient dose modifications. The results of 16
this analysis conducted for dose reductions is 17
shown here. 18
Overall, the proportion of patients in each 19
dose cohort who had dose reductions is shown in the 20
red box. The proportion of patients requiring dose 21
reductions and those requiring multiple dose 22
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reductions increased with increasing dose. 1
FDA postulates that patients who received 2
the higher doses of rociletinib likely had more 3
dose reductions because dose reductions to doses of 4
500 milligrams and above were unlikely to lead to a 5
decrease in exposure. This may indicate that the 6
applicant's proposed strategy to mitigate toxicity 7
at the proposed dose of 625 milligrams may not be 8
effective. 9
I will now discuss some adverse reactions of 10
special interest. Listed here are serious 11
toxicities that were observed in high frequency in 12
patients who received rociletinib. Also included 13
are other toxicities that have been observed in 14
patients who are treated with EGFR directed 15
therapies. 16
Before I describe the incidence of adverse 17
reactions of special interest, I would like to 18
review the role of NAT2 acetylation status on the 19
occurrence of toxicity in patients who received 20
rociletinib. As you heard previously, M502 and 21
M460, the major metabolites of rociletinib, are 22
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primarily responsible for hyperglycemia and QTc 1
prolongation. 2
These two metabolites undergo N-acetylation 3
by the enzyme N-acetyltransferase 2, or NAT2, to 4
form other metabolites. The NAT2 polymorphism 5
results in variable activity in the NAT2 enzyme 6
with individual patients classified as slow, 7
intermediate, or rapid acetylators. 8
Patients who are slow acetylators have a 9
high exposure to M502 and M460 metabolites compared 10
to intermediate or rapid acetylators. In the 11
United States approximately 40 to 60 percent of 12
white and black patients are slow acetylators. 13
Data on the NAT2 genotype and the inferred 14
acetylator status were available for 303 patients 15
who received rociletinib at doses ranging from 500 16
to 1000 milligrams. The X-axis on each box shown 17
here represents increasing exposure from left to 18
right of rociletinib, so the parent drug, and the 19
metabolites M502 and M460. 20
The exposure to parent drug, rociletinib, 21
was similar across the phenotypes as shown in the 22
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first box. However, NAT2 slow acetylators had 1
higher M502 and M460 exposures compared to 2
intermediate or rapid acetylators indicating that 3
slow acetylators are at greater risk for 4
hyperglycemia and QTc prolongation. 5
QTc prolongation was a common adverse 6
reaction in patients who received rociletinib. 7
Prolonged QTc interval can lead to serious and 8
potentially fatal cardiac arrhythmias, such as the 9
polymorphic ventricular tachyarrhythmia termed 10
Torsades de pointes. Torsades de pointes can 11
degenerate into ventricular fibrillation and lead 12
to sudden death. 13
The International Council for Harmonization 14
of Technical Requirements for Pharmaceuticals for 15
Human Use, or ICH, has published the E14 document, 16
which is a guideline for the clinical evaluation of 17
QT interval prolongation and pro-arrhythmic 18
potential for non-anti-arrhythmic drugs. 19
The correlation between a specific change in 20
QTc interval and the risk of fatal arrhythmias has 21
not been clearly established. However, increases 22
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in the QTc interval do appear to identify drugs 1
with a high risk of Torsades de pointes. 2
The ICH E14 document states that drugs that 3
prolong the mean QTc interval by greater than 20 4
milliseconds have a substantially increased 5
likelihood of being pro-arrhythmic. In addition, 6
marked QTc increase is defined as QT interval 7
greater than 500 milliseconds or a change in QTc of 8
greater than 60 milliseconds. 9
The NCI-CTCAE relies on QTc interval of 10
greater than 500 milliseconds, and increase in QTc 11
over baseline of 60 milliseconds or more, as 12
criteria for severe or life threatening QTc 13
prolongation in individual patients. 14
Please note the NCI-CTCAE definitions for 15
grade 3 and grade 4 QTc prolongation shown here. 16
FDA's QT interdisciplinary review team has 17
identified a population mean increase in QTc over 18
baseline of 30 milliseconds as likely to identify 19
drugs with an increased risk. As will be shown on 20
the next slide, based on any of these measures, 21
rociletinib is a drug with pro-arrhythmogenic 22
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potential. 1
This table provides a summary of the change 2
in the QTc interval from baseline following 3
initiation of rociletinib. Focusing on the red 4
box, in patients who received rociletinib, the mean 5
change in QTc is 36 milliseconds. 6
Seventy-six percent of patients had a mean 7
QTc increase over baseline of greater than 8
30 milliseconds, and for 34 percent of patients, 9
the change was greater than 60 milliseconds. 10
Three patients experienced ventricular 11
tachyarrhythmias, including one patient who 12
experienced Torsades de pointes. There were two 13
sudden deaths. The review of each of these 14
patients' case report forms yielded no identifiable 15
cause of death. 16
Please note that Torsades de pointes is very 17
infrequently captured in clinical databases, even 18
for those drugs known to have significant 19
pro-arrhythmic effects. Therefore, the observation 20
of even one case of Torsades de pointes, and the 21
occurrence of other clinical arrhythmias, indicates 22
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the substantial risk of treatment with rociletinib. 1
Furthermore, single-arm trials inadequately 2
characterize the true incidence of fatal adverse 3
reactions such as fatal ventricular 4
tachyarrhythmias, as death may be attributed to 5
progressive disease. 6
Recall that M460 is the rociletinib 7
metabolite responsible for QTc prolongation and 8
that slow acetylators have the highest exposure to 9
M460. This slide shows the incidence of QTc 10
prolongation by NAT2 acetylator status. 11
The top half of the table shows the 12
incidence as reported by the investigator while the 13
bottom half shows it by central ECG measurement. 14
In both assessments, the incidence of QTc 15
prolongation is highest in the slow acetylators 16
compared to the intermediate or rapid acetylators. 17
This is a listing of drugs that are approved 18
for oncology indications and that are known to 19
cause QTc prolongation. Rociletinib is listed in 20
red for the purposes of comparison. Overall, 21
patients who receive the approved drugs in clinical 22
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trials had a mean increase in QTc interval ranging 1
from 10 to 35 milliseconds. 2
Patients who received rociletinib had a mean 3
increase of 36 milliseconds. One to 4 percent of 4
patients receiving the approved drugs had a QTc 5
interval greater than 500 milliseconds. The 6
corresponding incidence is 13 percent for patients 7
who received rociletinib. 8
Hyperglycemia is another adverse reaction of 9
special interest in this application. As a 10
reference, the definitions for hyperglycemia 11
severity, according to the NCI-CTCAE, are listed 12
here. Grade 3 hyperglycemia is defined as fasting 13
glucose greater than 250 milligrams per deciliter 14
up to 500 milligrams per deciliter. Grade 4 15
hyperglycemia is defined as fasting glucose greater 16
than 500 milligrams per deciliter. 17
This slide summarizes the incidence of 18
hyperglycemia as shown earlier and provides 19
additional information regarding important clinical 20
factors. Over half of the patients who received 21
rociletinib had hyperglycemia, and a third had 22
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grade 3 or grade 4 events. 1
Forty-nine percent of patients required 2
anti-hyperglycemia medication following initiation 3
of rociletinib. Insulin was required for the 4
management of hyperglycemia in 23 percent of those 5
patients who required treatment for hyperglycemia. 6
Importantly, metformin was initiated 7
prophylactically in the absence of grade 2 to 8
grade 4 hyperglycemia in 9 percent of patients who 9
received anti-hyperglycemia treatment. This was 10
not consistent with protocol specified guidelines. 11
This slide shows the incidence of 12
hyperglycemia by NAT2 acetylator status. Patients 13
who were slow acetylators had a high incidence of 14
hyperglycemia and a higher incidence of grade 3 and 15
grade 4 events. 16
Other noteworthy adverse reactions include 17
pancreatitis, which occurred in 4 percent of 18
patients, and pneumonitis, which occurred in 19
3 percent of patients. The incidence of cataracts 20
was 10 percent, and the majority of patients who 21
developed cataracts required surgical management. 22
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To summarize, treatment with rociletinib 1
resulted in the following, an overall response rate 2
of 30.2 percent in a pooled analysis of patients 3
who received rociletinib 500, 625 or 750 milligrams 4
administered twice daily. The median duration of 5
response is 8.9 months. 6
These results must be compared to available 7
therapies for the treatment of second-line non-8
small cell lung cancer. Treatment with docetaxel 9
and ramucirumab confers an overall response rate of 10
23 percent, and this treatment regimen has 11
demonstrated improvement on overall survival. 12
Nivolumab was also approved on the basis of 13
improvement on overall survival. This treatment 14
resulted in an overall response rate of 19 percent 15
and a median duration of response of 17 months. If 16
approved, patients may forgo these treatments to 17
receive rociletinib. 18
To summarize the safety, common adverse 19
reactions in patients who received rociletinib 20
included hyperglycemia, diarrhea, nausea, QTc 21
prolongation, and vomiting. Common grade 3 or 22
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higher adverse reactions included hyperglycemia, 1
QTc prolongation, and cataracts. 2
Other serious adverse reactions were 3
pancreatitis, ventricular tachyarrhythmias such as 4
Torsades de pointes, and two sudden unexplained 5
deaths. Treatment modifications were frequent with 6
over half of patients experiencing treatment 7
interruptions or dose reductions. 8
Overall, there remain considerable 9
uncertainties regarding the efficacy, safety, and 10
the appropriate dose for rociletinib. With respect 11
to the benefit of treatment with this drug, the key 12
question is whether an overall response rate of 13
30 percent and a median duration of 9 months is 14
better than available therapy. An affirmative 15
response to this question is a requirement for 16
accelerated approval. 17
With respect to safety, key issues include 18
considerable risks of serious adverse reactions 19
such as serious hyperglycemia, which occurred in a 20
third of patients who received rociletinib. 21
Another key safety concern is that by most 22
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standards used to assess the risk of potential 1
fatal cardiac arrhythmias, rociletinib is an 2
arrhythmogenic drug, and the risk of death from 3
arrhythmias may be underestimated in single-arm 4
trials. 5
Thirdly, the risk of increased exposure to 6
toxic metabolites may be explained by NAT2 7
acetylator status. However, uncertainty remains 8
regarding the measures that may be necessary to 9
address this risk. 10
With respect to the dose, the available data 11
do not support a dose of 625 milligrams 12
administered twice daily. At this dose, Clovis' 13
proposed dose reduction strategy to reduce to 14
500 milligrams is unlikely to lead to a decreased 15
exposure to the rociletinib toxic metabolites, and 16
thus may not be an effective risk mitigation 17
strategy. 18
Ultimately, the benefit of rociletinib must 19
be weighed against the serious and life-threatening 20
toxicities observed in patients who received 21
rociletinib and the considerable uncertainties that 22
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remain at this time. The FDA requests the advice 1
of the ODAC on the questions listed here. Thank 2
you very much for your attention. 3
DR. ARMSTRONG: Thank you. Before we move 4
on to clarifying questions, I'd like for the 5
audience to know that we've opened up Room 1504 as 6
an overflow room. It's down the hall back there, 7
so for those of you who are standing, there's some 8
extra space. Also, committee member, Dr. Rajan, 9
could you introduce yourself? 10
DR. RAJAN: I'm Arun Rajan, a staff 11
clinician in the thoracic oncology branch at the 12
NCI. 13
Clarifying Questions to the Presenters 14
DR. ARMSTRONG: Thank you. So we'll now 15
taking clarifying questions for the presenters. 16
Please remember to state your name for the record 17
before you speak. And if you can, please direct 18
your questions to a specific presenter, whether 19
from FDA or from the applicant. And you can let 20
Jennifer know about a question. 21
Dr. Menefee? 22
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DR. MENEFEE: Michael Menefee, Mayo Clinic, 1
Florida. I had two questions for the applicant. 2
The first is regarding the sequencing of T790M 3
inhibitors. 4
There are some published data that have 5
looked at -- or have demonstrated activity of 6
osimertinib after patients have received 7
rociletinib, and I wanted to know, do we have the 8
converse? Do we have any data, either published or 9
unpublished, where rociletinib has been used? 10
I know 008 and 019 did not study that 11
population, but outside of those studies, do you 12
have any data? 13
DR. ROLFE: So, no we don't. 14
DR. MENEFEE: Okay. So then, the extension 15
of that question -- and this may be better suited 16
to Dr. Camidge -- when I think about this drug, I 17
start thinking about how could we potentially -- is 18
it going to be used in the clinic, should approval 19
be granted. And it's just not very clear to me how 20
it's going to be used because we already have a 21
drug in this space that has at least equivalent 22
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activity, if not greater. We have a drug that is 1
perhaps less toxic. 2
So it's hard to see where you would use this 3
drug in the first-line setting for a patient with a 4
T790M mutation. Then, are we using this drug as a 5
second-line agent? And if so, the studies that 6
currently being evaluated weren't really designed 7
to evaluate it in that setting. 8
So I'm just curious if the drug was 9
available today, how would you envision using it in 10
exception of a patient that might have 11
cardiomyopathy, which might not be a good candidate 12
for the other available agent. 13
DR. CAMIDGE: Ross Camidge, medical 14
oncologist. Hi. Thank you for that question. I 15
can imagine three possible scenarios where you 16
might want to reach for this drug as opposed to 17
osimertinib. I'm assuming that's your question as 18
opposed to this versus chemotherapy or 19
immunotherapy. 20
The first, as you've kindly volunteered, 21
there are some people who have preexisting risk 22
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factors that you might say that the risk of 1
osimertinib, which has a proven anti-HER2 activity, 2
and people with preexisting cardiac failure, might 3
make you reach for the rociletinib first. The 4
second is people who you try osimertinib with the 5
best possible intentions, but they just don't 6
tolerate it, and that does happen every day in the 7
clinic. 8
Then, the third one, which is perhaps your 9
first question is, is there going to be a 10
population who might initially benefit from 11
osimertinib, progress, and then might they benefit 12
from this drug? 13
There's some very interesting data coming 14
out in terms of the mechanisms of acquired 15
