Special Thanks! Exchange_Slides_June3.pdf · response 3 (1.3) 1 (0.4) 2 (1.3) 1 (0.6) 2 (2.4) 0 0 1 (1.3) 0 0 0 0 Partial response 97 (42.7) 111 (45.5) 86 (53.8) 102 (58.3) 52 (62.7)

Special Thanks!

Presented by

Supported by an independent educational grant from AstraZeneca

EGFR-MUTATED METASTATIC NSCLC: Opening Remarks

Suresh S. Ramalingam, MDProfessor of Hematology and Medical Oncology

Assistant Dean for Cancer Research Emory University School of Medicine

Roberto C. Goizueta Chair for Cancer Research Deputy Director, Winship Cancer Institute of Emory University

Atlanta, GA

Disclosures: Dr. Ramalingam has disclosed he is a consultant for Amgen, Ariad, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Genentech, Lilly, Merck.

Non-small Cell Lung Cancer

• Improvements in outcomes have been achieved for all stages of NSCLC

• Early detection will shift the proportion of patients to earlier stages of the disease

• Targeted therapies and immune checkpoint inhibitors provide robust benefits

• Molecular selection allows for personalized therapy

Recently FDA-Approved Drugs for NSCLC

• EGFR• Osimertinib• Necitumumab

• ALK• Alectinib• Brigatinib• Ceritinib

• ROS1• Crizotinib

• Other Targeted Therapy• Ramucirumab

• Immune Checkpoint Inhibitors• Nivolumab

• Pembrolizumab

• Atezolizumab

FDA Prescribing Information.

Hirsch FR, et al. Lancet. 2016.

Mutation Landscape for Lung Adenocarcinoma

Treatment Algorithm for Advanced NSCLC

*Bevacizumab/necitumumab added when appropriate

Stage IV NSCLC

EGFR, ALK or ROS1

Targeted therapy

PD-L1 ≥50%No targetable

mutation

Pembrolizumab

PD-L1 <50%No targetable

mutation

Platinum-based chemotherapy*

Molecular testing for EGFR, ALK,

ROS1

IHC for PD-L1 Expression

NCCN NSCLC Guidelines Version 6.2017.

EGFR Mutation

• EGFR is Predictive and Prognostic

• Predictive

• If you give EGFR inhibitor to a patient with EGFRmutation they respond well. Without mutation, these agents don’t work well.

• Prognostic

• Patients with EGFR mutation do better than patients without EGFR mutation.

EGFR Mutated NSCLC

• ~10-15% of all NSCLC in the United States

• Exon 19 and 21 mutations account for nearly 90% of all EGFR mutations

• EGFR TKI is superior to chemotherapy for patients with EGFR activating mutation

• Exon 20 insertion is not sensitive to EGFR TKI therapy

• Resistance to therapy emerges in approximately 9-13 months with 1st/2nd generation TKIs


Should Specific EGFR Mutation Type (Exon 19 vs. 21)

Drive Treatment Selection?Moderator: Mark G. Kris, MD, FACP, FACCP

Chief, Thoracic Oncology ServiceMemorial Sloan-Kettering Cancer Center

Professor of Medicine, Cornell University Medical CollegeNew York, NY

DEBATE 1

Case • A 72 year old man, born in Cleveland, developed hip pain

• He is a 50 pack year smoker who quit 7 years ago

• A chest CT revealed bilateral lung and multiple lesions in ribs

• A pelvis MRI revealed bony lesions consistent with metastases

• His exam is normal

• KPS 70%

• A core needle biopsy of a lung lesion revealed adenocarcinoma

• Additional cores have been submitted for multiplex NGS testing.

• Immunohistochemistry was negative for L858R, ALK, and PD-L1 but positive for a 15 bp deletion in EGFR exon 19 (EGFR-E746; clone 6B6)

AUDIENCE VOTE

A. No, Evidence is Lacking

B. Yes, Specific Mutations Should Guide TKI Selection

SHOULD SPECIFIC EGFR MUTATION TYPE

(EXON 19 VS. 21) DRIVE TREATMENT SELECTION?

Tony S.K. Mok, BMSc, MD, FRCPCProfessor and Chair

Department of Clinical OncologyThe Chinese University of Hong Kong

Hong Kong, China

POINT: No, Evidence is Lacking

COI Disclosures

Grant/Research Support AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, SFJ Pharmaceuticals, Roche, Merck Sharp & Dohme, Clovis Oncology, Bristol-Myers Squibb, Eisai, Taiho

Speaker’s Fees AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Bristol-Myers Squibb, Taiho

Major Stock Shareholder Sanomics Ltd.

Advisory Board AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Clovis Oncology, Merck Serono, Merck Sharp & Dohme, Novartis, SFJ Pharmaceutical, ACEA Biosciences, Vertex Pharmaceuticals, Bristol-Myers Squibb, geneDecode, OncoGenex, Celgene, Ignyta, Cirina

Board of Directors International Association for the Study of Lung Cancer (IASLC), Chinese Lung Cancer Research Foundation Ltd., Chinese Society of Clinical Oncology (CSCO), Hong Kong Cancer Therapy Society (HKCTS)

NoNo?

No!!!

19 = 21?

Basic Biology of EGFR Mutation

Exon 19 deletion: commonly 15 base-pair delete = loss of 5 amino acidExon 21 point mutation: L858R, change of single nucleotide = change of 1 amino acid

Paez JG, et al. Science. 2004.

French Cooperative Thoracic Intergroup (IFCT) Database (N=1,837)

All patients (N=1,837)

Exon 18 (N=102)

Exon 19 (N=931)

Exon 20 (N=102)

Exon 21 (N=702)

P

Histology (N=1,837)

Squamous 23 (1.3%) 0 14 (1.5) 2 (2.0) 7 (1.0) NS

Adenocarcinoma 1563 (85.1%) 87 (85.3) 791 (85.0) 88 (86.3) 597 (85.0)

Large Cell 26 (1.4%) 3 (2.9) 14 (1.5) 1 (1.0) 8 (1.1)

Other 225 (12.2%) 12 (11.8) 112 (12.0) 11 (10.8) 90 (12.8)

Smoking History (N=1,158)

Smoker 142 (12.3%) 9 (20%) 68 (11.5%) 10 (19.2%) 55 (11.8%) 0.002

Former smoker 323 (27.9%) 19 (42.2%) 152 (25.6%) 17 (32.7%) 135 (28.8%)

Never-smoker 693 (59.8%) 17 (37.8%) 373 (62.9%) 25 (48.1%) 278 (59.4%)

Personal history of cancer (N=1,177)

Yes 226 (19.2%) 9 (18.4) 105 (17.5) 11 (19.6) 101 (21.4) NS

No 951 (80.8%) 40 (81.6) 494 (82.5) 45 (80.4) 372 (78.6)

Leduc C, et al. Ann Onc. 2016.

French Cooperative Thoracic Intergroup (IFCT) Database

PFS and OS with First-line EGFR TKI in Exon 19 and 21

Leduc C, et al. Ann Onc. 2016.

