American Journal - Amazon S3 · BreasT CanCer HER2-Positive Breast Cancer: Update on New and Emerging Agents ... American Journal Hematology/ ... Not an official event of the 2015

T h e

TH

E O

FFICIAL J

OU

RN

AL O

F o f

Thyroid CanCer

Thyroid Cancer: Molecular Pathogenesis, Tyrosine Kinase Inhibitors, and Other New TherapiesTiffany N. Tanaka, MD, Sindura K. Alloju, MD, Deborah K. Oh, MD, PhD, and Ezra E.W. Cohen, MD

Lymphoma

Clinical Controversies of Double-Hit LymphomaDeborah M. Stephens, DO, and John W. Sweetenham, MD

BreasT CanCerHER2-Positive Breast Cancer: Update on New and Emerging AgentsAlexandra Drakaki, MD, and Sara A. Hurvitz, MD

meLanomaBRAF Inhibitors and the “Lazarus Syndrome”—An Update and PerspectiveLena Furmark, MD, and Anna C. Pavlick, MDn

CLiniCaL ConTroversiesNegative Is Positive: A Plea to Publish All Studies Regardless of OutcomeDebu Tripathy, MD

A m e r i c a n

J o u r n a l

H e m a t o l o g y /

O n c o l o g y ®

a peer-reviewed resource

for oncology education

ajho

www.AJHO.com issn 1939-6163 (print) issn 2334-0274 (online)

Volume 11 Number 4 4.15

immunoTherapy CME-certified enduring materials sponsored by Physicians’ Education Resource®, LLC

Immunotherapeutic Approaches to the Treatment of Squamous Non-Small Cell Lung Cancer

Friday, May 29, 2015Hilton Chicago, International South Ballroom720 South Michigan Avenue, Chicago, IL7:00 pm to 9:00 pm

Live streaming available via online webcast

Register online now…

This is a program not to be missed! Registration is complimentary.

TARGETING PATHWAYS, EFFICACY, AND COMBINATIONS

Transforming Immuno-Oncology

Across Solid Tumors

Join us live in Chicago or live streaming webcast from anywhere!Learn about the latest and greatest in state-of-the-art immuno-oncology strategies for the management of solid tumors.

Transforming Immuno-Oncology Across Solid Tumors: Targeting Pathways, Efficacy, and Combinations is a live symposium to be held in conjunction with the annual meeting in Chicago. Immuno-oncology is one of the hottest areas in cancer research and drug development. These innovative treatments for cancer may ultimately prove to be game-changers that radically alter treatment paradigms for a number of the solid tumors oncologists manage. The sheer volume of basic science and therapeutic developments that continue to emerge in this field makes the annual meeting in Chicago the perfect venue for an immuno-oncology program geared to meet the needs of the busy oncologist who strives to maintain cutting-edge knowledge in the care of their patients with the most difficult-to-treat tumors.

Key topics on the agenda include how these radically new strategies will be applied to manage patients with:• Lungcancer• Squamouscellcarcinomaoftheheadandneck;and• Mesotheliomaandothersolidtumors

Renowned experts in these fields will also discuss how immuno-oncology combinations will be applied to the management of solid tumors.

Earn up to 2.0 AMA PRA Category 1

Credits™

Program Chair

RoyS.Herbst,MD,PhDYale Cancer Center Yale School of Medicine New Haven, CT

Faculty

JulieBrahmer,MDJohns Hopkins Sydney Kimmel

Comprehensive Cancer CenterBaltimore, MD

BarbaraBurtness,MDYale Cancer CenterNew Haven, CT

NaiyerRizvi,MDColumbia University Medical Center New York, NY

Notanofficialeventofthe2015ASCOAnnualMeeting.NotsponsoredorendorsedbyASCOorConquerCancerFoundation.

Physicians’EducationResource®,LLCisaccreditedbytheAccreditationCouncilforContinuingMedicalEducationtoprovidecontinuing medical education for physicians.

Physicians’EducationResource®,LLCdesignatesthisliveactivityfor a maximum of 2.0 AMA PRA Category 1 Credits™.Physiciansshould claim only the credit commensurate with the extent of their participation in the activity.

This activity is supported by an educational grant from AstraZeneca.

PER®complieswiththePhysicianPaymentsSunshineActaspartoftheAffordableCareAct.Accordingly,wemayberequiredtocollectinformation on transfers of value provided to any covered recipient under the Act.