resistance to these drugs, and I hinted at that, 16
but they do appear to be a different spectrum of 17
resistance mechanisms, so they may not be 18
cross-resistant. 19
DR. ARMSTRONG: Dr. Fojo? 20
DR. FOJO: I had a couple of questions, and 21
before I appear to be somewhat critical, I commend 22
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the company for conducting the trial in the United 1
States in U.S. patients because that's always 2
helpful in approving a drug for U.S. patients. 3
Could we see CO-37? And where I'm going to 4
go with this is what makes me feel uncomfortable 5
that I don't understand everything about this drug. 6
This is a really nice waterfall plot, and the back-7
of-the-envelope calculation says that 60 percent of 8
the patients had greater than 30 percent reduction, 9
and yet the overall response rate is 30 percent, 10
basically, which to me says that half -- of these 11
60 percent, 30 percent of these 60 percent, had a 12
response that was not durable. 13
That to me says one of two things, either 14
the drug's not very good and it can't hold the 15
response, or the drug is toxic, and it gets 16
discontinued after the response has been achieved, 17
and then the response is quickly lost, and you 18
can't maintain it. 19
So that it's toxic I think is clear. You 20
know, 20 percent dose discontinuation, 50 to 21
70 percent dose reduction or dose interruption, 22
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that's a drug with a fair amount of toxicity. And 1
it's not in the grade 3-4 toxicities, it's not in 2
the QTc prolongation. Nobody walks in and says, 3
"Doc, this QT prolongation is just -- I can't take 4
this any longer." The hyperglycemia, the same 5
thing, which is why you looked at dose toxicities, 6
and you say, look, no dose reduction. 7
So when I try to find out here why is this 8
drug being discontinued or reduced, I just don't 9
see it; a little bit of nausea, a little bit of 10
fatigue, no diarrhea, no skin rash. So there's 11
something here that's missing as far as I'm 12
concerned, and I wonder if you could tell me what 13
that is. Or is it just I'm sick and tired of this 14
drug, and that's why I'm discontinuing it? 15
Then the other thing, which is what the FDA 16
is getting at, is the dose of 500 and 625. Not to 17
be trivial, but by way of a note to self, if in 18
January you say to the FDA that we're going to go 19
to 625, and in February the FDA says, no, don't do 20
that, in March, a month before the ODAC, you don't 21
do that. And that's what you did. 22
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But I actually think that you've got data of 1
sorts that tells you that, in fact, the FDA is 2
right, that 500 and 625 are not different because 3
when you've added this extra dose level to the 4
study, and you've now got 300, 300 and 300 -- so 5
you've got 300 patients in the 625 and 300 in the 6
500, and you're telling us the study's not powered 7
to tell the difference between 500 and 625, you're 8
telling us that a 600 patient study embedded in 9
this, with 300 in each arm, won't be able to tell 10
the difference, which to me means that there's 11
actually no difference, or very, very small 12
difference. 13
So number one, what causes these dose 14
reductions? What is in the dose discontinuations, 15
since it's not the grade 3, 4 toxicities? And 16
number two, really, what is the data that 625 is 17
better than 500, and why can't we see it with a 18
300-patient-in-each-arm study? 19
DR. ROLFE: So to answer the first part of 20
your question regarding lack of confirmation of 21
responses, I'll show you the data. But what it 22
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shows is that it's predominately due to disease 1
progression between the first restaging and the 2
second restaging scan rather than to 3
discontinuation for toxicity or other reasons. 4
So here's the data on a slide. For 5
500-milligram, 625-milligram doses, I'm showing the 6
reasons that an initial PR was not confirmed. I 7
mean, you can see that, by far, the commonest 8
reason is development of progressive disease 9
between the two scans. This was progressive 10
disease either in CNS only or below the neck, plus 11
or minus above the neck. 12
DR. FOJO: That can't be all the data 13
because you showed data for 625, and that was 100 14
and some odd patients. And 30 percent of those 15
patients are not confirmed, so that can't be that 16
then you have 11 and 1 and 1, so this is missing 17
data. 18
DR. ROLFE: So let me clarify. The 19
waterfall plot shows one element of RECIST, so 20
that's the change in the size of the target 21
lesions. RECIST has two other elements, which is 22
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progression or non-progression of non-target 1
lesions as well as development of new lesions 2
between restaging scans. 3
So the waterfall plot is a very objective 4
measure that can be displayed easily on a graph, 5
but it just shows one of the RECIST components. So 6
every person who developed the 30 percent shrinkage 7
on the waterfall plot does not necessarily have a 8
RECIST response. 9
DR. FOJO: Okay. I still don't understand 10
it. There were 170 patients, which is what I 11
suspect is in the waterfall plot. Thirty percent 12
of them, or 51 roughly, would have had a response 13
that then wasn't confirmed, and you showed us what 14
happened with 13. 15
DR. ROLFE: Well, the 13 patients were the 16
patients who had a RECIST response based on one 17
restaging scan, so a response according to all the 18
3 components of RECIST, and 13 patients did not 19
confirm that response subsequently. 20
DR. FOJO: So then I'm assuming the other 38 21
had the drug discontinued and had progression for 22
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that reason? 1
Do you follow? I mean, 60 percent of the 2
patients, or about 60 times 170, about 102 3
patients, had greater than 30 percent reduction. 4
And then only 30, 32 percent, or about 51 patients, 5
have a confirmed response. So there's 50 some odd 6
patients -- there's somebody who seems to get it in 7
the group that wants to answer and maybe -- 8
DR. FIGG: While he's getting ready to 9
answer that, do we have the 500, the waterfall for 10
500? 11
DR. FOJO: Yes. Go ahead. 12
DR. YURASOV: Sergey Yurasov, oncology. If 13
I can have the table that shows response rates. So 14
the response rates, as Dr. Lindsey Rolfe pointed 15
out, are based on RECIST .1, 1.1, so 3 components, 16
the waterfall plot showing only the target lesion 17
reduction. 18
So for 170 patients at 625 that you're 19
referring to, 32 percent of patients actually had 20
confirmed response. So out of those 32 percent, 21
the data that Dr. Rolfe showed shows that 22
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12 percent -- 12 patients that had an initial 1
partial response didn't make it to those 2
32 percent, but not from a target lesion on the 3
waterfall plot. 4
DR. FOJO: No, no, no, no. So I won't 5
belabor this if I'm the only one who's lost, but 6
the numbers just aren't adding up. So these would 7
be 32 percent who had a confirmed -- 8
DR. ARMSTRONG: Perhaps, for more 9
clarification, is how many patients does this 10
represent on slide CO-37? You don't actually say 11
how many patients this is. 12
DR. ROLFE: So one patient is represented by 13
one of the bars. We can get back to you on that 14
after the break with the precise number. 15
DR. ARMSTRONG: And then the second part of 16
your question, Dr. Fojo? 17
DR. FOJO: Yes. So the second part of the 18
question is, what is the data that makes you so 19
confident that 625, not -- what is shown here, the 20
FDA has I think appropriately raised concerns that 21
there's no difference. And what is that data that 22
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you don't even think that a 600-patient trial with 1
300 in each arm is going to show a difference? 2
So it can't be so robust data. If you 3
really had robust data you only need 100 patients 4
in each arm, and you'd get the difference. You're 5
enrolling 600 patients essentially in a sub-study 6
within the large study, and you're not going to be 7
able to tell us that 625 is better than 500. 8
Again, to me that says the FDA is right, 625 9
is no better. And since toxicity is what's going 10
to be important, I think in this discussion, you 11
want to go to where there's less toxicity. 12
DR. ROLFE: So I'll answer the first part of 13
the question, then I'll ask my statistician 14
colleague to specifically address the statistical 15
assumptions in the confirmatory study. 16
So we agree with FDA that you cannot 17
distinguish between 500 and 625 milligrams based on 18
PK data. Our concern is that the lower bound of 19
the confidence interval for response rate at 20
500 milligrams is 14 percent. And I think the 21
500-milligram data set taken alone does not provide 22
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an accurate representation of the activity of 1
rociletinib. 2
In the phase 1 part of the study, we studied 3
lower doses than 500 milligrams, but they were with 4
a different form of the drug, the free-base form. 5
At the next lowest dose, we studied 7 patients 6
T790M positive in phase 1, and of those 7 patients, 7
none responded. So taken together we believe that 8
625 milligrams BID is a more accurate 9
representation of the drug's activity. 10
To answer the second part of your question, 11
Dr. Isaacson, please take us through the 12
statistics. 13
DR. ISAACSON: Jeff Isaacson, senior 14
director of biostatistics and data management with 15
Clovis. I think it's fair to say we agree, the 16
difference in response rate, about maybe 10 percent 17
between the two groups is going to take a lot of 18
patients to show that, probably in the order of 400 19
patients per arm. So yes, the phase 3 trial, as it 20
stands, isn't powered to pick up that small a 21
difference. 22
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DR. ROLFE: And can I further clarify that 1
the phase 3 study enrolls T790M positive and T790M 2
negative patients. Therefore, we do not expect to 3
get 300 T790M positive patients per arm; more like 4
150. 5
DR. FOJO: Okay. 6
DR. ARMSTRONG: Dr. Roth? 7
DR. ROTH: I would dispute the contention 8
about picking the lower end of the confidence 9
interval. I mean, you have half as many patients 10
treated at 500 as you do at 625, so you're going to 11
have a wider confidence interval. 12
But to build on what Tito was saying, if you 13
really believe that 625 is better, why don't you 14
replace the 500 arm in the phase 3 trial? Why add 15
a third arm and then have it powered such that you 16
can't compare 500 and 625? My concern is that we 17
will know no more about what the right dose is for 18
this drug after 900 more patients than we do now. 19
DR. ROLFE: Well, we were fortunate to be 20
able to study relatively large numbers of patients 21
in our phase 2 program at each of the doses, but I 22
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don't think we can say definitively which is the 1
best dose at the moment. Therefore, we are 2
intending to pursue both doses in a randomized, 3
controlled phase 3 study and to compare each one of 4
those doses against standard of care just to 5
confirm superiority. 6
DR. ROTH: So at the end of that trial, and 7
if both those doses are superior to standard single 8
agent chemotherapy, and you don't have enough 9
patients to compare the two doses, how are you 10
going to tell me what dose is correct? 11
DR. ROLFE: Well, assuming the risk and 12
benefit looks similar in each treatment arm, we 13
would assume that 500 milligrams was the best dose 14
as demonstrated in the randomized phase 3 study. 15
DR. ARMSTRONG: Did that answer your 16
questions? Yes. 17
Dr. Rini? 18
DR. RINI: So I have a question. I think 19
it's at a couple points about accelerated approval. 20
One is that there has to be an advantage over 21
standard therapy, so I think what we've heard is 22
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that there's probably a 10 percent response rate 1
advantage of this drug over say nivo and the other 2
drugs that are available, not including the drug 3
just approved under accelerated approval. 4
The other part of accelerated approval is 5
meaningful clinical benefit. So I guess the real 6
question, the crux of the question is, is that 7
delta, a 10 percent increase response rate, does 8
that represent meaningful clinical benefit? 9
My real question is, do you have data about 10
symptom control, quality of life, narcotic use, 11
something in this population that I imagine is very 12
advanced in refractory, right, and I assume has a 13
lot of symptoms that would support that delta of 14
10 percent as being clinically beneficial? 15
DR. ROLFE: So we don't have quality-of-life 16
data available. 17
Could Dr. Carbone comment on symptomatic 18
changes in the patients that he's treated, please? 19
DR. CARBONE: David Carbone, medical 20
oncologist. First of all, the assumption of a 21
delta in the response of 10 percent is not a solid 22
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one because the response rates in single-arm 1
studies are not really comparable across studies. 2
For example, when carboplatin and paclitaxel first 3
came out, the first 2 or 3 phase 2 studies showed a 4
60 percent response rate, and the real value is 5
more like 25. 6
My clinical experience with this drug is 7
more in line with the waterfall plot than with the 8
objective response rate. I've treated in our 9
clinic 18 patients with this drug. Virtually, 10
every one experienced substantial and immediate 11
clinical benefit with often a decrease in side 12
effects from first or second-line agents, such as 13
afatinib, which, by the way, is very often started 14
at the dose below recommended by the FDA for 15
toxicity reasons as well. 16
Does that answer your question? 17
DR. RINI: My question was, are there 18
objective data, though? I believe you, and I think 19
the waterfall is impressive, but I'm just wondering 20
about some objective measure of that. 21
DR. CARBONE: That's a company question. 22
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DR. ROLFE: So no, we don't have a 1
quality-of-life readout from this study, however, 2
in the randomized phase 3 study, there are 3
quality-of-life measures built in to that as is 4
appropriate in a randomized setting. 5
Just to be completely clear, we did do 6
quality-of-life questionnaires in the single-arm 7
studies, however the NDA was submitted based on an 8
interim data cut while the studies were still 9
enrolling, and we have not got that readout yet. 10
DR. ARMSTRONG: Dr. Figg? 11
DR. FIGG: I have three broad questions, and 12
I'm going to let you answer after each one. So on 13
page 44 of the document you provided, you stated 14
that the Cmax and AUC of the parent compound, the 15
metabolite 502, 544, were reduced by 69 percent to 16
72 percent when co-administered with omeprazole. 17
Of the last sentence of that paragraph, you go on 18
to say that there is no drug interaction with 19
omeprazole. 20
How could you conclude that? Furthermore, 21
what about the metabolite 460? And did you test 22
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other agents that altered GI pH, such as H2 1
antagonists? And why did you not include these in 2
the proposed label? 3
DR. ROLFE: Dr. Jaw-Tsai? 4
DR. FIGG: Pardon? 5
DR. JAW-TSAI: Sarah Jaw-Tsai, Clovis 6
Oncology. The rociletinib solubility is pH 7
dependent. So therefore, when you increase the pH 8
in the presence of PPI, you tend to see this 9
decrease in exposure. 10
We have results from the clinical 11
pharmacology study conducted in healthy subject. 12
We saw a 70 percent reduction in the Cmax and AUC. 13
However, in the population PK analysis, where we 14
have a bigger number of patient population, they 15
took the PPI as we recorded in their concomitant 16