Meta-analysis of First Line TKI vs. Chemotherapy: Exon 19 vs 21

Trial HR 95% CI HR 95% CI

Exon 19 deletions Exon 21 L858R substitution

ENSURE 0.20 0.12 to 0.33 0.54 0.32 to 0.91

EURTAC 0.27 0.17 to 0.43 0.53 0.29 to 0.97

LUX-Lung 3 0.28 0.18 to 0.44 0.73 0.46 to 1.16

LUX-Lung 6 0.20 0.13 to 0.32 0.32 0.19 to 0.54

NEJ002 0.24 0.15 to 0.38 0.33 0.20 to 0.54

OPTIMAL 0.13 0.07 to 0.24 0.26 0.14 to 0.48

WJTOG 3405 0.42 0.26 to 0.66 0.69 0.44 to 1.07

All 0.24 0.20 to 0.29 0.48 0.39 to 0.58

Never-smoker Current or former smoker

Lee CK, et al. J Clin Oncol. 2015.

19 May Not be Exactly the Same as 21

Does it really drive our treatment

decision?

WJOG5108L: Gefitinib vs. ErlotinibResponse to Treatment

Number of Patients (%)

Full-Analysis Set EGFR Mutation-Positive

Ex19del L858RUncommon

mutationWild Type

ResponseErlotinib(n=227)

Gefitinib(n=244)

Erlotinib(n=160)

Gefitinib(n=175)

Erlotinib(n=83)

Gefitinib(n=78)

Erlotinib(n=67)

Gefitinib(n=80)

Erlotinib(n=7)

Gefitinib(n=12)

Erlotinib(n=41)

Gefitinib(n=43)

Completeresponse 3 (1.3) 1 (0.4) 2 (1.3) 1 (0.6) 2 (2.4) 0 0 1 (1.3) 0 0 0 0

Partial response 97 (42.7) 111 (45.5) 86 (53.8) 102 (58.3) 52 (62.7) 51 (65.4) 31 (46.3) 45 (56.3) 3 (42.9) 3 (25.0) 5 (12.2) 1 (2.3)

Stable disease 71 (31.3) 61 (25.0) 47 (29.4) 40 (22.9) 22 (26.5) 14 (17.9) 22 (32.8) 19 (23.8) 2 (28.6) 5 (41.7) 17 (41.5) 14 (31.6)

Progressive disease 46 (20.3) 61 (25.0) 17 (10.6) 25 (14.3) 4 (4.8) 10 (12.8) 10 (14.9) 12 (15.0) 1 (14.3) 3 (25.0) 17 (41.5) 25 (58.1)

Not evaluable 10 (4.4) 10 (4.1) 8 (5.0) 7 (4.0) 3 (3.6) 3 (3.8) 4 (6.0) 3 (3.8) 1 (14.3) 1 (8.3) 2 (4.9) 3 (7.0)

Objective responseP

100 (44.1) 112 (45.9) 88 (55.0) 103 (58.9) 54 (65.1) 51 (65.4) 31 (46.3) 46 (57.5) 3 (42.9) 3 (25.0) 5 (12.2) 1 (2.3)

.686 .476 .965 .174 .419 .079Disease Control RateP

171 (75.3) 173 (70.9) 135 (84.4) 143 (81.7) 76 (91.6) 65 (83.3) 53 (79.1) 65 (81.3) 5 (71.4) 8 (66.7) 22 (53.7) 15 (34.9)

.279 .517 .113 .744 .829 .083

Urata Y, et al. J Clin Oncol. 2016.

WJOG5108L: Gefitinib vs. Erlotinib

Urata Y, et al. J Clin Oncol. 2016.

Pooled Analysis of LUX Lung 3 and 6: OS Benefit Only in Exon 19

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Time (months) Time (months)

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

1.0

0.8

0.6

0.4

0.2

0

Esti

mat

ed O

S p

rob

abili

ty

236 230 223 217 202 192 173 160 145 131 117 90 50 38 22 6 1 0

119 113 103 95 87 72 63 55 51 43 38 27 14 9 1 1 0 0AfatinibChemo

No of patients

183 181 167 154 141 128 111 91 80 70 64 51 27 20 11 3 0 0

93 86 82 78 75 69 61 55 50 40 32 25 20 14 9 4 1 0AfatinibChemo

No of patients

Del19Afatinibn=236

Chemo n=119

Median, months 31.7 20.7

HR (95%CI), P-value

0.59 (0.45–0.77), P=.0001

L858RAfatinibn=183

Chemo n=93

Median,months 22.1 26.9

HR (95%CI), P-value

1.25 (0.92–1.71), P=.1600

Exon 19 Exon 21

1.0

0.8

0.6

0.4

0.2

0

Esti

mat

ed O

S p

rob

abili

ty

Yang JC, et al. Lancet Oncol. 2015.

Confounding Factors

1. Cross over rate to second line TKI

2. Cross over rate to second line chemo

3. Portion of patients who had treatment beyond progression

4. Incidence of CNS metastasis

LUX Lung 7: Study Design

• Treatment beyond progression allowed if deemed beneficial by investigator

• RECIST assessment performed at Weeks 4, 8 and every 8 weeks thereafter until Week 64, and every 12 weeks thereafter

ECOG PS=Eastern Oncology Cooperative Group performance status; HRQoL=health-related quality of life; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; RECIST=Response Evaluation Criteria In Solid Tumors; TTF=time to treatment failure

Afatinib 40 mg once daily†

Gefitinib 250 mg once daily

Primary endpoints:

• PFS (independent)• TTF• OS

Secondary endpoints:• ORR• Time to response• Duration of response• Duration of disease control• Tumor shrinkage• HRQoL• Safety

*Central or local test†Dose modification to 50, 30, 20 mg permitted in line with prescribing information

1:1

• Stage IIIB/IV adenocarcinoma of the lung

• EGFR mutation (Del19 and/or L858R) in the tumor tissue*

• No prior treatment for advanced/metastatic disease

• ECOG PS 0/1

Stratified by •Mutation type (Del19/L858R) • Brain metastases (present/absent)

Park K, et al. Lancet Oncol. 2016.

PFS by Independent Review

P=.0176

P=0.018427%

18%

8%

15%

Time (months)

Esti

mat

ed P

FS p

rob

abili

ty

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33 36 39 42

Afatinib(n=160)

Gefitinib(n=159)

Median PFS (months) 11.0 10.9

HR (95% CI) 0.73 (0.57–0.95)

P value 0.0165

No. of patients

Afatinib

Gefitinib

160 142 112 94 67 47 34 27 21 13 6 3 1 0 0159 132 106 83 52 22 14 9 7 5 3 3 1 1 0


LUX Lung 7: OS in the Overall Population and Patient Subgroups

Median follow-up: 42.6 months (as of 08 April 2016)

Factors N HR (95% CI)

Total 319 0.86 (0.66–1.12)

EGFR mutation L858R

Del19

133

186

0.92 (0.62–1.36)

0.83 (0.58–1.17)

Brain metastases

Absent

Present

268

51

0.81 (0.61–1.07)

1.16 (0.61–2.21)

Baseline ECOG PS

0

1

98

221

1.32 (0.80–2.18)

0.75 (0.55–1.02)

Gender Male

Female

122

197

0.80 (0.53–1.21)

0.88 (0.63–1.24)