ASCO15-Immuno-Symposium-Asize_01.indd 1 3/31/15 5:46 PM

Table of Contents

Thyroid CanCer

Thyroid Cancer: Molecular Pathogenesis, Tyrosine Kinase Inhibitors, and Other New Therapies Tiffany N. Tanaka, MD, Sindura K. Alloju, MD, Deborah K. Oh, MD, PhD, and Ezra E.W. Cohen, MDThe discovery of several molecular markers in thyroid cancer heralds an exciting new era of preci-sion medicine, allowing for refined prognostication and therapeutic strategy. Although the mortality rate for thyroid cancer is relatively low, persistent and recurrent disease may occur in 20% to 30% of patients afflicted with this disease; thus, a deeper understanding of its molecular pathogenesis is needed.

Lymphoma

Clinical Controversies of Double-Hit LymphomaDeborah M. Stephens, DO, and John W. Sweetenham, MDDouble-hit lymphoma has been identified as a subset of diffuse large B-cell lymphoma with poor clin-ical outcomes. As minimal data about this subtype of lymphoma have been published, many contro-versies in diagnosis and treatment surround it. In this article, the authors review the current definition, proper diagnosis, central nervous system prophylaxis, current treatment regimens, and potential novel therapeutic options for double-hit lymphoma.

BreasT CanCer

HER2-Positive Breast Cancer: Update on New and Emerging Agents Alexandra Drakaki, MD, and Sara A. Hurvitz, MD Since the approval of trastuzumab for HER2-positive metastatic breast cancer in 1998, outcomes for patients diagnosed with this innately aggressive form of cancer have vastly improved. Several new therapies have been developed for HER2-positive breast cancer, including lapatinib, pertuzumab, and trastuzumab emtansine (T-DM1), and several emerging agents are currently being evaluated in clinical trials. In this review, the currently available therapies for HER2-positive breast cancer are described and innovative HER2-directed approaches that are currently under investigation are explored.

meLanoma

BRAF Inhibitors and the “Lazarus Syndrome”—An Update and Perspective Lena Furmark, MD, and Anna C. Pavlick, MDIdentification of the BRAF mutation as an effective therapeutic target in approximately 50% of patients with metastatic melanoma has dramatically impacted the landscape of melanoma treatment. These drugs have a very rapid onset of action and can quickly reverse a clinical decline of a patient with met-astatic melanoma, but typically have a limited duration of activity. Many tumors will develop resis-tance within months of treatment and tumors will again progress. Combining dual targets like BRAF and MEK inhibitors has improved the time to progression and survival, but has not demonstrated any consistent long-term durability of responses. Continued research with multiple targeted therapies and targets with immunotherapy are under way. This article provides a state-of-the-art review and per-spective on the efficacy and toxicities of BRAF and MEK targeted therapies for metastatic melanoma. CLiniCaL ConTroversies

Negative Is Positive: A Plea to Publish All Studies Regardless of OutcomeDebu Tripathy, MDPositive results from clinical trials naturally get the headlines in the media and are published in the more prestigious and higher-impact journals. But what about negative results? They also get pub-lished, but less frequently and with more delays. Many investigators abandon negative studies and focus their time elsewhere, leaving these bodies of work in the dark and unavailable, even in cyber-space. This article explores why it’s important to publish negative studies.

5

10

17

24

30

Table of Contents (continued)

Cme

CME-certified enduring materials sponsored by Physicians’ Education Resource®, LLCimmunoTherapy

Immunotherapeutic Approaches to the Treatment of Squamous Non-Small Cell Lung CancerThis CME-certified article is designed to aid physicians in assessing new data in immunotherapy for squamous cell lung cancer, including patient-specific treatment regimens and monitoring for adverse events during thera-py, and applying these data to their practices.