medicine list. In that patient population, we did 17
not see a decrease in the rociletinib, either Cmax 18
or AUC, as compared to the patients that did not 19
take the PPI. 20
DR. FIGG: Well, I'm not sure, then, I would 21
agree with your assessment. I mean, if the PK data 22
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shows that it changes the AUC so significantly, it 1
seems like you should call that a drug interaction. 2
Furthermore, did you see that those individuals in 3
the clinical trial actually had responses? 4
Nonetheless, let's move on to the next one. 5
We know that the M460 is responsible for the QTc 6
changes. You also know that it has a long 7
half-life, 50 some hours. You also know that the 8
PK exposure by NAT2 genotyping showed that slow 9
acetylators status is associated with higher levels 10
of M460. 11
We also know that 51 percent of the slow 12
acetylators have a QTc of greater than 13
60 milliseconds, which is only 22 and 23 percent 14
for those that are rapid and intermediate. Why 15
would you not want to, a priori, genotype for NAT2? 16
DR. ROLFE: Well I'll answer from the 17
sponsor perspective, and then I'll ask Dr. Kowey to 18
comment from an expert cardiology perspective. The 19
NAT2 slow acetylators comprise half the patients. 20
We believe that thorough QT monitoring and 21
management strategies should be required for all 22
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patients that are treated with rociletinib, and 1
that patients who are intermediate or the small 2
number who are rapid acetylators would not require 3
any less thorough risk management for this effect. 4
We have done the NAT2 genotyping in a 5
subgroup of patients within these two single-arm 6
studies, and we're continuing to study the signal 7
in the randomized phase 3 study in order to obtain 8
a larger amount of data to get a more definitive 9
analysis. 10
Does that answer your question? 11
DR. FIGG: Okay. My last one is just a 12
general one. Have you run the drug against a panel 13
of transporters to figure out movement both in and 14
out of cells? 15
DR. ROLFE: Sorry. Can you repeat the last 16
phrase? 17
DR. FIGG: To understand which transporters 18
are involved in the movement of the drug. 19
DR. ROLFE: So we've done hERG testing, and 20
it has an inhibitory effect on the potassium 21
channel, but nothing more than that. 22
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DR. FIGG: No, I'm referring to the ABC 1
transporters, the OATP transporters, et cetera, 2
which is important in also predicting drug 3
interactions. It sounds like you probably haven't 4
done it yet. 5
DR. ROLFE: Dr. Jaw-Tsai. 6
DR. JAW-TSAI: Yes, we have evaluated the 7
potential effect of the rociletinib, the inhibitor 8
of the transporters. OATP1B1 and 1B3, under the 9
criteria as set up by the FDA's DDI guidance, 10
rociletinib does not meet the threshold to do a 11
drug-drug interaction. 12
However, under the guidance, P-gp, that's 13
the only transporters that rociletinib is required 14
to do a DDI study, and we have conducted a study 15
with digoxin as a probe substrate of P-gp. In that 16
study, we saw about 30 percent increase in the 17
exposure, which was measured by Cmax and AUC, in 18
the presence of the rociletinib. So it's a weak 19
inhibitor of P-gp in vivo. 20
DR. SONG: This is Pengfei Song, a clinical 21
pharmacology reviewer at FDA. Rociletinib is a 22
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substrate and inhibitor of P-gp and BCRP, but is 1
not a substrate of hepatic uptake transporter 2
OATP1B1 or 1B3. Rociletinib is an inhibitor of 3
OATP1B1, 1B3, OCT1 and OCT2, weakly interact with 4
OAT1 but not always with OAT3. 5
The sponsor conducted in vitro studies 6
evaluating the DDI potential and conducted an 7
in vivo study with P-gp substrate. The interaction 8
is generally mild. Thank you. 9
DR. ARMSTRONG: Dr. Pazdur? 10
DR. PAZDUR: I just wanted to follow up on 11
something that Dr. Figg mentioned because it is 12
something that we want thoroughly discussed in the 13
discussion phase, and that is the role of NAT2 14
acetylator status, and we think that that is a very 15
important issue for the committee to focus on. 16
Here again, between the rapid acetylators 17
and the slow acetylators, you see significant 18
differences in toxicity, not only with regard to QT 19
status, but also with regard to hyperglycemia. And 20
we believe that the risk-benefit really differs 21
between these two populations. 22
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So this is something we really want the 1
committee to hone in on. We don't have an 2
available test at this time marketed, I don't 3
believe, to look at this. And the other issue is, 4
for the ongoing phase 3 study -- and this is my 5
question to the sponsor -- are they looking at 6
acetylator status prospectively in the phase 3 7
study? 8
DR. ROLFE: Yes, we are. 9
DR. PAZDUR: And how are you doing that? 10
DR. ROLFE: Patients have to provide 11
additional consent because it's a genomic test, and 12
we're using the same laboratory that we used for 13
the two studies you see here. So it's using the 14
CLIA test that's available in the U.S. by Genelex. 15
DR. FIGG: And you're using germline DNA, 16
right? 17
DR. ROLFE: Correct. 18
DR. ARMSTRONG: Thanks. Dr. Szabo? 19
DR. SZABO: Eva Szabo, medical oncology, 20
NCI. I have two questions. Since it appears that 21
almost half the people, 40 to 47 percent of the two 22
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doses, actually had one or more dose reductions, do 1
you have any data about the response rates and the 2
duration of response in those people who were at 3
lower doses, since a lot of them wind up being at 4
less than 500 milligrams BID? That's one question. 5
The other question is something that we 6
never focus on, are all the other drugs that people 7
take to support taking the drug that we're focusing 8
on. In this case, about half of them received a 9
variety of anti-diabetic agents, and those don't 10
act similarly. 11
You had some people taking insulin, others 12
taking insulin sensitizers would drop down your 13
levels of insulin. Do you have any data about 14
those who had the various types or classes of 15
drugs, insulin lowering, insulin raising, and how 16
they did in terms of responses and duration of 17
response? 18
DR. ROLFE: Dr. Yurasov? 19
DR. YURASOV: Let me start with your first 20
question about the effect that dose reductions have 21
on the relationship between the dose reductions and 22
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efficacy, and I will bring up the slide for both 1
patients at 500 and 625. 2
So starting from the top, 470 patients that 3
were treated with 625 milligram dose, 93 patients, 4
as you pointed out, experienced a dose reduction. 5
And then we show the confirmed overall response 6
rate for those patients actually is comparable to 7
what we're seeing overall with durable responses, 8
the duration of response 8.8 months. And for 9
500 milligram, the data follows a similar trend. 10
Your second question, in terms of usage of 11
anti-hyperglycemia medications and relationship to 12
efficacy, you're correct, a number of patients used 13
different types of medications, metformin as was 14
already brought up previously used fairly commonly 15
in this patient population. And we actually didn't 16
see a significant relationship between metformin 17
responses. 18
Now of course -- and I bring up this slide 19
with the data that shows you broken out by dose, 20
and we can just focus on overall response rate in 21
the right column. So patients who received 22
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metformin while on study versus patients who did 1
not receive metformin in the lower part of the 2
table. 3
So response rates are comparable. Now, of 4
course there is a caveat to this that metformin is 5
a variable that is introduced during the treatment, 6
so these patients, the duration of observation is 7
different for the two subgroups. 8
DR. ARMSTRONG: Did that answer your 9
question? Great. 10
Dr. Orza? I'm sorry, we're going to push 11
the break back a little bit just so we can continue 12
to ask questions, so it will probably be at 11:00. 13
DR. ORZA: Michelle Orza. I have requests 14
for additional data to help me make the two 15
comparisons I think we're being asked to make. The 16
first is with approved available therapies, and 17
we've seen the data on the objective response rate 18
for the approved therapies and this drug, and this 19
drug has a higher ORR than the approved ones. But 20
we don't know anything about the overall survival, 21
and apparently we don't know anything about the 22
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quality of life or the clinical outcomes. 1
But is there anything that shows us side-by-2
side the side effect profiles on that comparison? 3
I didn't see anything in either the sponsor's 4
materials or FDA's that would help sort of make 5
that comparison directly. 6
Then the second comparison seems to be 7
between this drug and the other -- I'm going to 8
pronounce it wrong -- osimertinib, that has 9
accelerated approval where the ORR is not as good, 10
and we don't know anything about overall survival 11
for either. But I'd also like to see the side 12
effect profiles and the experience of the patient 13
side-by-side for both of those. 14
DR. ARMSTRONG: Maybe I can ask the agency 15
to address that. 16
DR. BLUMENTHAL: Yes, just to clarify, first 17
of all on your second point, actually the ORR for 18
osimertinib is double that of rociletinib, so about 19
59 percent versus 30 percent. And the duration of 20
response is about 12 months at the medians with 21
osimertinib versus about 9 months with rociletinib. 22
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With respect to side-by-side comparisons for 1
toxicities, I think Drs. Carbone and Camidge 2
alluded to it earlier. From our perspective, we 3
did have a slide comparing the QTc risk with 4
rociletinib versus other approved oncology agents 5
that also have warnings or boxed warnings or even 6
REMS programs. 7
At least if you look at the proportion of 8
patients with QTc prolongation of 500 or greater, 9
it was about 3 times that of vandetanib, which is 10
another drug considered to be highly 11
pro-arrhythmogenic. 12
As far as other toxicities with nivolumab, I 13
think Dr. Carbone alluded to it. Nivolumab is 14
generally well tolerated. There are a fraction of 15
patients who get serious autoimmune type adverse 16
events, which can be pretty serious. Docetaxel and 17
ramucirumab/docetaxel, there are chemotherapy type 18
toxicities, and then ramucirumab, a VEGF type 19
agent, so not a lot of additive toxicity there, 20
some hypertension, some proteinuria, and then some 21
serious toxicities as well. 22
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DR. ARMSTRONG: But I will point out this is 1
the problem when you're looking at a single-arm 2
phase 2 and trying to figure out whether or 3
not -- then you're doing cross-trial comparisons, 4
and those are fraught with problems. But I didn't 5
know if -- 6
DR. ROLFE: I'd like Dr. Kowey to comment 7
specifically on the cardiovascular risk from his 8
expert perspective. 9
DR. KOWEY: Peter Kowey, cardiologist and 10
electrophysiologist in Philadelphia. I wanted to 11
comment on this vandetanib issue because I think 12
it's extraordinarily important. It is a precedent 13
setting drug in that it did have a central tendency 14
effect on QT interval, which is very similar to 15
what we're seeing here, almost identical. 16
I would not use the outlier analysis, the 17
categorical analysis, in that study to compare to 18
this; that that is the number of people who went 19
over 500 milliseconds in the vandetanib experience 20
versus this application, for lots of reasons. 21
First of all, cross-trial comparisons, as 22
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several people have already said, are very, very 1
hazardous. How you define it and how frequently 2
you sample, and who's reading, and what time points 3
is really very, very critical to this categorical 4
analysis issue. 5
So what I would focus on if I were the 6
committee in that table is the central tendency 7
effect, because I believe that that has the most 8
robust reflection of the true repolarization 9
changes. And as you know, vandetanib was approved, 10
and it was labeled, and it has been used 11
successfully for patients with medullary thyroid 12
cancer, with I think fairly good clinical success 13
to this point. 14
DR. PAZDUR: Could I just jump in here? The 15
vandetanib trial was a randomized trial, so we had 16
a random -- I mean, we had a comparator arm really 17
to look at here. This is the major question that 18
we're focusing on, is what this QT prolongation 19
means in a single-arm trial where you don't have a 20
comparator, you have very sick patients here. And 21
we look at attribution of death is a very, how 22
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should I say it, ambiguous area here. 1
Here again, we don't know what's going on 2
with this drug in a sense with QT, and that's one 3
of the uncertainties that we're trying to highlight 4
here. But we did have a randomized trial that led 5
to the approval of vandetanib, so we were able to 6
really to characterize this. 7
DR. ARMSTRONG: And with two unexplained 8
sudden deaths, you do add those and almost double 9
the rate or not. That's certainly an issue. 10
DR. FIGG: Do we know the NAT2 status on 11
those two deaths? 12
DR. ROLFE: They were both slow acetylators. 13
DR. ARMSTRONG: Thank you. Dr. Rajan? 14
DR. RAJAN: Thank you. My question was 15
actually very closely related to what Dr. Szabo 16
just asked, and it was specifically about 17
metformin. And I think you answered my question 18
about the response rates and those who did and did 19
not receive metformin. If I remember correctly, 20
the numbers were 40 some percent and 23 percent or 21
so. 22
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So I'll just make a comment at this time, 1
and I'd just say there was a letter written in 2
response to the original rociletinib paper in 3
August of last year. And in that they had this 4
waterfall plot of T790M positive patients who had 5
responses. I think there were a bunch of 6
responses, 27 partial responses among whom 7
38 -- about 38 percent of patients got metformin. 8
For the doses that we are talking about, the 9
625 milligram dose, 4 out of 5 patients got 10
metformin. So it's just something to keep in mind, 11
and I just wanted to highlight that. Thank you. 12
DR. ARMSTRONG: Thank you. Dr. Nowakowski? 13
DR. NOWAKOWSKI: Good afternoon. 14
Nowakowski, Mayo Clinic. A question to the 15
sponsor. In your presentation, you alluded that 16
early on, it was decided, from the feedback from 17
investigators, that the dose 750 milligrams is not 18
the way to go. I just want to clarify if all the 19
toxicity has been captured in the slides 43 to 45, 20
or was there any other feedback from the 21
investigators why the 750 milligrams was not the 22
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way to develop it. 1
DR. ROLFE: Dr. Camidge, could you take 2
that? 3
DR. CAMIDGE: Ross Camidge, medical 4
oncology. So let me see if I've got your question 5
right. So your question was what was the clinical 6
experience with 750 milligrams? 7
DR. NOWAKOWSKI: Right. In the 8
presentation, it was alluded that there was an 9
early feedback from the investigators that 10
750 milligrams was toxic. And I just would like to 11
understand, was there any additional feedback apart 12
from what's being presented as far as toxicity is 13
concerned about 750 milligrams, which you decided 14
this is not a feasible dose to develop? 15
DR. CAMIDGE: I mean, we're looking at it in 16
a group of patients, and some people did tolerate 17
it. But the overall impression was that the 18