Age <65 years

≥65 years

177

142

0.66 (0.46–0.94)

1.22 (0.82–1.81)

Race Non-Asian

Asian

137

182

0.78 (0.52–1.17)

0.95 (0.67–1.33)

Smoking hx Never smoked

Light ex-smoker

Other current/ex-smokers

212

40

67

0.92 (0.67–1.28)

1.13 (0.55–2.28)

0.63 (0.36–1.11)

Afatinib(n=160)

Gefitinib(n=159)

Median, mo 27.9 24.5

HR (95% CI)P-value

0.86 (0.66–1.12)0.2580

Favors afatinib Favors gefitinib41/4 1

156 153 148 139 125 111 104 94 81 74 61 50 36 30 12 2 0

153 148 142 133 119 105 90 80 71 62 56 48 44 27 7 0 0

No. at risk:

Afatinib

Gefitinib

1.0

0.8

0.6

0.4

0.2Esti

mat

ed O

S p

rob

abili

ty

Time (months)

0 3 6 9 12 1815 21 24 27 30 33 36 39 42 45 48 51

0

160

159

Paz-Ares L, et al. Ann Oncol. 2017.

1/16 16

OS By EGFR Mutation Exon 19 vs. 21Del19

Afatinibn=93

Gefitinibn=93


HR (95% CI)P-value

0.83 (0.58–1.17).2841

L858R

Afatinibn=67

Gefitinibn=66


HR (95% CI)P-value

0.91 (0.62–1.36).6585

1.0

0.8

0.6

0.4

0.2

0

Esti

mat

ed O

S p

rob

abili

ty

No. at risk:AfatinibGefitinib

67 65 57 43 33 24 15 10 166 62 54 39 28 23 19 10 0

0 6 12 18 24 30 36 42 48

Time (months)Time (months)

1.0

0.8

0.6

0.4

0.2

0

Esti

mat

ed O

S p

rob

abili

ty

No. at risk:

0 6 12 18 24 30 36 42 48

93 88 82 68 61 50 35 20 193 86 79 66 52 39 29 17 0

AfatinibGefitinib

Paz-Ares L, et al. Ann Oncol. 2017.

ARCHER 1050: Randomized Phase III Study Dacomitinib vs. Gefitinib

Advanced NSCLC• Adenocarcinoma• EGFR exon 19/21

mut+• First-line

treatment• PS 0-1

RANDOMIZE

Dacomitinib 45mg daily

Gefitinib 250mg daily

1

1

N= 440 patients

Primary endpoint in PFS

14.8 vs 9.5 months

Stratification

-Race

-Exon 19 v 21

ASCO 2017June 6, 2017

www.clinicaltrials.gov; NCT01774721.

AURA 3 Study Design

T790M+

(N=420)

T790M- Not eligible for enrollment

Osimertinib(80 mg PO daily)

Platinum-based doublet chemotherapy* every

3 weeks

Central testing of biopsy

samples at time of EGFR TKI resistance

Randomize patients 2:1

*Pemetrexed 500 mg/m2 + carboplatin AUC5 or Pemetrexed 500 mg/m2 + cisplatin 75 mg/m2

AUC5=area under the plasma concentration–time curve 5 mg/mL−1 per minute;EGFRm+=EGFR mutation-positive; EGFR-TKI=EGFR tyrosine kinase inhibitor;NSCLC=non-small cell lung cancer; T790M+=T790M mutation-positive; T790M-=T790M mutation-negative

Primary endpoint:

PFS

Mok TS, et al. N Engl J Med. 2017.

• Analysis of PFS by BICR was consistent with the investigator-based analysis: HR 0.28 (95% CI 0.20, 0.38), P<0.001; Median PFS 11.0 vs. 4.2 months.

Population: intent-to-treatProgression-free survival defined as time from randomisation until date of objective disease progression or death; calculated using the Kaplan-Meier approach. Progression included deaths in the absence of RECIST progression.Tick marks indicate censored data; CI, confidence interval

AURA 3 Primary Endpoint:PFS by Investigator Assessment

Exon 19 AZD9291 80 mg191 89 (46.6) 0.34 0.24, 0.46

Chemotherapy88 69 (78.4)

L858R AZD9291 80 mg83 47 (56.6) 0.46 0.30, 0.71


Missing/

unknownAZD9291 80 mg

5 4 (80.0) NC NC



Exon 19 May Be Different From Exon 21

However, the Choice of Therapy Would Have No Impact on

Independent Outcome!

Should EGFR Mutation Type Drive Treatment Decision?

NO!!!!

Lecia V. Sequist, MD, MPHAssociate Professor of Medicine

Harvard Medical School Massachusetts General Hospital Cancer Center

Boston, MA

COUNTERPOINT: Yes, Specific Mutations Should Guide TKI Selection

Disclosures

• Consultant for ARIAD, AstraZeneca, Bristol-Myers Squibb, and Genentech.

Not all EGFR mutations are the same

I grant the data are not perfect, but…

Predictive vs. Prognostic Biomarker

Mukohara T. Breast Cancer (Dove Med Press).2015.

IPASS: EGFR+ Prognostic and Predictive


Treatment by

subgroup interaction

test,p<0.0001

EGFR Deletion 19 Mutation is Prognostic

…is it also predictive?Jackman DM, et al. Clin Cancer Res. 2006; Riely GJ, et al. Clin Cancer Research. 2006.

LUX-Lung 3 and 6: Design

Randomization2:1

• Stage IIIB/IV Adenocarcinoma of the lung• Presence of EGFR mutation in the tumor tissue*• No prior treatment with chemotherapy for advanced/metastatic disease or EGFR inhibitors• ECOG PS 0 or 1

Afatinib 40mg once

daily

LUX-Lung 3:Cisplatin + pemetrexed

up to 6 cyclesLUX-Lung 6:

Cisplatin + gemcitabineup to 6 cycles

Primary endpoint: PFS (independent review)Secondary endpoints: ORR, DCR, OS, PRO, safety

*EGFR29:19 deletions in exon 19, 3 insertions in exon 20, L858R, L861Q, T790M, G719S, G719A, G719C (or G719X), S768I Sequist LV, et al. J Clin Oncol. 2013; Wu YL, et al. Lancet Oncol. 2014.

Stratification by EGFR mutation type: Del 19/L858R/otherand by race (LUX-Lung 3 only): Asian/non-Asian

LUX-Lung 3 and 6: OS in Common Mutations

Yang JC, et al. Lancet Oncology. 2015.

Yang JC, et al. Lancet Oncol. 2015.

Erlotinib/Gefitinib Meta-analysis

Lee CK, et al. JNCI 2017.

LUX Lung 7: Study Design

• Treatment beyond progression allowed if deemed beneficial by investigator

• RECIST assessment performed at Weeks 4, 8 and every 8 weeks thereafter until Week 64, and every 12 weeks thereafter

Afatinib 40 mg once daily†

Gefitinib 250 mg once daily

Primary endpoints:

• PFS (independent)• TTF• OS

Secondary endpoints:• ORR• Time to response• Duration of response• Duration of disease control• Tumor shrinkage• HRQoL• Safety

*Central or local test†Dose modification to 50, 30, 20 mg permitted in line with prescribing information

1:1

• Stage IIIB/IV adenocarcinoma of the lung

• EGFR mutation (Del19 and/or L858R) in the tumor tissue*

• No prior treatment for advanced/metastatic disease

• ECOG PS 0/1

Stratified by •Mutation type (Del19/L858R) • Brain metastases (present/absent)


LUX Lung 7: Showed No Diff OS

Median OS: Afatinib GefitinibExon 19 del 30.7 m 26.4 mL858R 25.0 m 21.2 m

Resp Rate:Exon 19 del 73% 66%L858R 66% 42%

Park K, et al. Lancet Oncol. 2016; Paz-Ares L, et al. Ann Oncol. 2017.

Importantly….

• In LL7 toxicity patterns differed with more diarrhea, rash for afatinib and more ALT/AST ↑ for gefitinib

• An equal number of patients dropped out of each arm for toxicity (n=10 in each arm)

• QoL improvements were similar in each arm


Structure of EGFR protein

Eck MJ, Yun CH. Biochem Biophys Acta. 2010; Kannan S, et al. Sci Rep. 2017.

wildtype

L858R

Del 19

• All have quinazoline core

• Afatinib has an acrylamide group that leads to its covalent binding

• Both gefitinib and afatinib are halogenated, which may affect its interaction with water molecules within the ATP binding site

Chiba M, et al. BMC Cancer. 2017.

Each Drug Interacts with the EGFR Receptor in a Unique Manner

AfatinibErlotinibGefitinib

ATP Pocket is Affected by TKI and Mutation

Wildtype

L858R

Del 19

Afatinib

Gefitinib

Erlotinib

Kannan S, et al. Sci Rep. 2017.

Conclusion

• Is there perfect evidence that afatinib is the best choice for exon 19 deletion mutant patients?

NO• Is there a pattern of data that suggest there may be

a benefit for afatinib in del19 patients?

YES• In my practice, I lean toward afatinib

for del 19 patients

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwilzOGUg_HTAhXFMyYKHcbvBEoQjRwIBw&url=http://onehoosierteacher.blogspot.com/2011/11/electoral-college-huh.html&psig=AFQjCNHl33rjIK6p5fU8yxzPovJqizzW0A&ust=1494907649247831

NOW WHAT DO YOU THINK?

A. No, Evidence is Lacking

B. Yes, Specific Mutations Should Guide TKI Selection

SHOULD SPECIFIC EGFR MUTATION TYPE

(EXON 19 VS. 21) DRIVE TREATMENT SELECTION?

Moderator: Pasi A. Jänne, MD, PhDProfessor of Medicine

Harvard Medical SchoolDana-Farber Cancer Institute

Boston, MA

Understanding Mechanism of Resistance to Therapy:

Tissue vs. Liquid Biopsy?

DEBATE 2

Case• 56 yo female, never smoker from Los Angeles developed new

onset cough

• Chest CT revealed a dominant RUL mass; multiple liver and bone metastases seen on PET/CT

• Core needle biopsy of RUL mass revealed adenocarcinoma; molecular testing demonstrated an EGFR L858R mutation

• She was started on erlotinib

• Quick resolution of symptoms; grade 2 rash; PR by CT

• 14 months later follow up scans demonstrated growth in RUL mass and new bilateral lung nodules.

AUDIENCE VOTE

A. Tissue Biopsy is the Gold Standard

B. Liquid Biopsy Should be the New Standard of Care

TISSUE OR LIQUID BIOPSY?

POINT: Tissue Biopsy is theGold Standard

Mark G. Kris, MD, FACP, FACCPChief, Thoracic Oncology Service

Memorial Sloan-Kettering Cancer CenterProfessor of Medicine, Cornell University Medical College

New York, NY

Disclosures

Consultant for AstraZeneca

Additional Disclosures

I was born a medical oncologist but was raised by thoracic surgeons

I am a chemotherapy guy who has gone molecular

I am a wanna be neurologist

Tissue Biopsy the Gold Standard to Detect EGFR Mutations Introduction

• All patients get a biopsy

• Targeting EGFR not enough

• Multiplex NGS testing provides the most comprehensive view

• Blood-based testing

• Inherently less sensitive – low DNA content

• Can be slower

• Right test for some…not all

• DNA fragments of 120-200bp with half life of ~2 hours

• Real-time, non-invasive, multi-lesions

• Cheaper only because it does not require a biopsy

• Often very low amount of ctDNA in the sea of wild type DNA - ”Needle in a farm”

• Specific to tumor

Diaz Jr LA, Bardella A. J Clin Oncol. 2014.

Other Cytology Specimens Can Also Be Used For NGS

NGS

FNA

Pleural Effusions and other ExfoliativeSpecimens

Cell Free DNA

FACT: Cytology Specimens Have a Lower Failure Rate Than Core Biopsies

Percent failure rate

Adapted from Shiau CJ, et al. J Thorac Oncol. 2014.

0 2 4 6 8 10 12

Biopsy

Cell Pellet

Cytology

Resection

Percent Failure Rate

Optimal Biopsy Procedure Includes FNA and Core

FNA (3 passes)

Core biopsy (3 cores)

Cell block IMPACT

Evolution of Multiplexed Testing Platforms

• Now-Gen• MSK LC-MAP• 8 genes• Point mutations only

• Next-Gen• MSK IMPACT• 468 genes• Point mutations plus deletions,

insertions, amplifications• Comparable costwww.mskcc.org/msk-impact.

MSK-IMPACTIntegrated Mutation Profiling of Actionable Cancer Targets

Capture DNA for410 cancer genes*

Next-genSequencing

(500 - 1000 x)

DNA from FFPE Tumorand Normal cells

Align to genome

and analyze

www.mskcc.org/msk-impact;Won HH, et al. J Vis Exp. 2013; Cheng D, et al. J Mol Diagnostics. 2015.

Somatic Mutations (Tumor-Normal Pairs):Base Substitutions

Small IndelsCopy Number Alterations

Select Rearrangements

*As of February 2017, 468 genes

Jordan EJ, et al. Cancer Discovery. 2017.

MSK IMPACT

Gallant JN, et al. Cancer Discov. 2015.

EGFR-KDD Kinase Domains (GLY 696-PRO 1370)

Gallant JN, et al. Cancer Discov. 2015.

DNA Sequence Not The Whole Story

• DNA Sequencing

• Copy Number Changes

• Fusion Proteins

• Epigenome

• Gene expression profiling

• Proteome

Courtesy of Thomas Lynch, MD.

Couzin-Frankel J. Science. 2013.

Reck M, et al. N Engl J Med. 2016.

Tissue Biopsy the Gold Standard to Detect EGFR Mutations Conclusions

• For the foreseeable future, we have tissue the instant cancer is diagnosed

• Tissue-based tests the standard of care. No need to validate

• NGS tissue-based testing platforms more complete, expandable, and less costly

• Tiny specimens needed, cytology ok

• Until tissue is unnecessary to diagnose cancer, use it

COUNTERPOINT: Liquid Biopsy Should be the New Standard of Care

Tony S.K. Mok, BMSc, MD, FRCPCProfessor and Chair


Hong Kong, China

COI Disclosures

Grant/Research Support AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, SFJ Pharmaceuticals, Roche, Merck Sharp & Dohme, Clovis Oncology, Bristol-Myers Squibb, Eisai, Taiho

Speaker’s Fees AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Bristol-Myers Squibb, Taiho

Major Stock Shareholder Sanomics Ltd.