hyperglycemia, the fatigue, tended to be more 19
prominent. It's interesting that the modeling of 20
the PK didn't suggest a difference in exposure, yet 21
the clinical experience was that there was a 22
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difference. So there may be some questions about 1
the validity of the model because that's very 2
different from my own experience and that of the 3
other investigators. 4
DR. NOWAKOWSKI: Okay. The other question 5
relates to the protocol amendments. This protocol 6
had a number of amendments during its course, and 7
the one on April 17, 2014 specified that the 8
patients who are not eligible, based on the 9
potassium or magnesium levels, were eligible for 10
replacement. Then, if they were meeting the 11
values, then they could enter the protocol. 12
Do you have a sense, or the data, how many 13
patients actually required replacement of potassium 14
or magnesium to enter the protocol? And if you do, 15
do you have any sense if the cardiac toxicity was 16
higher in the patients who required replacement to 17
enter the protocol, since we know that the patients 18
who are hypokalemic or have hypomagnesemic at 19
baseline are at the risk of recurrent electrolyte 20
abnormalities later on? 21
DR. ROLFE: So we don't have that data 22
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available, but in the risk mitigation plan moving 1
forward, we will recommend that patients have 2
normal potassium, magnesium, and that it's 3
maintained within the normal range throughout the 4
duration of rociletinib therapy. 5
DR. NOWAKOWSKI: So in the mitigation plan, 6
if the patients were hypokalemic, you would not 7
allow them to be replaced to normal level to enter, 8
to be treated? 9
DR. ROLFE: Patients who had potassium below 10
the lower limits of the reference range in 11
screening were able to be enrolled if, following 12
supplementation, that took their potassium into the 13
normal range. 14
DR. NOWAKOWSKI: Right. And then moving 15
forward, would you still allow it, or would you say 16
that just the patients with normal electrolytes 17
should be treated in the future with this? 18
DR. ROLFE: So we would still allow it. 19
Supplemented patients could go in as per normal 20
practice. 21
Dr. Kowey, could you add to that? 22
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DR. KOWEY: Peter Kowey again. You're 1
absolutely correct, that maintenance of potassium, 2
magnesium, are extraordinarily important in 3
managing patients with drugs that have the 4
potential to prolong the QT interval. 5
I don't have an answer to your question 6
about the pro-arrhythmic rates, but I can tell you 7
that repleting potassium and magnesium, as has been 8
put into place in this protocol and in the 9
randomized trial, is more than adequate. And there 10
are monitoring parameters that have been put into 11
place that the investigators need to adhere to. So 12
it's very, very important. 13
DR. ARMSTRONG: Okay, question answered. 14
Dr. Fojo? 15
DR. FOJO: So you were going to tell us in 16
the waterfall plot, because actually as I look at 17
today's thing where you can see the lines a little 18
better, I couldn't see it on my printout. It 19
begins to appear that maybe not all the 20
625-milligram patients are in that waterfall plot. 21
How many of the 170 are in that waterfall plot? 22
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DR. ROLFE: So we will get back to you with 1
the specific number right after the break. 2
DR. FOJO: Right after the break. Okay. 3
DR. ROLFE: But can I just explain one 4
limitation of a waterfall plot is that it can only 5
include patients who have a measurable target 6
lesion at baseline that is subsequently scanned and 7
measured again. So it does not include patients 8
who don't have a secondary staging scan for 9
whatever reason. 10
DR. FOJO: Yes, what is going to emerge is 11
that this is not representative of the population 12
at large, which is worrisome because you start off 13
with -- I mean, you have 400 percent -- 400 14
percent -- 400 patients in the safety, you've got 15
325 in the efficacy. Boom. We lost 20 percent for 16
whatever reason. Even within that 325, there were 17
10 percent that didn't have -- where you said 18
missing data, we don't have anything. It starts a 19
subset. 20
Then, I had another question. When was the 21
last patient enrolled in these two trials that 22
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we're looking at, the 008 and the 019? 1
DR. ROLFE: Dr. Yurasov, could you explain 2
the difference between the safety and efficacy? 3
And while he's preparing, I'll answer the question 4
about enrollment. 5
DR. FOJO: Right. 6
DR. ROLFE: The enrollment cutoffs were 7
different according to each dose. As FDA 8
mentioned, we did not enroll the doses in parallel, 9
they were enrolled sequentially. 10
DR. FOJO: Right. 11
DR. ROLFE: So the 750-milligram data set is 12
the most mature. 13
DR. FOJO: Right. 14
DR. ROLFE: And the enrollment cutoff for 15
750 milligrams was 31st of December 2014, and it's 16
the same date for 625 milligrams. Five hundred 17
milligram cohort was the last cohort to enroll, so 18
the enrollment cutoff is slightly later. I think 19
it's March 2015, something like that, for the 20
500-milligram cohort. 21
DR. FOJO: Yes. So then, let me follow up 22
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on that because that's what I thought. I mean, 1
somewhere in here, those were the numbers I came up 2
with. 3
What bothers me is, with the duration of 4
response, there's a ton of patients that are 5
censored for the duration of response. Actually, 6
the numbers that we're seeing for median are not 7
real numbers, they're Kaplan-Meier estimates of the 8
median duration of response. 9
Why is it that a year ago, when we enrolled 10
the last patient, you tell us that most of the 11
responses occur quickly, within the first 12
assessment, which appears to be the case. So even 13
the last patient that was enrolled would have at 14
least 10 months of follow-up by the time we come 15
here today, and probably 9 months when you were 16
getting this ready for us. 17
Why is it that the past 6 months, there's 18
hardly any patients? I mean, you can see in the 19
750, it drops off dramatically. So when you look 20
today, the number at risk and the number of events 21
past 6 months, you can see that the majority of 22
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patients are censored, and the FDA thing that was 1
submitted to us, you can see the tick marks. 2
Why don't we have longer follow-up on these 3
patients, all of whom have now been on study 13 4
months? And that would be -- you know, it starts 5
to get a little bit concerning that this data is 6
incomplete. Now, we're going to find out that the 7
waterfall plot is incomplete. We already had 8
incomplete data from before. 9
It just leaves a lot of gaps in the data, in 10
a single-arm trial where we really want to know 11
what's going on, especially practically all of them 12
were and the United States. It shouldn't be so 13
difficult to get this data and gather it for the 14
committee. 15
DR. ARMSTRONG: Let's go ahead and give them 16
some time to answer. 17
DR. ROLFE: We did perform an updated 18
duration of response analysis based on a later data 19
cut applied to all patients. We updated the 20
duration of response analysis with a September 2015 21
data cut. The duration of response rates are very 22
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stable, and I will be able to show you them right 1
here. This slide shows 500- and 625-milligram 2
doses only with a September 2015 data cut for the 3
NDA data set. And you can see that the duration of 4
response is very comparable with the duration of 5
the response in the original NDA. I could get back 6
to you after the break with 750 milligrams if that 7
will be useful. 8
DR. FOJO: This is good enough. 9
DR. FASHOYIN-AJE: May I ask what the number 10
of patients is in that figure, in each of the dose 11
groups? 12
DR. ROLFE: So in the Kaplan-Meier curve 13
that I just put up? 14
DR. FOJO: Yes. 15
DR. FASHOYIN-AJE: Yes. 16
DR. ROLFE: It is virtually identical to the 17
number of patients in the NDA. There may have been 18
1 or 2 additional responders since the NDA data cut 19
who would be included. But again, I can get back 20
to you with those precise numbers after the break. 21
I would like to ask Dr. Yurasov to clarify 22
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the question around efficacy and safety data sets 1
because it's an important one. 2
DR. YURASOV: So let me go back to the slide 3
that we had in our core presentation. As you 4
pointed out, 400 patients, this is our safety 5
population, 325 patients is our efficacy 6
population. 7
Now, the efficacy population has all 8
patients who received rociletinib who had T790M 9
status confirmed and who had a scan submitted for 10
IR. Out of those 325 patients, there were patients 11
who did not have measurable disease, but based on 12
the approach, we agreed with the FDA they are 13
included in the efficacy population. 14
So when we go to the waterfall plot that I 15
showed, in that waterfall plot, you will see less 16
than 170 patients at 625 because some of them did 17
not have a measurable disease. That's the reason 18
for discrepancy. 19
DR. ROLFE: And please, would you display 20
the slide that has the flow chart regarding T790M 21
positive and negative? 22
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DR. ARMSTRONG: We have a ton of people who 1
want to ask questions. 2
DR. ROLFE: Okay. 3
DR. ARMSTRONG: We can show this later if 4
you need to. 5
DR. ROLFE: Sure. 6
DR. ARMSTRONG: So we can get to break. 7
Dr. Cole? 8
DR. COLE: I would like to ask about the 9
representativeness of the sample. Any time you 10
pool multiple studies together, you run the risk of 11
getting a total population as representative of 12
neither original target population. 13
I was wondering, the epidemiologist part of 14
me would take these data and kind of compare with 15
other studies to make sure that the demographics 16
and all the prognostic indicators line up with the 17
general population, and possibly do some analysis, 18
sensitivity kind of analysis, to see how my 19
confidence intervals and my estimates might move 20
around a bit when doing that. 21
I think it's important here because the 22
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response rate of 30 percent that was observed seems 1
to be improved over historical controls, but the 2
gap is not really very large when you factor in the 3
possibility that there could be some selection bias 4
or there could be variability in the estimates. 5
I'm just wondering if you did any kinds of 6
additional analyses in the epidemiologist kind of 7
realm to look at the sensitivity of the results to 8
differences in the population compared to general. 9
DR. ROLFE: Well, I'll answer from the 10
sponsor's perspective, and I will ask Dr. Camidge 11
to comment from the wider population perspective. 12
We did a number of subgroup analyses within the 13
studies, and we showed that within all the 14
subgroups we looked at, the response rate was very 15
consistent. 16
So those were the sensitivity approaches 17
that we took. Dr. Camidge, could you comment on 18
the overall population similarities? 19
DR. CAMIDGE: So there were certain clinical 20
and demographic factors associated with having an 21
EGFR mutation, which will make it look somewhat 22
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different than a standard lung cancer population. 1
There's a higher incidence of those of East Asian 2
origin, a higher incidence of never smokers, a 3
slight female bias. So it's never going to look 4
exactly the same as an unselected lung cancer 5
population. 6
I think one thing just to factor in when 7
you're talking about not a big difference in the 8
objective response rate is a very significant 9
difference in what delivering the therapy means. 10
One is an oral therapy with most of the adverse 11
events made up of potentially asymptomatic 12
abnormalities, the other standard comparator to 13
intravenous with a lot more in the way of 14
symptomatic toxicities, as I'm sure you're aware. 15
DR. ARMSTRONG: A final question from 16
Dr. Mager. And I just will remind all the panel 17
members that during the questions to the committee 18
and committee discussions, if there are other 19
burning questions, we can ask at that time. 20
DR. MAGER: Just a quick question regarding 21
risk management strategy. It follows on, actually, 22
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Dr. Figg's question earlier. Given the extreme 1
variability in the M460 concentrations, the lack of 2
a priori genotyping, and the relatively strong 3
relationships between the concentrations and the 4
adverse events, why therapeutic drug monitoring 5
wasn't at least considered as part of the risk 6
management strategy. 7
DR. ROLFE: We believe that frequent ECG 8
monitoring is a better strategy because it actually 9
reads out on the event. 10
DR. ARMSTRONG: Is that it? 11
So we'll now take a 10-minute break. Panel 12
members, please remember that there should be no 13
discussion of the meeting topic during the break 14
amongst yourselves or with any member of the 15
audience. We will resume in 10 minutes at 11:17. 16
(Whereupon, at 11:07 a.m., a recess was 17
taken). 18
Open Public Hearing 19
DR. ARMSTRONG: I'll ask everybody to take 20
your seats, and we'll move to the open public 21
hearing section. 22
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Both the Food and Drug Administration and 1
the public believe in a transparent process for 2
information gathering and decision making. To 3
ensure such transparency at the open public hearing 4
session of the advisory committee meeting, FDA 5
believes that it is important to understand the 6
context of an individual's presentation. 7
For this reason, FDA encourages you, the 8
open public hearing speaker, at the beginning of 9
your written or oral statement to advise the 10
committee of any financial relationship that you 11
may have with the sponsor, its product, and if 12
known, its direct competitors. 13
For example, this financial information may 14
include the sponsor's payment of your travel, 15
lodging, or other expenses in connection with your 16
attendance at the meeting. Likewise, FDA 17
encourages you at the beginning of your statement 18
to advise the committee if you do not have such 19
financial relationships. If you choose not to 20
address this issue of financial relationships at 21
the beginning of your statement, it will not 22
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preclude you from speaking. 1
The FDA and this committee place a great 2
importance on the open public hearing process. The 3
insights and the comments provided can help the 4
agency and this committee in their consideration of 5
the issues before them. 6
That said, in many instances and for many 7
topics, there will be a variety of opinions. One 8
of our goals today is for this open public hearing 9
to be conducted in a fair and open way where every 10
participant is listened to carefully and treated 11
with dignity, courtesy, and respect. Therefore, 12
please speak only when recognized by the 13
chairperson. Thank you for your consideration. 14
Will speaker number 1 step up to the podium 15
and introduce yourself? Please state your name and 16
any organization you're representing for the 17
record. 18
DR. GOTTSCHALK: Hi. Thank you for the 19
opportunity to speak today. My name is Dr. Lauren 20
Gottschalk. I received my PhD in cellular and 21
molecular medicine from Johns Hopkins School of 22
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Medicine and previously worked as a cancer 1
researcher. I'm speaking today on behalf of the 2
National Center for Health Research. 3
Our research center scrutinizes scientific 4
and medical data and provides objective health 5
information to patients, providers, and policy 6
makers. We do not accept funding from 7
pharmaceutical companies, and therefore I have no 8
conflicts of interest. 9
We understand that patients who have T790M 10
positive lung cancer are tired and frustrated 11
because time after time, they're given a cancer 12
therapy only to be told it is not working to treat 13
their cancer. So the promise of a new drug that 14
will successfully treat their specific form of 15
cancer, even down to the exact mutation, can sound 16
very promising. However, based on the data 17
presented today, we think you'll agree that 18
rociletinib does not meet FDA's standards of proven 19
safety or effectiveness. 20
First, we're concerned with the efficacy of 21
rociletinib. The objective response rate of about 22
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30 percent does seem promising, but several 1
important caveats need to be kept in mind. 2
Accelerated approvals can often lead to more 3
lenient clinical trials, including the single-arm 4
studies used here. 5
We believe that without proper controls an 6
accurate assessment this drug's efficacy and safety 7
cannot be made. The surrogate endpoint used for 8
the studies, objective response rate, has in the 9
past been shown to be a poor indicator of cancer 10
drug efficacy. 11
A study from December of last year looked at 12
cancer drugs that were approved by the FDA over a 13
recent five years based on surrogate endpoints. In 14
postmarket studies, only 14 percent of these 15
approved cancer drugs were found to improve patient 16
survival, and yet our center found that all of the 17
unproven cancer drugs were still on the market, 18
many costing more than $100,000 per year. These 19
results show that surrogate endpoints such as 20
objective response rate too often provide false 21
hope while costing patients more than they can 22
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afford. 1
In this study, there's also a possible red 2
flag warning. Only one patient had a complete 3
response out of the 98 patients who actually had an 4
observed response to the drug. This makes it seem 5
unlikely that the drug will be found to be 6
effective in controlled clinical trials. 7
The ongoing randomized phase 3 trials 8
comparing this drug to chemotherapy should give a 9
better idea of overall survival in patients. Until 10
those results are available, the FDA should not 11
approve yet another drug that could easily fail to 12
be effective for T790M patients. 13
In addition to questioning the efficacy, we 14
are also very concerned with the safety profile. 15
The drug had numerous side effects that would 16
directly decrease a person's quality of life, 17
diarrhea, fatigue, nausea and vomiting in 18
approximately half of the patients. Meanwhile most 19
patients suffered for almost two months before 20
learning that the drug wasn't working for them. 21
Even more troubling were the high incidences of 22
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serious adverse effects, such as hyperglycemia and 1
QT prolongation. 2
As a result, the side effects resulted in 3
most patients reducing, interrupting, or stopping 4
their dosing completely. Since there was no 5
standardized method for reducing dosage in 6
patients, this makes it difficult to accurately 7
assess the efficacy of this drug. 8
In conclusion, we realize that there is 9
currently an unmet need for a drug to treat 10
patients whose NSCLC has become resistant to 11
first-line TKI therapies via the T790M mutation. 12
However, this does not warrant the approval of yet 13
another drug that will not significantly improve 14
outcomes for these patients. 15
Fortunately, there's hope on the horizon, as 16
mentioned here before, because of the preliminary 17
results for osimertinib for the same patients and 18
appears to be more effective with fewer serious 19
side effects. 20
For rociletinib to be worthy of FDA 21
approval, studies are needed to determine which 22
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subgroups of patients are most likely to benefit 1
from treatment and determine how to reduce the 2
number of adverse events experienced by these 3
patients, perhaps by looking at NAT2 status again 4
as mentioned here today. 5
Additionally, these studies should have the 6
proper control group and outcome measures to 7
demonstrate effectiveness as measured to clinically 8
relevant endpoints, such as overall survival. 9
Thank you for your time. 10
DR. ARMSTRONG: Thank you. 11
Will speaker number 2 step up to the podium, 12
introduce yourself? Please state your name and any 13
organization you're representing for the record. 14
MS. PENA: Good morning. My name is Glenda 15
Pena, and I've been an oncology nurse for 22 years. 16
I'd like to thank each of you for giving me the 17
opportunity to honor my dad's memory by telling his 18
story. I know he would be proud of me today if he 19
knew that my being here today to tell his story 20
could make a difference in the lives of many. I'd 21
also like to express my gratitude to Clovis 22
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Oncology for supporting my travel here today and 1
making this possible. 2
My dad, Mickey Mutter, was one of the 3
bravest, wisest, Godliest men that I've ever known. 4
He was in the army, and he served his country in 5
Vietnam where he was exposed to Agent Orange. When 6
he retired from the army as lieutenant colonel 7
after 20 years of service, he went to work at 8
Kennedy Space Center for safety. 9
He retired at 57 so he could volunteer his 10
time for his church, community, and family, and I 11
always joked to him and my mom that they should go 12
back to work to rest. He babysat his 13
grandchildren, volunteered his time working for 14
hospice, he worked at his church as handyman, 15
fixing anything and everything, and he mentored and 16
helped people through Stephen ministry. 17
In December of 2011, our family was 18
blindsided when scans revealed that he had stage 4 19
lung cancer. How dare they tell us that my dad, my 20
hero, was dying? Dad was started on cabazitaxel 21
and Avastin before he had his EGFR status back 22
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because we wanted him started on treatment as soon 1
as possible. One of the hardest things I've ever 2
had to do in my life was see my dad sitting in that 3
chemo chair for the first time. 4
He completed six cycles and stayed on 5
Avastin maintenance until he showed progression in 6
August 2012. His treatment was changed to Tarceva 7
since he had tested positive for the EGFR mutation. 8
In February 2013, his PET scan showed 9
increased activity in his lung lesions, so Alimta 10
was added, and he had stable disease for 13 cycles, 11
but unfortunately in October, we learned that the 12
cancer had outsmarted the chemo and progressed. 13
He was referred to Moffitt Cancer Center and 14
was put into a phase 1 clinical trial with afatinib 15
and dasatinib, but after a few months, a bone scan 16
revealed lesions in his back and ribs. He got 17
radiation and was able to go back on trial, but 18
shortly after that, in May, a brain scan was done, 19
and the results were devastating. 20
The cancer had gone to his brain. He got 21
more radiation, and the symptoms were controlled, 22
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but other scans soon revealed that he had lesions 1
in his adrenals, pancreas, and liver. The cancer 2
was out of control, but he wasn't willing to give 3
up the fight. 4
I heard about a clinical trial for PD1 and 5
PDL1 for lung cancer at Florida Hospital, but when 6
Dr. Mekhail looked at his case after the referral, 7
he said, "I think I might have something better for 8
you," and a biopsy of an enlarged lymph node 9
revealed the T790 mutation. 10
He was placed into the clinical trial 11
CO1686, which we now know is rociletinib. When he 12
went in for the first results of his CAT scan at 13
five weeks, Dad and Mom sat there crying while they 14
were being told that the target lesions in his 15
lungs had decreased significantly, and the lesions 16
in his liver, pancreas, as well as some of the 17
smaller lesions in his lungs, were completely gone. 18
Finally, we had some hope. 19
He tolerated the rociletinib very well. His 20
medical team at Florida Hospital monitored him 21
closely for glucose and heart issues. He never 22
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experienced any issues with his blood sugar, and 1
although he did have some subtle changes in his EKG 2
readings a couple of times, it was nothing that 3
prevented him from staying on trial. His GI 4
symptoms were mild and tolerable. And because the 5
medication helped palliate his symptoms from his 6
cancer, he was able to scratch off several items 7
from his bucket list. 8
He went to the Grand Canyon with my mom and 9
their best friends. He traveled to Georgia to see 10
family. And he was able to continue doing the 11
things that he loved to do, like working in the 12
yard, fishing, and taking walks to the beach with 13
my mom. 14
He did well with stable disease for five 15
months, but unfortunately in February 2015, he 16
developed neurological symptoms again, and the 17
cancer had returned to his brain. He was taken off 18
the medication while he went through a second round 19
of whole brain radiation and was able to return to 20
study for a short time, but then he developed 21
obstructive pneumonia. 22
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He was placed on steroids and antibiotics 1
and had to have another CAT scan to determine if he 2
could be put back on the trial. Before we could 3
get the results, on April 25, 2015, Michael Dean 4
Mutter, devoted husband, dad, and friend, went home 5
to heaven to be with his best friend, Jesus. 6
I was so grateful that I could be there with 7
him on his journey, and I know that if even one 8
person could be helped by the use of rociletinib, 9
he'd be willing to fight his battle again. I know 10
how much quality-of-life matters, and I know that 11
this medication gave him the opportunity to do 12
things that he wouldn't have otherwise been able to 13
do. 14
My dad had five more months to create 15
memories with my mom, his children, and his 16
grandchildren, and that wouldn't have been possible 17
without this medicine. 18
I know that there is another medicine 19
currently approved for the T790 mutation, but the 20
more options available for people like my dad, the 21
better. I truly believe that if we had known about 22
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this medicine sooner, it is possible he would be 1
with us today. And although there are no 2
guarantees, I want to be a part of spreading the 3
word that there is hope with rociletinib. Thank 4
you. 5
DR. ARMSTRONG: Thank you. 6
Will speaker number 3 step up to the podium, 7
introduce yourself? Please state your name and 8
organization that you're representing for the 9
record. 10
MS. TOMLINSON: My name is Celia Ruiz 11
Tomlinson. I am a 75-year-old lung cancer patient. 12
I'm representing myself. First of all, I thank the 13
board for allowing me to share my experience with 14
lung cancer and Clovis Oncology for making my trip 15
possible. 16
I am a retired engineer entrepreneur, a 17
published author, and a professional motivational 18
speaker. Growing up in a Manila slum, awash with 19
rotten trash and human waste, I transcended numbing 20
poverty and became a civil engineer in the 21
mid-1960s when female engineers were unheard of. 22
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Buoyed by that success, I came to the United States 1
in 1968 legally, alone with only $300 and my 2
diploma. 3
To my rude awakening, the American engineers 4
confronted me with fierce resistance. Through 5
sheer tenacity, I gained acceptance. In 1983, I 6
founded an engineering company with $2000 from my 7
own pocket. As its own president and CEO, I grew 8
the firm and received national entrepreneurial 9
leadership awards. Twenty-five years later, in 10
2008, I sold the business and retired. 11
Four years into retirement, in the summer of 12
2012, I had a cough that didn't seem to go away. A 13
visit to my doctor led to an image of a golf 14
ball-sized tumor at the bottom of my left lung, and 15
tiny nodules, too many to count, in both lungs. 16
Biopsy followed. The diagnosis, non-small 17
cell lung cancer, stage 4. Prognosis, eight months 18
to live, a year at most. True to character, I 19
faced the dire prognosis with aplomb, but spunk 20
alone can't fight cancer. Drugs are needed. 21
At the time, FDA had just approved Tarceva 22
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for the first-line treatment of my type of cancer. 1
My oncologist put me on Tarceva, 150 milligrams 2
daily. No immediate side effects for one week. On 3
the eighth day, rash blanketed my face and my 4
chest. We cut the dosage in half, and the rash 5
went away. After 100 days on Tarceva, the main 6
tumor shrank 80 percent. Subsequent CAT scans 7
showed a stability. My quality of life was good. 8
After 20 months, my oncologist suspected 9
resistance and suggested that I participate in the 10
rociletinib clinical trials. Having qualified, I 11
was accepted. I took 1500 milligrams of 12
rociletinib daily. For four months, no side 13
effects. My quality of life was great. 14
On the fifth month, my blood sugar elevated. 15
My oncologists and I worked with metformin to 16
control the hyperglycemia. Later, we reduced the 17
rociletinib dosage to 1000 milligrams. One day, I 18
went on a three-day drug vacation. When I resumed 19
medication, the hyperglycemia mysteriously 20
disappeared. 21
I have been on rociletinib now for two 22
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years. It's stable with zero side effects the last 1
12 months. My awesome quality of life allows me to 2
blog, inform, and inspire other cancer patients. 3
Today is a far cry from the summer day of 4
2012 when the first oncologist sort of declared me 5
a dead woman walking. I implore the board to 6
please remember my story when deciding on the fate 7
of rociletinib. A cancer drug affects each patient 8
differently. It has been very good to me, 9
therefore having more approved drugs is better than 10
having less. Thank you. 11
DR. ARMSTRONG: Thank you. 12
Will speaker number 4 step up to the podium? 13
Please introduce yourself, state your name and any 14
organization that you're representing for the 15
record. 16
MS. FIGUERAS: Distinguished members of the 17
Oncology Drug Advisory Committee and other guests, 18
my name is Anita Figueras, and I am 64 years old. 19
I come to you from Russell, New York, a tiny rural 20
township in the Adirondack foothills. Clovis 21
Oncology supported my travel here today. Clovis 22
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has not reviewed my statement. My words are my 1
own. 2
I am married and have been with my husband 3
for more than 40 years. He can't be with me today 4
because he is town supervisor of our little town, 5
and he has a board meeting tonight. I have a 6
stepson, three grandchildren, and a daughter who is 7
here with me today. She is a biostatistician and a 8
post-doctoral fellow at the NCI. 9
At the time of my diagnosis with lung 10
cancer, I was finance and personnel manager, plus 11
farm business management educator, for a non-profit 12
that is part of New York State's Cooperative 13
Extension Network. It was a big job that required 14
more than full-time effort from me, and the first 15
decision I made the day I learned that I have 16
advanced cancer was to retire. 17
I was diagnosed with stage 4 adenocarcinoma 18
of the lung in June 2014. I had one 3-centimeter 19
tumor in my upper left lobe, a pleural effusion on 20
my left lung, and metastases to lymph nodes. My 21