Advisory Board AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Clovis Oncology, Merck Serono, Merck Sharp & Dohme, Novartis, SFJ Pharmaceutical, ACEA Biosciences, Vertex Pharmaceuticals, Bristol-Myers Squibb, geneDecode, OncoGenex, Celgene, Ignyta, Cirina

Board of Directors International Association for the Study of Lung Cancer (IASLC), Chinese Lung Cancer Research Foundation Ltd., Chinese Society of Clinical Oncology (CSCO), Hong Kong Cancer Therapy Society (HKCTS)

Standard

Noun

1. A level of quality or attainment• Quality, grade, degree, worth, merit

2. Something used as a measure, norm or model in comparative evaluation

Standard of Care of….What?

1. EGFR mutation positive lung cancer

2. ALK re-arrangement positive lung cancer

3. Lung cancer with uncommon mutation

4. Lung cancer without actionable mutations

DiagnosisEGFR exon

19/21

ResistanceEGFR exon 20 T790M

What is positive is truly positive: Specificity

What is negative is truly negative: Sensitivity

EGFR Mutation Analysis of FASTACT 2 Using Real-time PCR-based Blood Test

397 (88%) patients

consented

268 (59.4%) samples available

241 (53.4%)samples

analyzable

451 (100%) patients

consented

447 (99.1%) samples available

447 (99.1%)samples

analyzable

PLASMA SAMPLES

TISSUE SAMPLES

Mok T, et al. Clin Cancer Res. 2015.

224 patients with matched

tumor and plasma samples

• Total of 238 patients had both tumor and baseline plasma samples with available EGFR mutation analysis results

• Sensitivity: 75% (72/96)

• Specificity: 96% (137/142)

• Positive predictive value: 94% (72/77)

• Negative predictive value: 85% (137/161)

• Overall concordance: 88% (209/238)

EGFRActivating Mutations

p-EGFR Mut+

(Plasma)

p-EGFR Mut-

(Plasma)Total

t-EGFR Mut+ (Tumor)

72 24 96

t-EGFR Mut-(Tumor)

5 137 142

Total 77 161 238

Concordance Between Tumor and Plasma Samples


Plasma and Tumor EGFR Status is Equally Predictive


Meta-analysis on cf DNA for EGFR Mutation

• 3110 subjects (27 studies)

• Tissue EGFR mutation status as gold standard

• Pooled Analysis• Sensitivity 62%

• Specificity 96%

• Diagnostic odd ratio 0.91

• Area under summary ROC 0.91

Sensitivity is technology

dependent, egBEAM vs Sanger

High specificity implies clinical applicability for

selection of first line EGFR TKI

Qiu M, et al. Cancer Epidemiol Biomarkers Prev 2015.

Advantage of Liquid Biopsy for EGFR Mutation

• Non-invasive

• Fast

• Relatively economical (saved the cost of invasive procedure)

• Highly specific and relatively sensitive

DiagnosisEGFR exon

19/21

ResistanceEGFR exon 20

T790M

What is T790M?

Threonine Methionine(ACG) (ATG)

Arcila ME, et al. Clin Cancer Res. 2011.

Mechanisms of Resistance to TKI

Yu H, et al. Clin Cancer Res. 2013.

Clinical Data on Digital PCR

IMPRESS(Enrollment period: March 2012‒December 2013)

Primary• PFSSecondary• OS

• ORR

• DCR

• Safety and tolerability

• Health-related quality of lifec

Exploratory• Biomarkers (incl. T790M

EGFR mutation) at enrollment

• Age ≥18 years (≥20 years in Japan)

• WHO PS 0-1

• Histologically confirmed Stage IIIB / IV EGFRmutation-positive advanced NSCLC

• Chemotherapy-naïve

• Achieved CR / PR ≥4 months or SD >6 months with first-line gefitinib

• Disease progression (RECIST)a <4 weeks prior to study randomization

Patients Cisplatin75 mg/m2

+Pemetrexed

500 mg/m2 (≤6 cycles)+

Gefitinib 250 mg

Cisplatin75 mg/m2 IV

+Pemetrexed

500 mg/m2 IV (≤6 cycles)+

Placebo 250 mg

Endpoints

Soria JC, et al. Lancet Oncol. 2015.

T790M by BEAMing Digital PCR

T790M subtype: ctDNA detection by BEAMing

• For patients with plasma samples available for biomarker analysis, there was a slight imbalance between treatment arms with the number of patients with T790M positive- / negative-mutation status

1Diehl et al. 2006

Gefitinib,% (n/N)

Placebo, % (n/N)

Total,% (n/N)a

T790M (+) 61.8 (81/131)

46.9(61/130)

54.4 (142/261)

T790M (-) 35.1(46/131)

45.4(59/130)

40.2 (105/261)

aIncludes unknowns• T790M ctDNA status assessed at baseline • BEAMing digital PCR assay conducted at a central laboratory (positivity defined as ≥0.02% mutant DNA fraction) • BEAMing analysis limited only to Exon 19 del, L858R, & T790M – did not test for uncommon EGFR sensitizing

mutations

No matched tissue

Diehl F, et al. Nat Methods. 2006.

Oxnard GR, et al. J Clin Oncol. 2016.

Plasma cfDNA for T790M from AURA 1 Study

402 patients enrolled onto AURA phase Iescalation and expansion cohorts

308 patients eligible for this biomarker analysis

71 patients with no central tumour genotyping results

37 patients with no centralplasma genotyping results

216 patients eligible for diagnostic comparison, with both central tumour and

plasma genotyping available

237 patients eligible for analysis of tumour genotype and outcome

271 patients eligible for analysis of plasma genotype and outcome

94 patients excluded:

• 60 previously untreated

• 9 with a known EGFR mutation other than L858R or exon 19 deletion

• 25 with no known EGFR mutation by tissue or plasma genotyping

• Sensitivity was 82–86% for sensitising mutations and 70% for T790M

• False positive rate was 3–4% for sensitising mutations but higher (31%) for T790M, perhaps due to heterogeneous presence of a resistance mutation missed in the reference tumorbiopsy

• Sensitivity for T790M was highly associated with detection of a sensitising mutation in cfDNA

Data cut-off: 1 May 2015; 19 del, exon 19 deletion; sens positive, detectable TKI-sensitive EGFRmutation; sens negative, no detectable TKI-sensitive EGFR mutation

Sensitivity/Specificity of Plasma GenotypingSensitivity of each assay Specificity of each assay

0.001

100

10

1

0.1

0.01

0.001

N/D

97.5% 96.5% 69.0%

19 del n=80

L858Rn=143

T790Mn=58

0.06

0.04

100

0.1

0.01

N/D

Sensitivity of T790M assay

plasmasens positive

n=137

plasmasens negative

n=21

80.3% 4.8%

10

1

0.06

100

10

1

0.1

0.01

0.001N/D

82.3% 86.3% 70.2%

0.060.04

19 del n=136

L858Rn=73

T790Mn=158

Alle

lic f

ract

ion

(%

)