oncologist at the Community Cancer Center advised 22
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basing treatment on a genetic analysis of the 1
cancer, and the biopsy results were EGFR Exon 19 2
deletion. I began treatment with erlotinib in 3
mid-August 2014. 4
Initially, I had an excellent response, but 5
by February 2015, my cancer started showing signs 6
of resistance. I was aware from research I had 7
done that two drugs were being tested in clinical 8
trials that could be my best second line of 9
treatment. 10
A web search led me to the Clovis clinical 11
trial navigation service, which matched me to an 12
open phase 2 trial being conducted at Roswell Park 13
Cancer Institute. This trial was logistically 14
feasible, and I enrolled in the trial in April 15
2015. A new biopsy came back positive for the 16
T790M mutation, and I took my first dose of 17
rociletinib on June 11, 2015, taking 500 milligrams 18
twice daily. 19
I had a very good response to rociletinib 20
with 43 percent reduction in cancer across all 21
sites over the first 12 weeks of treatment, and 22
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stability after that. I also experienced side 1
effects, including hyperglycemia. 2
My blood sugar levels rose dramatically 3
about two weeks after beginning treatment with 4
spikes in the 400s, and I started losing weight. 5
After little success with metformin, glimepiride, 6
and diet changes, my trial oncologist collaborated 7
with my general practitioner, who has much 8
experience with controlling diabetes. 9
We added Jardiance to my drug regime. Blood 10
sugar levels stabilized in short order, and we were 11
able to discontinue metformin after a few weeks. 12
This led to a big increase in my feelings of 13
wellbeing, and I stopped losing weight. 14
Twice we had to reduce my dose of 15
rociletinib due to QT interval prolongation. My CT 16
scans remain stable at a three-quarter's dose, but 17
my cancer started to progress at a half dose, and I 18
left the clinical trial on February 18th. 19
My quality of life on rociletinib was 20
excellent overall. I was able to lead my life with 21
no restrictions, to travel, exercise, shovel snow, 22
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to walk the dog, be a volunteer income tax 1
preparer, and to help my husband put up the 2
firewood that we depend upon for heat in the 3
winter. There were days when I almost forgot that 4
I have a serious and incurable disease. 5
I am here today because even though my run 6
on rociletinib was cut short by QT interval 7
prolongation, I had eight very good months on this 8
drug. As you consider your recommendation about 9
this drug, please keep in mind the preciousness of 10
quality of life to people in my situation. 11
Please also consider the individuality of 12
cancer, that different patients with similar 13
biopsies can have different responses to 14
treatments. Both patients like me and our doctors 15
need options because one drug will not suit all. 16
Thank you. 17
DR. ARMSTRONG: Thank you. Is speaker 18
number 5 here? 19
(No response.) 20
DR. ARMSTRONG: If not, we'll move to 21
speaker number 6. Please step up to the podium and 22
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introduce yourself. State your name and any 1
organization you're representing for the record. 2
DR. SPIRA: Good morning. Thank you for 3
having me here. My name is Dr. Alex Spira. I am 4
board certified medical oncologist, just across the 5
river, with Virginia Cancer Specialists, whom I 6
represent. I'm here as an investigator who treated 7
about 20 to 30 patients on the study. We were 8
active investigators and our organization, but not 9
myself, received compensation from them. I did 10
previously do some consulting work, but Clovis did 11
not pay for any time or travel today. 12
I appreciate you giving me an opportunity to 13
speak at this open hearing today. I have used 14
rociletinib and have seen many of my patients 15
benefit. As I have said, we have put about 20 or 16
30 patients on the studies presented here today. 17
These patients are mainly from the Virginia, 18
Maryland, but also throughout the entire East 19
Coast. And it's safe to say that without these 20
treatments, these patients would not have lived 21
nearly as long or as well as they did. 22
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Although there is another third generation 1
EGFR TKI, osimertinib, from my perspective, there 2
is still an unmet need for another treatment for 3
these patients with EGFR mutated T790M positive 4
non-small cell lung cancer. Adding new options to 5
a clinician's treatment regimen and armamentarium 6
is always beneficial, especially for patients who 7
may not respond or may not tolerate current 8
therapies. 9
As you've heard with the data today, 10
platinum-based cytotoxic chemotherapy is rarely a 11
good option for these patients. They do not tend 12
to respond, and they do not tend to tolerate it 13
very well. These also adversely affect the 14
patient's quality of life, in my opinion, far more 15
than rociletinib. Furthermore, the other TKIs are 16
associated with rash and other toxicities that may 17
compromise the tolerability, and it's always nice 18
to have a different option for patients. 19
In my clinical experience treating patients 20
on these studies, I believe it clearly has a 21
favorable risk-benefit profile, especially as 22
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related to any of the current standard of care 1
treatments. It's also important to have options to 2
sequence patients, and we may very well learn that 3
some drugs work where others fail. 4
From my perspective as an investigator and 5
physician, there is clearly value in granting 6
accelerated approval under the provisions of the 7
21 CFR to very promising molecules, especially 8
those that are indicated for patients who have very 9
limited treatment options. 10
Following accelerated approval, clinical 11
benefit will obviously need to be confirmed in the 12
phase 3 randomized study as you've heard, although 13
again, based upon experience, chemotherapy we know 14
is very toxic and very unlikely to work. 15
In closing, I would like to ask the 16
committee to consider making a very positive 17
recommendation to approve rociletinib for the 18
treatment of advanced EGFR mutated T790M positive 19
non-small cell lung cancer. And if approved, based 20
upon my clinical experience and seeing tons of 21
patients, there is no doubt that these patients 22
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will benefit where they have otherwise very limited 1
treatment options. Thank you. 2
DR. ARMSTRONG: Thank you. 3
Will speaker number 7 please step up to the 4
podium and introduce yourself? Please state your 5
name and any organization you're representing for 6
the record. 7
MR. PACE: Madam Chairman and members of the 8
Committee, I appreciate the opportunity to be here 9
today, and I want to thank Clovis Oncology for 10
helping to support my travel, but I have no 11
financial interest whatsoever in the company. 12
My name is Russell Pace. I'm 87 years old, 13
going on 57. I live in Midlothian, Virginia with 14
my wife, Margaret, who is with me here today, and I 15
have six kids, age 28 to 61, so I've had a long and 16
fruitful life and a very lucky man. 17
After graduating from college, I volunteered 18
for the Air Force. I served three years during the 19
Korean War, part of the time as assistant director 20
of intelligence for 315th Air Division in the Far 21
East. 22
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After that, I went to law school and later 1
practiced law with a firm here in Washington, DC, 2
and then left the practice to co-found a large 3
financial service company, which was very 4
innovative in putting stockbrokers in the New York 5
Wall Street firms into the annuity business. And 6
we licensed and trained about 40,000 of them, and 7
they sold over $2 billion worth of business for us 8
in just a couple of years. 9
So it was a very exciting interesting time, 10
and I've been very fortunate in all the challenges 11
and opportunities that have been presented to me in 12
my life. 13
I never thought about my mortality or about 14
the fact that I was getting old, even at 81, until 15
I was diagnosed with small cell lung cancer in 16
December in 2010. My pulmonologist told me, and my 17
family, that with good luck, I might have nine 18
months to live, and I better get my house in order. 19
But he didn't know that my new cancer 20
doctor, the doctor that just testified here a 21
moment ago, Dr. Alex Spira, what he had in mind for 22
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me. So I went on chemo for about four months, and 1
then he put me on Tarceva, which saved my life for 2
over four years, a full four years. 3
I guess when it appeared that it might no 4
longer be effective to me, Dr. Spira talked to me 5
and was instrumental in getting me enrolled in this 6
clinical trial. And I started taking this drug in 7
July of last year, and been on it 9 months. And 8
the results appear to have been very successful. 9
As a matter of fact, Dr. Spira has indicated that 10
from the CAT scans that I've had over the last 11
several months, that he can't see any cancer 12
anymore. It's almost as it I don't have -- haven't 13
had it. 14
I also would like to say to you that I've 15
had no side effects. The only one possible one 16
that I could relate was a little bit of fatigue, 17
which I've been complained to Dr. Spira that why in 18
the heck can't I get strong and do the things that 19
I used to do. And he said, "Hell, Russell. You're 20
87 years old. What do you expect me to do -- what 21
else for you to do with me?" 22
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(Laughter). 1
MR. PACE: But I did develop a little curly 2
hair with Tarceva, and I was hoping this drug would 3
help to continue it, but it seems to be gradually 4
disappearing, but I have no complaints about that. 5
I'm very grateful to Dr. Spira and Clovis 6
for helping to extend my life. My family, my 7
friends, and my business associates thank you. It 8
has allowed me to continue to be active in business 9
and to innovate in a number of new business 10
ventures with my children and others. 11
Dr. Spira and Clovis are performing a great 12
public service in their fight against cancer. I 13
know that you members of the Committee have a job 14
to do, but I must tell you that in my opinion this 15
drug should be approved so that many others like me 16
may benefit from its use. I appreciate your 17
thoughtful consideration and thank you. 18
DR. ARMSTRONG: Thank you. Will speaker 19
number 8 step to the podium, introduce yourself? 20
Please state your name and organization you're 21
representing for the record. 22
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MR. CAUGHRAN: Yes, good morning. My name 1
is Scott Caughran. I'm 43 years old, and I live 2
with my family in Bend, Oregon. I would like to 3
thank Clovis Oncology for supporting my travel so 4
that I could be here today. 5
My wife and caregiver, Darcy, is here with 6
me today. We've been together for over 20 years. 7
We have three children, two daughters age 16 and 8
13, and a terror of a 3-year-old son. I'm an 9
active duty lieutenant colonel in the Oregon 10
National Guard where I proudly served as an 11
infantry officer. 12
Prior to my diagnosis, I was an incredibly 13
driven and busy person. I spent a lot of time away 14
from home working, professional travel, and 15
attending training courses. I deployed four times 16
in service to our country. I filled my free time 17
with family activities, achieving a high level of 18
fitness, and completing college degrees that would 19
give me a professional edge and prepare me for life 20
after the military. 21
I served my state and community through 22
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involvement in various special committees and 1
coalitions, leading to national recognition at both 2
the Pentagon and the White House. I no longer 3
work. I would have retired from the military this 4
coming January. I now focus on making up lost time 5
and making the most of the time I have left. 6
Eighteen months ago, I was about six months 7
into a deployment in Afghanistan. I was the task 8
force commander responsible for security throughout 9
the entire city of Kabul and the surrounding areas, 10
an area populated by almost 4 million residents 11
that were conducting their first democratic 12
presidential election. I was entrusted with the 13
lives of over 800 soldiers from several countries 14
to accomplish my mission. 15
For six months, I had been fighting 16
increasing pain in my side and was having 17
difficulty improving my fitness. One night the 18
pain got bad. I couldn't sleep. I got up to 19
shower thinking maybe it would help. I ended up 20
passing out from a standing position and landing on 21
my face on a tile floor. I laid there for about 22
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30 minutes before I came to and crawled to get 1
help. 2
I received an x-ray shortly thereafter at 3
the local military hospital, and all at once I was 4
told I had stage 4 lung cancer, that I would be 5
medically evacuated out of Afghanistan in a matter 6
of hours, with no opportunity to say goodbye to my 7
soldiers, and that I had two to six months left to 8
live. 9
I was told I probably had cancer in excess 10
of two years, and that my right lung was full of 11
fluid from a pleural effusion and probably had been 12
for months. That night, I made several tough phone 13
calls to my family to let them know I was coming 14
home early and why. 15
My biopsy showed that I had the EGFR 16
mutation so I was prescribed Tarceva. The Tarceva 17
worked for me for eight months, but I fought hair 18
loss and severe rashes on my upper body and face, 19
and continuously open sores on my head. Once 20
Tarceva quit working, a second biopsy showed the 21
T790M mutation. I then went through six chemo 22
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treatments with no positive effect in order to 1
become eligible for the rociletinib drug trial. 2
Prior to the trial I also lost my ability to 3
walk due to a cancer tumor on my spine. I was 4
taking 240 milligrams of extended release morphine 5
daily, plus wearing a fentanyl patch in order to 6
control severe pain. I had lost almost 30 pounds 7
from my previously healthy weight. 8
Rociletinib quickly improved my physical 9
condition. The cancer in my lung decreased 10
significantly in size, and the fluid in my lung 11
dried up. With the help of back surgery, I became 12
able to walk again. I've gained back 20 of my 30 13
lost pounds. My pain medication has been decreased 14
by over 75 percent, and I'm largely pain free. 15
My original 625-milligram dose of 16
rociletinib was reduced to 500 milligrams as a 17
result of increasing glucose levels. I was 18
prescribed metformin to take as needed, and my 19
glucose has remained fairly stable. I have not 20
suffered from rashes or any other major side 21
effects, and I've now been on rociletinib for six 22
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months. 1
Rociletinib has given me more energy than 2
I've had during any other treatment or since I was 3
diagnosed. I've been able to work around the 4
house, do yard work, play with my kids, attend 5
sports competitions and school performances, visit 6
with family and friends, and travel. 7
I traveled here today because rociletinib 8
has made a tremendous difference in my life. I'd 9
like to see the FDA approve this drug so it can be 10
available to others to benefit them as it has 11
benefited me. It's given me the gift of life, 12
months of quality time with my family, the 13
opportunity to watch my kids compete, perform, and 14
grow, to achieve a greater level of financial 15
stability for those I'll leave behind, and the 16
energy to complete those last few bucket lists. 17
I don't believe I would be alive today 18
without rociletinib. When you're fighting a 19
disease that strikes randomly and harshly, any drug 20
or treatment that stops or slows the spread of 21
cancer is a blessing. Thank you. 22
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Questions to the Committee and Discussion 1
DR. ARMSTRONG: Thank you. 2
The open public hearing portion of this 3
meeting is now concluded, and we will no longer 4
take comments from the audience. The committee 5
will turn its attention to address the task at 6
hand, the careful consideration of the data before 7
the committee as well as the public comments. 8
We'll now proceed with the questions to the 9
committee and panel discussions. 10
I'd like to remind public observers that 11
while this meeting is open for public observation, 12
public attendees may not participate except at the 13
specific request of the panel. I'll ask the FDA to 14
review the questions. 15
DR. FASHOYIN-AJE: Thank you. The FDA 16
requests the advice of the ODAC to discuss whether 17
the benefit-risk profile of rociletinib is 18
favorable in the proposed indicated population. 19
Thank you. 20
DR. ARMSTRONG: Are there any questions or 21
comments regarding the wording of the question? 22
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(No response.) 1
DR. ARMSTRONG: If not, we'll open the 2
question to discussion. So the issue is the 3
benefit-risk profile of rociletinib in the 4
population. Discussion? Go ahead. 5
MS. GILLESPIE: As a lung cancer advocate, 6
or survivor, I understand the importance of new and 7
innovative drugs to give everyone a little more 8
time for the next possible drug. However, I feel 9
that we need to have more responsibility on the 10
safety and efficacy of drugs that come to the FDA. 11
I am still on the fence on this one because I'm not 12
real sure how much risk there is as opposed to 13
benefit. 14
DR. ARMSTRONG: Thank you very much. 15
Maybe I'll take chair's prerogative here and 16
just to -- and honestly, in spite of the very 17
positive comments from the speakers from the 18
audience who are a group that's done well with this 19
drug, I think it's very difficult for us to look at 20
a single-arm study in a subgroup of non-small cell 21
lung cancer and try to look particularly at the 22
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toxicities in relation to the benefits. 1
We have certainly heard that, compared to 2
historic controls, that there's a better response 3
to this drug, but those historic controls are 4
actually in a broader population of non-small cell 5
lung cancer patients and don't include -- and are 6
not enriched for the EGFR mutation carriers who do 7
better. Thus, that 10 percent or so difference in 8
outcome may or may not really be significant. And 9
unfortunately in a non-randomized trial and a 10
single-arm phase 2, it's really difficult to know 11
that. 12
The second is that we see that, based on the 13
metabolism of this agent, that about half the 14
population are at risk for excess toxicities, both 15
the cardiac toxicities and potentially arrhythmias 16
and sudden cardiac death, as well as hyperglycemia, 17
which certainly can be dealt with, but it still is 18
a significant issue and is high grade in about a 19
third of the patients. 20
My feeling would be that some sort of risk 21
stratification in terms of looking at this agent 22
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with regard to the metabolism, I think, is 1
certainly in order; not necessarily saying that you 2
have to limit the population that can get this, but 3
that really trying to better understand. And I 4
know we've mentioned it several times, but I think 5
just looking at QT prolongation is probably not 6
sufficient. 7
We might end up with actually a much better 8
risk-benefit ratio if we were really looking at 9
this in the population that doesn't have the 10
toxicities and the side effect. 11
I'm also concerned about the dosing issue. 12
I think we've heard the issue between the 500 and 13
the 625 that there potentially is very little 14
difference. And yet, we still have this very large 15
900-patient study that's going to look at both 16
doses. And the statistician says there's still not 17
going to be enough patients on the 300 milligrams 18
of each of those doses to really probably be able 19
to give a difference. 20
I think the dosing is going to be an 21
important issue and potentially is going to be an 22
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important issue with regard to the toxicity and the 1
risk-benefit. That's my feeling. 2
Dr. Orza? 3
DR. ORZA: I have another question actually 4
for the FDA, but it goes to trying to understand 5
the proposed population and if there is a 6
population that we can define narrowly enough that 7
really needs this as an option or not. 8
I thought Dr. -- I'm going to say your name 9
wrong -- Fashoyin-Aje, on one of your last slides 10
when you were doing the efficacy summary, I thought 11
you said there was a concern that people might 12
choose this over available therapies known to be 13
effective and improve survival. 14
Is that what you said? Can you say a little 15
more about that? 16
DR. FASHOYIN-AJE: Yes. So if approved, 17
rociletinib would be approved to be used in the 18
same space as the available therapy we discussed; 19
so second-line treatment of non-small cell lung 20
cancer following progression on an EGFR TKI 21
therapy, and sometimes after chemotherapy, doublet 22
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chemotherapy. 1
DR. ORZA: And this drug does not compare 2
favorably with those other drugs, and so we 3
wouldn't want it to be -- we want it to be maybe a 4
third choice or a last resort? 5
DR. FASHOYIN-AJE: I think that's our 6
question to the committee. We are concerned about 7
the serious and life-threatening risks in patients 8
who receive rociletinib. 9
So while the numeric overall response rate 10
may be better when you compare to available 11
therapies -- notwithstanding all the limitations 12
we've discussed about comparing overall response 13
rate across several studies, but if you're just 14
looking at the number, there are serious risks 15
associated with the use of this drug, which may not 16
confer an improvement over the therapies that are 17
already approved. That is our question to the 18
committee. 19
DR. ORZA: So is there any way to put 20
parameters on a population that would use this as a 21
last resort but would nonetheless need to have that 22
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as an option? Is there a way to do that with the 1
labeling or with the indications? 2
DR. FASHOYIN-AJE: I think Clovis would have 3
to define a population in which the benefit 4
outweighs the risks with the use of rociletinib. 5
That's the job of the applicant. 6
DR. BLUMENTHAL: I agree completely. The 7
other important caveat to note is that this drug 8
wasn't studied in patients who progressed on 9
nivolumab or on docetaxel plus ramucirumab. 10
Furthermore, we don't know what the benefits would 11
be in that patient population. 12
So the proposed indication is for T790M 13
positive patients who have progressed on an EGFR 14
TKI. The other studies, although they were 15
conducted in broader populations like nivolumab 16
versus docetaxel, was an all-comers and has a 17
survival advantage. 18
So the question we are raising is, given 19
that there are known survival advantages for some 20
of these agents, they would be foregoing those 21
agents to potentially go on rociletinib. 22
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DR. ARMSTRONG: Does that answer your 1
question? 2
DR. ORZA: Yes. 3
DR. ARMSTRONG: Great. Dr. Figg? 4
DR. FIGG: So I'm going to give you my take 5
on the drug. I would like to see the company in 6
their phase 3 actually stratify for NAT2. I think 7
that you're going to find that those that are NAT2 8
slow metabolizers are going to be those that have a 9
higher risk of side effects, and thus you need to 10
actually monitor EKGs and blood glucose more 11
closely. So to me, that would be the first thing. 12
I also think that 500 is probably the 13
correct dose, especially if you consider that there 14
is no increasing AUC with increasing dose, so it's 15
hard to say that you're going to have a higher 16
response. The only thing you're going to end up 17
doing is have a higher side effect at some level 18
probably. 19
I'm also very, very concerned about the 20
variability in the pharmacokinetics, which is based 21
upon the GI pH, and there are changes in GI pH that 22
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could alter the plasma concentration substantially. 1
So thus, I really believe that the 500 is better 2
for that. 3
DR. ARMSTRONG: Any other discussion about 4
the risk and benefit? Tito? 5
DR. FOJO: I think we have some trouble with 6
the benefit. It's not clear. To me, it's not as 7
clear as I would like it to be. And it's certainly 8
not clear whether 625 is any better than 500. As I 9
stated before, I think the overwhelming inclination 10
in that is that there's no difference to that. And 11
whether 625 is more toxic than 500, I don't think 12
we know that either, but one would tend to think 13
that it might be. 14
I think we have difficulties with the 15
toxicity, and to be honest, is what I said, which 16
is I don't understand why this drug is being 17
discontinued. I actually think we've focused on 18
QTc prolongation and hyperglycemia, and those are 19
probably not going to be major issues. 20
I mean, even if you look at the sudden 21
deaths, it occurred at 4 and 13 days, not quite 22
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when you would expect, certainly the 4 day, to be a 1
complication of the drug or the metabolite, which 2
had probably not yet accumulated to any great 3
level. And we know, as Dr. Carbone pointed out, 4
that these are generally patients that have 5
complicated diseases and have a lot of other 6
reasons why they might experience a sudden death. 7
So I personally -- the QTc I think is 8
manageable. The consultant was talking about 9
managing potassium and magnesium and all of that, 10
and I think it will be. I think Dr. Figg is right, 11
when we look at the acetylator status, we'll even 12
get a better handle on that. 13
So I think all of that eventually is 14
manageable, but at the present time, we just don't 15
have the data that we would like to have to know 16
really what the risk is and for absolute sure we 17
don't know the difference between 500 and 625. 18
Then maybe the FDA can comment. There 19
seemed to be a suggestion in one of the slides that 20
maybe even less than 500 might be effective. In 21
the data that you showed, it seems to start to drop 22
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off beneath 500, but then there's also the concern 1
that Dr. Carbone pointed out, afatinib is given at 2
a lower dose. I don't think we need to approve 3
another drug at a dose that then gets reduced and 4
where we don't know efficacy. 5
So I think we're missing a lot of 6
information here. I don't know if the FDA wants to 7
comment on the lower dose might even be something 8
that might be -- 9
DR. LIU: So this is Chao Liu from 10
pharmacometrics. If we can go to the FDA 11
presentation, the backup slide number 91. We do 12
have some data showing if we lower exposure from 13
the level at 500-milligram BID, we're probably 14
going to lose efficacy. 15
DR. FOJO: Below 500? 16
DR. LIU: From 500 to the next dose level, 17
say -- 18
DR. FOJO: Which would be 375 maybe. 19
DR. LIU: 375, yes. 20
DR. FOJO: Yes, right. 21
DR. LIU: So this plot is showing the ER 22
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analysis relationship based on the investigator 1
assessed ORR. And in here, there is another 2
formulation, a free-base formulation, where the 3
exposure is lower than the proposed 625 milligram 4
in the HBR formulation, where we could get some 5
information to see if we decreased exposure to 6
lower range, whether or not we have adverse 7
response rates. 8
According to this plot, it seems like if we 9
decreased exposure from the level at 500-milligram 10
BID to lower ranges, we probably are going to lose 11
efficacy. 12
DR. FOJO: But you also start to see how, if 13
we get the acetylator status, you might find that 14
there's a difference there, maybe at 375 in a low 15
acetylator -- I mean a high acetylator would make a 16
difference. A lot of things start to come into 17
play. To their credit, they're doing all of that 18
in this phase 3 trial, so I think we're going to 19
have a lot of answers. 20
DR. LIU: Right. 21
DR. KEEGAN: So I want to make something 22
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clear that's probably difficult to grasp. The 1
acetylator status has no effect on the exposure of 2
the parent compound, which is responsible for all 3
the efficacy. 4
DR. FOJO: Right. 5
DR. KEEGAN: So there's no reason to modify 6
the dose based on the acetylator status if you're 7
trying to preserve the efficacy. The real issue 8
is -- 9
DR. FOJO: Toxicity. 10
DR. KEEGAN: -- is that the toxicity will be 11
increased in the slow acetylators. There's a basal 12
level of toxicity regardless across all patients, 13
rapid, intermediate and slow, but that there's a 14
higher risk in the rapid acetylators. But this is 15
not a risk that can be mitigated by dose modifying 16
the slow acetylators because you're eliminate the 17
efficacy. 18
DR. FOJO: Yes, I understand that the 19
toxicity plays into ability to continue these type 20
of therapies, which I think all of us would agree 21
is a drug therapy that has to be continued to be 22
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effective and to have that long duration of 1
response. 2
I think the randomized phase 3 trial is 3
good. It's going to give a lot of information that 4
we don't have today that we wish we had today, is 5
my take on all of this. 6
DR. ARMSTRONG: Any other discussion 7
regarding the risk-benefit analysis? Sure. 8
DR. MENEFEE: Yes, Michael Menefee, Mayo 9
Clinic. I echo the comments that have already been 10
made. I think when we talk about benefit-risk 11
ratio, it really comes down to somewhat of timing 12
issues. I think the landscape of the management of 13
non-small cell lung cancer has changed a little bit 14
since the drug application would have been 15
submitted, and that has an impact on how I perceive 16
benefit-risk for this particular patient 17
population. 18
DR. FOJO: Yes, can I just -- 19
DR. ARMSTRONG: Go ahead. 20
DR. FOJO: They were going to tell us after 21
the break how many patients were in that waterfall 22
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plot, which I think is probably about two-thirds of 1
the patients. 2
DR. ARMSTRONG: Do you have the numbers for 3
the waterfall plot? Thank you. 4
DR. ROLFE: So of the 170 patients in the 5
625-milligram efficacy dosing group, 145 were in 6
the waterfall plot. The 25 who were not in the 7
waterfall plot either had no non-target lesion at 8
baseline, as measured by the independent reviewers, 9
or no subsequent restaging scans, so they 10
discontinued before the next scan. 11
Eighty-seven patients in that waterfall plot 12
had a best target lesion reduction of 30 percent or 13
more, and of those, 55 had a confirmed response. 14
Dr. Camidge is going to give some additional 15
clinical context here. 16
DR. CAMIDGE: So I think what you correctly 17
pointed out is that a waterfall is that first 18
snapshot, the best response. It doesn't have to 19
include a confirmed response, and so a lot of what 20
we're seeing here is the ones that weren't 21
confirmed. Most of them were due to progression, 22
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sometimes within the central nervous system, which 1