Oxnard GR, et al. J Clin Oncol. 2016

Data cut-off: 1 May 2015

Plasma cfDNA Positivity in T790M is Predictive of Tumor Response

**

100

60

–20

–60

–100

20

80

40

–40

–80

0

Plasma T790M positive

Plasma T790M negative

Plasma T790M unknown

ORR (95% CI): 62% (54, 70)

Tumour T790M positive (n=173)

*

100

60

–20

–60

–100

20

80

40

–40

–80

0

Tumour T790M positiveTumour T790M negativeTumour unknown

ORR (95% CI): 63% (55, 70)

Plasma T790M positive (n=164)

Tumor +ive T790M: RR 62%Plasma +ive T790M: RR 63%

What happen to the plasma+ive/

tumor-iveT790M patients


• Cases T790M negative in tumorand T790M positive in plasma were further studied using orthogonal plasma genotyping assays: ddPCR or real-time PCR

• Of 18 “false positives”, 14 could be confirmed using an orthogonal assay

• Note, no false positives for T790M were seen in 100 NSCLC cases with no known EGFR mutation

Understanding Plasma T790M “False Positives”

PtCentral tumor genotyping for

T790M

Central plasma BEAMing

for T790M

T790M allelic fraction

(BEAMing)

T790M detected with

alternative assay

Alternative plasma assay

used

1 Not detected Detected 7.051% Yes ddPCR



4 Not detected Detected 2.036% Yes cobas








12 Not detected Detected 0.191% No ddPCR



15 Not detected Detected 0.091% No ddPCR

16 Not detected Detected 0.080% No cobas

17 Not detected Detected 0.073% No cobas


5PR

8SD

5PD

Oxnard GR, et al. J Clin Oncol. 2016

Best Objective Response

PR

PD

PD

PR

PR

SD

SD

PD

SD

PD

PR

SD

PD

SD

SD

SD

PR

SD

• These data support consideration of a paradigm where plasma genotyping is used as a screening test for T790M, prior to performing an EGFR resistance biopsy

FFPE, formalin-fixed paraffin-embedded

New Paradigm

Acquired resistance to EGFR-TKI

FDA approved plasma assay for T790M and sensitising

mutations

T790Mnegative

T790Mpositive

Skip biopsy, start third gen. EGFR-TKI

Biopsy, FDA approvedFFPE assay for T790M

T790Mpositive

T790Mnegative

Third gen. EGFR-TKI

Chemotherapy


Clinical data on ARMS

Plasma cfDNA vs Tissue EGFR Mutation Analysis in AURA Extension and AURA 2 (Using Real-time PCR)

N=873 screened patients – pooled AURA Phase II studies(N=401 in AURA extension; N=472 in AURA2)

N=710FFPE tissue tested

N=551 (77.6%)Matched plasma

N=440T790M positive

N=257T790M negative

N=13Invalid test



N=8Matched plasma

Jenkins S, et al. ELCC. 2016. Abstract 1340_PR.

Real-time PCR Plasma Test versus Tissue Test as a Reference Method

Real-time PCR Plasma Test Performance

Pooled AURA Phase II studies (AURA extension and AURA2)

L858RExon 19 deletion

T790M

Using real-time PCR tissue test as reference

PPA/sensitivity 75.6% 85.1% 61.4%

NPA/specificity 98.1% 98.0% 78.6%

OPA/concordance 90.9% 90.0% 65.4%

Differences in detection of T790M using tissue and plasma are thought to reflect tumour biology and molecular heterogeneity in

the resistance setting

Jenkins S, et al. ELCC. 2016. Abstract 1340_PR.

AURA 3: EGFR Mutation Analysis

Patients screened(N=1036)

Plasma samples not tested in patients screened in China due to sample export limitations (n=120)Patients with no plasma available for testing (n=268)

Patients included in plasma ctDNA analysis

(N=648)Patients with invalid T790M plasma result (n=3)Patients with a plasma T790M test result but invalid tissue result (n=19)Patients with a plasma T790M test result but not tested for tissue T790M (n=62)

Patients with tissue T790M negative status (n=205)• Patients with plasma T790M positive status (n=47)• Patients with plasma T790M negative status (n=158)

Patients with tissue T790M positive status (n=359)• Patients with plasma T790M positive status (n=184)

• Randomized to treatment (n=172)• Patients with plasma T790M negative status (n=175)

• Randomized to treatment (n=168)

• Central confirmation of tumor EGFR T790M mutation status was performed using a real-time PCR EGFR mutation test

• All patients were required to provide a blood sample at screening for retrospective testing for EGFR T790M in plasma ctDNA using a real-time PCR EGFR mutation test


Liquid Biopsy Should Be the New Standard of Care

Yes for diagnosisEGFR exon 19/21

-Moderate sensitivity-High specificity

Yes for resistantEGFR exon 20 T790M

-Moderate sensitivity-Moderate specificity (explained by tumor

heterogeneity)


A. Tissue Biopsy is the Gold Standard

B. Liquid Biopsy Should be the New Standard of Care

TISSUE OR LIQUID BIOPSY?

Treating T790M-Mediated Acquired Resistance to 1st Line EGFR TKIs:

Monotherapy vs. Combination Approaches

Moderator: Tony S.K. Mok, BMSc, MD, FRCPCProfessor and Chair


Hong Kong, China

DEBATE 3

Case• 78 year old Chinese lady with stage IV EGFR exon 19

mutation positive lung cancer

• Presented with solitary brain met and mediastinal/ axillary LN met

• Treated with SBRT and erlotinib with excellent response

• After 13 months, she started to progress in the axillary and mediastinal LN

• PET-CT showed multiple new liver metastasis

What is Your Next Step?

A. Change to afatinib

B. Biopsy the axillary LN for T790M analysis

C. Start on systemic chemotherapy with Pemetrexed/Carboplatin

D. Start on immunotherapy with either nivolumab or pembrolizumab

• Biopsy of axillary LN performed

• Confirmed T790M positive while exon 19 mutation is also present

Case Continued…..

WHAT IS YOUR NEXT STEP?

A. Osimertinib Monotherapy

B. Clinical Trial of Osimertinib Combination Therapy

POINT: Single Agent Therapy with 3rd Generation TKIsSuresh S. Ramalingam, MD

Professor of Hematology and Medical Oncology Assistant Dean for Cancer Research

Emory University School of MedicineRoberto C. Goizueta Chair for Cancer Research

Deputy Director, Winship Cancer Institute of Emory UniversityAtlanta, GA

Disclosures

• Ad hoc advisory board meetings• AstraZeneca, Ariad, Amgen, Boehringer Ingelheim,

Bristol Myers Squibb, Celgene, Lilly, Genentech, Merck.

Yu HA, et al. Clin Cancer Res. 2013; Sequist LV, et al. Sci Transl Med 2011.