was some aspect that hasn't been brought up in 2
terms of the penetration of this drug into the 3
brain. 4
A very high proportion of patients had a 5
history of CNS metastases. But what we weren't 6
really seeing was people coming off because of 7
adverse events. So I hope that clarifies your 8
question. 9
DR. FOJO: Yes, it does. 10
DR. ARMSTRONG: Thank you for the extra 11
information. 12
If there's no other discussion regarding the 13
risk-benefit, then I think we'll move to the vote. 14
Do you want to go ahead and read the vote question? 15
DR. FASHOYIN-AJE: The FDA seeks the 16
committee's advice on whether the results of the 17
randomized clinical trial, TIGER-3, should be 18
submitted before FDA renders a regulatory decision 19
on the application. Please vote. 20
DR. ARMSTRONG: If there isn't any further 21
discussion about this question, we'll begin the 22
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voting process. 1
DR. ORZA: Just a point of information. 2
DR. ARMSTRONG: Sure. 3
DR. ORZA: The results of this study are due 4
in 2018. Is that correct? 5
DR. ROLFE: Enrollment is scheduled to 6
complete in the second half of 2018, probably the 7
last quarter of 2018. The analysis is driven by 8
number of events observed, and that time point will 9
most probably occur right at the end of 2018 or in 10
the first half of 2019. 11
DR. FOJO: And just to clarify, a yes will 12
mean FDA should get this data before it makes a 13
decision. 14
DR. ARMSTRONG: Correct. 15
DR. FOJO: Okay. 16
DR. PAZDUR: Yes, means delay it. 17
DR. FOJO: Yes means delay. 18
DR. ARMSTRONG: Okay? I'm going to read the 19
question verbatim, and then go over the directions. 20
The question we're asking to vote on is, should the 21
results of the randomized clinical trial, TIGER-3, 22
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be submitted before the FDA makes a regulatory 1
decision on this application? 2
We'll be using electronic voting system for 3
this meeting. Once we begin the vote, the buttons 4
will start flashing and will continue to flash even 5
after you've entered your vote. Please press the 6
button firmly that corresponds to your vote. 7
If you are unsure of your vote, or you wish 8
to change your vote, you may press the 9
corresponding button until the vote is closed. 10
After everyone has completed their vote, the vote 11
will be locked in. The vote will then be displayed 12
on the screen. 13
The DFO will read the vote from the screen 14
into the record. Next, we will go around the room, 15
and each individual who voted will state their name 16
and vote into the record. You can also state the 17
reason why you voted as you did if you want to. 18
Any questions? 19
(No response). 20
DR. ARMSTRONG: If not, please press the 21
button on your microphone that corresponds to your 22
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vote. You'll have approximately 20 seconds to 1
vote. Please press the button firmly. After 2
you've made your selection, the light may continue 3
to flash. If you're unsure of your vote, or you 4
wish to change your vote, please press the 5
corresponding button again before the vote is 6
closed. No questions? 7
(Vote taken.) 8
LCDR SHEPHERD: For the record, the vote is 9
12 yes; 1 no; no abstain; no no voting. 10
DR. ARMSTRONG: Now that the vote is 11
complete, we'll go around the table and have 12
everyone who voted state their name, vote, and if 13
you want to, you can state the reason why you voted 14
as you did into the record. 15
DR. MAGER: Don Mager, the University of 16
Buffalo. I voted yes. I think it's quite clear 17
from the discussion today that the high variability 18
and overlapping exposures really makes any attempt 19
at a dose response an illusion. 20
I think the FDA has done a remarkable job at 21
examining the exposure response relationship, and 22
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that the dose that's proposed is really not 1
supported by the data. The lower bounds of a 2
single point estimate from a single-arm non-3
randomized study really doesn't justify the dose 4
that's been chosen. 5
In my question earlier about risk 6
management, again, I don't feel that they quite 7
have it. But given that we won't have NAT2 8
genotyping, we have to have minimally that or some 9
sort of therapeutic drug monitoring I think to 10
assess given the very tight relationship, actually, 11
between some of the exposure response in terms of 12
the adverse events. 13
I don't think the confirmatory trial will 14
necessarily give us any further information about 15
the dose. I think that's pretty well answered, but 16
I do think that it will provide additional efficacy 17
data that would be very useful in assessing the 18
risk-benefit. 19
DR. ARMSTRONG: Thank you. Dr. Orza? 20
Dr. Szabo? 21
DR. SZABO: Eva Szabo, NCI. So I voted yes. 22
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Though benefit-risk to me was not as clear as I 1
would like it at this stage, there are multiple 2
other drugs in the space currently. So how this 3
drug would be used currently was not clear to me, 4
and there are some very definite risks associated 5
with it. So I just felt that we need some more 6
information. 7
DR. ARMSTRONG: Thank you. Ms. Gillespie? 8
MS. GILLESPIE: Terry Gillespie. I voted 9
yes, and I'm going to abstain. 10
DR. ARMSTRONG: Save your voice. 11
DR. ORZA: Michele Orza. I voted no, which 12
is unusual for me because I'm a big fan of 13
outcomes. I would like to see the results of the 14
study, but I felt that -- I also voted very 15
narrowly on the question. 16
I think that 2018, 2019 is a long time to 17
wait, which is not to say that I would vote to 18
approve it today for accelerated approval. I think 19
there are a lot of questions that have to be worked 20
out. 21
I'm not confident that the study, even when 22
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it's done, will give us a lot of the answers we're 1
looking for. I'm concerned that there is a 2
population that could be benefiting from this in 3
the meantime and we need to do some more work to 4
identify that group and consider accelerated 5
approval for them. 6
DR. FIGG: William Figg, National Cancer 7
Institute. First, let me say that the public 8
comments from the individuals that had received the 9
drug, or are receiving the drug, was very 10
compelling. With that said, I did vote yes. And I 11
think it's just simply there are too many 12
unanswered questions that need to be addressed. I 13
am also concerned that the current phase 3 that is 14
ongoing doesn't answer all the necessary questions. 15
DR. NOWAKOWSKI: Grzegorz Nowakowski, Mayo 16
Clinic. I voted yes for the reasons, which were 17
already mentioned here. I think that the degree of 18
benefit over the standard therapy was not clear for 19
the data presented and the quality of the data were 20
not fully supporting it. More so though, I was 21
more concerned about the safety profile with the 22
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cardiac toxicity and the hyperglycemia. Also, the 1
fact that the dose was not well defined, it is 2
difficult to move this compound to move forward 3
with 500 or 625. 4
I think there's also an elephant in the 5
room, which is osimertinib. Although it was going 6
to accelerated approval, so we should not consider 7
this to be available, per FDA standards, it appears 8
to be less toxic in this space. So for this 9
reason, I think more data is needed on this very 10
promising compound, and that's why I voted yes. 11
DR. FOJO: Tito Fojo. I voted yes, and I've 12
stated my opinion. I do think that this is a drug 13
that has activity, yes. This is a drug whose 14
toxicity will be manageable, yes. I would say that 15
I'm concerned, with you, that it goes to 2018, 16
though that will be here unfortunately sooner than 17
we realize. 18
But maybe the company ought to go back to 19
the FDA and say, you know what, you were right; 500 20
is the same, why don't we just get rid of that 21
third arm and do a 600 patient trial, 300 with 22
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getting 500 or the few that have gotten 625 now 1
against 300 with chemotherapy, and you'll get done 2
sooner, and go forward with 500. Worry about 625 3
later. Get it approved sooner at 500. 4
DR. ARMSTRONG: Deb Armstrong. I voted yes 5
as well. I think we have the well-documented and 6
discussed issues about toxicity, dosing, and the 7
metabolism issue that I think has not been 8
completely addressed. But I guess, primarily, the 9
requirement for accelerated approval to have 10
superiority to current treatment I don't think has 11
been shown by the data that we have at this point 12
in time. 13
DR. ROTH: Bruce Roth from Wash U. I'd 14
agree with Deb. I did not think it met the 15
criteria to be accepted as superior to existing 16
therapy. And as Dr. Nowakowski also said, I think 17
that while we have the luxury of not considering 18
the osimertinib data, if this was approved today, 19
the same is not true of a practicing physician. 20
If you were going to prescribe a drug in a 21
T790 patient, would you pick the drug that had a 22
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59 percent response rate, a duration of response at 1
12.8 months, and a 2.7 percent incidence of QT 2
prolongation beyond 60 milliseconds, or would you 3
pick the 30 percent response rate with a median 4
duration of response of 9 months, where you have to 5
have a risk mitigation strategy for the QTc 6
prolongation, and half your patients are going to 7
be on an anti-hyperglycemic agent as well? 8
So I think, for me, it just did not meet the 9
criteria for accelerated approval. 10
DR. MENEFEE: I voted yes for many of the 11
reasons that have already been mentioned. I've 12
actually kind of seen the scenario that Dr. Roth 13
has just mentioned in clinical practice with 14
medullary thyroid cancer, where we have vandetanib 15
and cabozantinib, two drugs that were similar and 16
in the same space, and we don't know exactly how 17
best to use them, and it's not a good situation to 18
be in. 19
So it would be helpful to have studies that 20
were better designed that are going to help the 21
practitioner know exactly how to use the drug. And 22
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I share Dr. Figg's concern that TIGER-3 is 1
unfortunately not going to answer those questions 2
in terms of how to best use the drug in clinical 3
practice. 4
But I do think it's a good drug. I think 5
it's active. It's clearly helping some patients. 6
And I think a lot of the issues in terms of dosing 7
and toxicity can be managed, but we need better 8
study designs that are going to be useful for 9
practitioners. 10
DR. RINI: Brian Rini, Cleveland Clinic. I 11
voted yes. Similar to others, it's clearly an 12
active drug. Noting the response rate, the 13
waterfall shows activity, notwithstanding the 14
limitations that have been pointed out, and I think 15
a number of compelling patient and clinical 16
anecdotes from the treating physicians in the room 17
that, clearly, there's activity to this drug. 18
For me, it didn't pass the standard of being 19
clearly superior to the standard therapy at 20
present, noting all the limitations of cross-trial 21
comparisons, which are flawed, but which we've been 22
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doing all day because they're necessary. 1
Again, there wasn't really objective 2
evidence of clinical benefit, and that's what I 3
struggled with. I don't doubt there was. Again, 4
we heard it from the anecdotes that were mentioned, 5
but we weren't presented any data of that, of 6
quality of life, of narcotic use, of symptom 7
control, or something that would convince us that 8
this response rate, whatever the estimate ends up 9
being, is beneficial to patients. And again, I 10
don't doubt that it is, I just don't think that 11
evidence was presented. 12
With regard to dose, again, I agree with the 13
others it's a hugely complex issue. I think the 14
major problem, and this is not a problem just for 15
Clovis but for all of us who develop drugs, is we 16
really don't individualize dose. We pick an 17
average dose based on a small number of patients, 18
and then we try to shoehorn people into that dose. 19
And for some, it's probably too low, and for 20
others, it's too high. And we just sort of hope 21
for the best as we develop these drugs, and it's 22
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really not a smart way to do it. And again, that's 1
not a comment to this particular company but for 2
anybody in the room who develops drugs. 3
Having said that, I think the comments about 4
the ongoing phase 3 are very pertinent. So I would 5
either pick one dose, and you can pick 625 or 500, 6
just pick one dose and adequately test it, or power 7
the study for each of the doses. Power it to 8
compare. 9
This is not just from a regulatory 10
standpoint, but you want people to use your drug at 11
the end of the day, right, if it ultimately gets 12
approved. So you want data to say that the 13
benefit-risk is more favorable with one or the 14
other, and otherwise, you're going to end up just 15
with some underpowered data that won't really be 16
informative. And I think that's a shame to waste 17
those resources. 18
DR. RAJAN: Arun Rajan. So I voted yes. I 19
do believe, like all clinicians in the room, that 20
we should have multiple options at our disposal. 21
It's always better. And clearly, we have heard 22
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from patients and physicians that this drug does 1
benefit patients clinically. But having said that, 2
I think the risk-benefit ratio is informed by other 3
options that are available. And had there been no 4
option for T790M positive non-small cell lung 5
cancer, maybe I would have voted differently. 6
So I think there are unanswered questions. 7
There is an ongoing study. I really hope the 8
sponsor can work with the FDA to try and at least 9
attempt to amend the ongoing study to answer some 10
of these questions, so that in two years from now, 11
we're not in the same position where some of these 12
questions have to be debated. 13
But I think the main crux for answering yes 14
was that there is an alternative at the moment, 15
which, at least on the face of it, appears to be 16
safer and has a higher response rate. Thank you. 17
DR. COLE: Bernard Cole, University of 18
Vermont. I voted yes largely for the same reasons 19
that have been mentioned around the table. As a 20
biostatistician, member of the committee, I focus 21
my attention primarily on the statistical evidence. 22
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Of course, here we are trying to make two bridges. 1
The first is the bridge from a single-arm 2
study to a benefit, and the second is the bridge 3
from a surrogate endpoint to a clinically 4
meaningful outcome, such as progression-free 5
survival or overall survival advantage. And 6
unfortunately, the statistical evidence along these 7
lines was rather weak and just simply not able to 8
make that bridge. 9
I was very moved by the statements from the 10
audience and the patients who have undergone the 11
therapy, and I'm very hopeful that the phase 3 12
study will show a benefit that is a provable 13
benefit. 14
Adjournment 15
DR. ARMSTRONG: Thank you. I'd just like to 16
echo that the statements from the audience really 17
are quite moving. And this is a drug that I think 18
we would like to know where the right place is to 19
use this drug, and I don't think we have that 20
information yet. 21
We'll now adjourn the meeting. Panel 22
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members, please remember to drop off your name 1
badge at the registration table on your way out so 2
that they may be recycled. Thank you to everyone. 3
(Whereupon, at 12:25 p.m., the meeting was 4
adjourned.) 5
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