T790M is the Most Common Mechanism of Resistance to EGFR TKI

Osimertinib: AURA Study• Phase I, open-label, multicenter study of AZD9291 administered once

daily in Asian and Western patients with advanced NSCLC who have documented radiological progression while on prior therapy with an EGFR TKI (AURA; NCT01802632)

EscalationNot preselected by T790M status

ExpansionEnrollment by local testing followed by central laboratory confirmation* of T790M status or by central laboratory testing alone

Cohort 120 mg

T790M+

Cohort 240 mg

Cohort 380 mg

Cohort 4160 mg

T790M+

T790M-

T790M+

T790M-

T790M+

T790M-

Cohort 5240 mg

T790M+

1st-line EGFRm+

Biopsy

Rolling six design

Tablet

1st-line EGFRm+

Biopsy

*real-time PCR diagnostic testJänne PA, et al. N Engl J Med. 2015.

Osimertinib is a Mutation-specific T790 Inhibitor

ORR: 61%; Clinical benefit rate ~ 95%;Median PFS: 9.6 months

Jänne PA, et al. N Engl J Med. 2015.

20 mg 40 mg 80 mg 160 mg 240 mg

Be

st P

erc

en

tage

Ch

ange

fro

m B

ase

line

in T

arge

t-Le

sio

n S

ize 50

4030

20

100

-10

-20

-30

-40-50-6070

-80

-90-100

D*D*

DD

D

D

DDDD

DD

D DDD DDD

D D D

D DDD D D

DDDDD

D

Osimertinib in T790M NSCLC:AURA Phase 2 Study

N=201 Patients

Yang JC, et al. J Clin Oncol. 2017.

AURA Phase 2: Median PFS


Osimertinib is Superior to Chemotherapy (AURA 3)


Key eligibility criteria

• > 18 years (> 20 years in Japan)

• Locally advanced or metastatic NSCLC

• Evidence of disease progression following first line EGFR-TKI therapy

• Documented EGFRm and central confirmation of tumor EGFR T790M mutation from a tissue biopsy taken after disease progression on first-line EGFR-TKI treatment

• WHO performance status of 0 or1

• No more than one prior line of treatment for advanced NSCLC

• No prior neo-adjuvant or adjuvant chemotherapy treatment within months prior to starting first EGFR-TKI treatment

• Stable* asymptomatic CNS metastases allowed

R 2:1

Osimertinib (n=279) 80mg orally daily

Platinum-pemetrexed(n=140)

Pemetrexed 500 mg/m2 + carboplatin AUC5 or

cisplatin 75 mg/m2 Q3W for up to 6 cycles +

optional maintenance pemetrexed

Endpoints

Primary:

• PFS by investigator assessment (RECIST 1.1)

Secondary and exploratory:

• Overall survival

• Objective response rate

• Duration of response

• Disease control rate

• Tumor shrinkage

• BICR-assessed PFS

• Patient reported outcomes

• Safety and tolerability

Optional crossoverProtocol amendment allowed patients on chemotherapy to begin post-BICR confirmed progression open-label osimertinib treatment

*RECIST 1.1 assessment performed every 6 weeks until objective disease progression

Progression-free Survival


Tissue vs. Plasma T790M Positivity

Wu YL, et al. WCLC. 2016. Abstract MA08.03.

Comparison of Adverse EventsOsimertinib (N=279) Platinum-pemetrexed (N=136)

Any Grade Grade ≥3 Any Grade Grade ≥3

Number (%)

Diarrhea 113 (41) 3 (1) 15 (11) 2 (1)

Rash 94 (34) 2 (1) 8 (6) 0

Dry Skin 65 (23) 0 6 (4) 0

Paronychia 61 (22) 0 2 (1) 0

Decreased appetite 50 (18) 3 (1) 49 (36) 4 (3)

Nausea 45 (16) 2 (1) 67 (49) 5 (4)

Fatigue 44 (16) 3 (1) 38 (28) 1 (1)

Constipation 39 (14) 0 47 (35) 0

Vomiting 31 (11) 1 (<1) 27 (20) 3 (2)

Thrombocytopenia 28 (10) 1 (<1) 27 (20) 10 (7)

Anemia 21 (8) 2(1) 41 (30) 16 (12)

Neutropenia 22 (8) 4 (1) 31 (23) 16 (12)

Interstitial Lung Disease 10 (4) 1 (<1) 1 (1) 1(1)

QT prolongation 10 (4) 1 (<1) 1 (1) 0


New Treatment Paradigm for EGFR Mt+ NSCLC

1st/2nd

Gen TKI• Median PFS 9-13 months

Resistance• Biopsy

• Evaluate for SCLC conversion, T790M status

3rd Gen TKI

• Median PFS 9-13 months


COUNTERPOINT: Time to Study Combination Approaches

Pasi A. Jänne, MD, PhDProfessor of Medicine

Harvard Medical SchoolDana-Farber Cancer Institute

Boston, MA

• Consultant for: Astra Zeneca, Boehringer Ingelheim, Pfizer, Genentech/Roche, Chugai Pharmaceuticals, Merrimack Pharmaceuticals, Ariad, Ignyta, LOXO Oncology, Eli-Lilly

• Research Support: Astellas, AstraZeneca, Daiichi-Sankyo, PUMA, Eli-Lilly

• Stockholder in: Gatekeeper Pharmaceuticals

• Other: LabCorp – post-marketing royalties from DFCI owned intellectual property on EGFR mutations

Disclosures

The Need for Combination Therapies

• Diseases where combination therapies have had major therapeutic impact• HIV infection, Tuberculosis

• Cancers that can be cured with combination chemotherapy• Testicular cancer, Hodgkin’s disease, Non-Hodgkin’s lymphoma

• Cancers where combination targeted therapies improve survival• Breast cancer (Trastuzumab/pertuzumab) & melanoma (BRAF

and MEK inhibitors)

Successful Combination Therapies

• Lead to improved outcomes compared to single agent therapy

• Single agent Osimertinib PFS ~ 10 months

• The added toxicity is tolerable to justify the use of a combination therapy

• The combination is based on science

• Strategies to enhance the efficacy of Osimertinib

Phase II A+T Study: Erlotinib + Bevacizumab in EGFRMutation–Positive NSCLC – Study Design

Primary endpoint: PFS (RECIST v1.1, independent review)Secondary endpoints: OS, tumor response, QOL, safetyCorrelative research: biomarker assessment

PD

PDRANDOMIZE

Erlotinib 150 mg/day po+ Bevacizumab 15 mg/kg q3W

(N=77)†

• Chemotherapy naive• Stage IIIB/IV or postoperative

recurrent NSCLC • Nonsquamous • Activating EGFR mutations*

• Exon 19 deletion• Exon 21 L858R

• Age ≥20 years• PS 0-1• No brain metastasis

• (N=154)

1:1

Stratification:• Sex• Smoking status• Clinical stage• EGFR mutation type

Erlotinib 150 mg/day po(N=77)

*T790M excluded.†2 patients withdrew before treatment. Seto T, et al. Lancet Oncol. 2014.

75 72 69 64 60 53 49 38 30 20 13 8 4 4 077 66 57 44 39 29 24 21 18 12 10 5 2 1 0

00

1.0

EE+B

Number at risk Time, Months

4 8 122 6 10 14 18 22 2616 20 24 28

0.2

0.4

0.6

0.8

PFS

Pro

bab

ility

9.7 16.0

*Log-rank test, two-sided.

Erlotinib vs. Erlotinib/Bevacizumab: PFS

HR=0.54 (95% CI, 0.36-0.79)

P=0.0015*

N Median, Months

Erlotinib + Bev 75 16.0

Erlotinib 77 9.7

Seto T, et al. Lancet Oncol. 2014.

Efficacy of Nivolumab in Advanced NSCLC

Borghaei H, et al. N Engl J Med. 2015.

Gainor JF, et al. Clin Cancer Res. 2016.

EGFR Mutant Patients Rarely Benefit from Single Agent Immunotherapy

Ahn M, et al. Presented at ELCC 2016. Abstract 1360.

Incidence of Interstitial Lung Disease is Increased by Combining Osimertinib with Durvalumab

Gefitinib (n=133)

Placebo (n=132)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.2

0.3

0.1

0.0

0 2 4 6 8 10 12 14

Pro

bab

ility

of

PFS

Time of randomisation (months)Patients at risk:

GefitinibPlacebo

133132

110100

8885

4039

2517

125

64

00

IMPRESS – Continuation Gefitinib vs. Placebo with Chemotherapy

Gefitinib (n=133)

Placebo (n=132)

Median PFS, months 5.4 5.4

Number of events, n (%) 98 (73.7) 107 (81.1)

HRa (95% CI) = 0.86 (0.65, 1.13); P=0.273

Soria JC, et al. Lancet Oncol. 2015.

Evolution of Resistance Mechanisms in EGFR Mutant Lung Cancer Following Successive EGFR TKI Therapy

Erlotinib

OsimertinibT790M+

EGFR activating mutation

T790M+

T790M – plus unknown resistance

“Loss of T790M”

T790M+ plus unknown resistance

T790M+ plus C797S

= resistance mechanism due to activation of bypass or downstream signaling pathway

= EGFR C797S

= EGFR T790M

Oxnard et al. IASLC 2015;Thress et al. Nature Medicine 2015; Planchard et al. Ann Oncol 2015.

Ongoing & Planned Combination Studies with Mutant Selective EGFR Inhibitors

EGFR Inhibitor Osimertinib EGF816

Combination MEDI4736 INC280 (MET)

Savolitinib (MET) Nivolumab

Selumetinib

Necitumumab

Navitoclax

MLN0128

Gefitinib

JAKi

Bevacizumab

AXL Inhibitor

Efficacy of Osimertinib/Savolitinib in EGFRMutant Lung Cancer

Oxnard GR, et al. Presented at ASCO 2015. Poster 225.

Phase I Trial of Osimertinib & Selumetinib in EGFR Mutant Lung Cancer

Oxnard GR, et al. Presented at ASCO 2015. Poster 225.

Time to Study Combination Approaches

• Single agent osimertinib has limited efficacy

• Combination therapies have led to major clinical improvements in outcome of cancer patients

• Osimertinib is amenable to combination approaches due to its favorable side effect profile

A. Osimertinib Monotherapy

B. Clinical Trial of Osimertinib Combination Therapy


FUTURE DIRECTIONS:TKI Sequencing and Management of CNS

Metastases Suresh S. Ramalingam, MDProfessor of Hematology and Medical Oncology

Assistant Dean for Cancer Research Emory University School of Medicine

Roberto C. Goizueta Chair for Cancer Research Deputy Director, Winship Cancer Institute of Emory University

Atlanta, GA

Osimertinib: CNS Activity


AURA Phase 2 N=74 Pts

mPFS (with CNS mets) 7.1 months

mPFS (without CNS mets) 13.7 months

ORR (CNS) 64%

AURA Phase I Dose: First-line CohortsFirst-line Cohort Objective

• Safety and tolerability of osimertinib (80 mg or 160 mg daily orally) as first-line therapy for patients with EGFRm advanced NSCLC

Data cut-off: 4 January 2016Data from cohorts in grayed out boxes are not included in the analyses reported here

Key Inclusion Criteria:

• Aged ≥18 (≥20 in Japan)

• Locally advanced or metastatic NSCLC

• No prior therapy for advanced disease

• Measurable disease at baseline

• Patients must have EGFR mutation positive NSCLC (local test)

Key Exclusion Criteria:• Prior history of interstitial lung dx• Symptomatic brain metastases

Esca

lati

on

Cohort 120 mg

Negative

Cohort 240 mg

Cohort 5240 mg

Rolling Six Design

Cytology

Tablet

Negative

Cohort 3 80 mg

Negative

Cohort 4 160 mg

Positive Positive PositivePositive Positive

Biopsy Biopsy

T790M cohorts

First-line EGFRm80 mg

First-lineEGFRm 160 mg

Exp

ansi

on

Ramalingam S, et al. ELCC. 2016. Abstract LBA1_PR.

Osimertinib as 1st Line Therapy for EGFR Mt+ NSCLC

Ramalingam S, et al. ELCC. 2016. Abstract LBA1_PR.

80 mgN=30

160 mgN=30

TotalN=60

Median PFS, months (95% CI) NC (12.3, NC) 19.3 (11.1, 19.3) 19.3 (13.7, NC)

Remaining alive and progression-free, % (95% CI)12 months18 months

75 (55, 88)57 (36, 73)

69 (49, 83)53 (32, 70)

72 (59, 82)55 (41, 67)

Pro

bab

ility

of

PFS

Su

rviv

al 1.00.90.80.70.60.50.40.30.20.10.0

0 3 6 9 12 15 18 21 24 27

00

000

77

141619

2020

2223

2327

2629

3030

1st line 80 mg1st line 160 mg

Number of pts at risk: Month

160 mg

80 mg

FLAURA Study

• Metastatic NSCLC• No Prior Tx• EGFR exon 19/21 Mt

N=~450 pts

Osimertinib

Erlotinib/Gefitinib

Primary Endpoint: PFSStatus: Accrual Complete

www.clinicaltrials.gov; NCT02296125.

Optimal Sequencing of TKIs

Current Paradigm*

New Paradigm?

1st/2nd Gen TKI Osimertinib

Osimertinib Other Tx

Median PFS

Considerations:• Only 50-60% of patients will develop T790M after first-line therapy*• Mechanisms of resistance to first-line osimertinib• Osimertinib is better suited for combination regimens

*NCCN NSCLC Guidelines Version 6.2017.

Adjuvant Therapy for Early Stage NSCLC

• Optimal adjuvant therapy for EGFRmt patients• Chemotherapy vs. EGFR TKI vs. both?• Wu, et al. ASCO. 2017.

• ALCHEMIST Study (NCT02194738)• Adjuvant chemotherapy followed by TKI

• ADAURA Study (NCT02511106)• Adjuvant chemotherapy followed by osimertinib vs. placebo

www.clinicaltrials.gov; NCT02194738, NCT02511106.

Documents

Special Thanks! Exchange_Slides_June3.pdf · response 3 (1.3) 1 (0.4) 2 (1.3) 1 (0.6) 2 (2.4) 0 0 1 (1.3) 0 0 0 0 Partial response 97 (42.7) 111 (45.5) 86 (53.8) 102 (58.3) 52 (62.7)