32

Patrick I. Borgen, MDChairman, Department of Surgery Maimonides Medical CenterDirector, Brooklyn Breast Cancer ProgramBrooklyn, NY

Julie R. Brahmer, MDAssociate Professor, Oncology Johns Hopkins University School of

MedicineSidney Kimmel Comprehensive Cancer

CenterBaltimore, MD

Myron S. Czuczman, MDProfessor of OncologyChief, Lymphoma/Myeloma ServiceDepartment of MedicineHead, Lymphoma Translational Research

LaboratoryDepartment of ImmunologyRoswell Park Cancer InstituteBuffalo, NY

David R. Gandara, MDProfessor of MedicineDirector, Thoracic Oncology ProgramSenior Advisor to the DirectorDivision of Hematology/OncologyUC Davis Comprehensive Cancer CenterSacramento, CA

Andre Goy, MD, MSChairman and Director Chief of LymphomaDirector, Clinical and Translational Cancer ResearchJohn Theurer Cancer Center at Hackensack University Medical CenterHackensack, NJ

John M. Kirkwood, MDUsher Professor of Medicine, Dermatology

and Translational ScienceDirector, Melanoma and Skin Cancer

ProgramUPMC Hillman Cancer CenterPittsburgh, PA

Michael Kolodziej, MD National Medical Director, Oncology Solutions

Office of the Chief Medical Officer, AetnaHartford, CT

Maurie Markman, MDPresident, Medicine & ScienceNational Director, Medical OncologyCancer Treatment Centers of America

John L. Marshall, MDChief, Hematology and Oncology Director, Otto J. Ruesch Center for the

Cure of Gastrointestinal CancersLombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashington, DC

Joyce A. O’Shaughnessy, MDCo-Director, Breast Cancer ResearchBaylor Charles A. Sammons Cancer

Center Texas Oncology The US Oncology NetworkDallas, TX

Daniel P. Petrylak, MDProfessor of Medicine (Medical Oncology) and of UrologyCo-Director, Signal Transduction Research

ProgramYale Cancer Center and Smilow Cancer

HospitalNew Haven, CT

Ramesh K. Ramanathan, MDProgram Lead, Gastrointestinal OncologySenior Associate AttendingMayo Clinic, ArizonaClinical Professor, Translational Genomics

Research Institute (TGEN)Phoenix, AZ

PER® Executive Board/AJHO Editorial Board

VOL. 11, NO. 4 THE AMERICAN JOURNAL OF HEMATOLOGY/ONCOLOGY 3

Molecular Testing in Thyroid Cancer: Heading a Revolution in Treatment

Uncovering the molecular pathobiology of thyroid cancer has heralded an exciting new era of precision medi-

cine and revolutionized the way we treat this cancer. In this issue of The American Journal of Hematology/Oncology®

(AJHO), a peer-reviewed resource for oncology education and the official journal of Physicians’ Education

Resource®, LLC, Tiffany N. Tanaka, MD, Sindura K. Alloju, MD, Deborah K. Oh, MD, PhD, and Ezra E.W.

Cohen, MD, explore the molecular pathogenesis of thyroid cancer and the development of tyrosine kinase

inhibitors and other new therapies.

Double-hit lymphoma (DHL), a subset of diffuse large B-cell lymphoma, is associated with poor clinical

outcomes. Minimal data have been published about DHL, and as a result, there are many controversies sur-

rounding its diagnosis and treatment. Deborah M. Stephens, DO, and John W. Sweetenham, MD, review

the current definition, proper diagnosis, central nervous system prophylaxis, current treatment regimens, and

potential novel therapeutic options for DHL.

Outcomes for patients with HER2-positive metastatic breast cancer have vastly improved since the approv-

al of trastuzumab in 1998, and subsequently, several new therapies have been developed for HER2-positive

disease, including pertuzumab, lapatinib, and T-DM1. Advancements in this area continue, and Alexandra

Drakaki, MD, and Sara A. Hurvitz, MD, discuss currently available therapies and innovative HER2-directed

approaches under investigation.

Although BRAF inhibitors for melanoma can quickly—sometimes dramatically—reverse a clinical decline,

in the majority of cases, tumors develop resistance to these therapies and progress. Lena Furmark, MD, and

Anna C. Pavlick, MD, provide a state-of-the-art review of BRAF and MEK targeted therapies for metastatic

melanoma. The authors then discuss the roller coaster of emotions that patients, their families, and healthcare

providers face when patients dramatically respond to these therapies but then relapse.

Positive results from clinical trials make headlines, but in our “Clinical Controversies” column, AJHO edi-

tor-in-chief Debu Tripathy, MD, makes the case for publishing all trial results—positive and negative. Negative trials

avoid duplication of studies and may also contain important safety information that would otherwise be lost.

Our CME article highlights squamous cell lung cancer. Immunotherapy, with the recent approval of the

PD-1 checkpoint inhibitor nivolumab, has opened new treatments for this cancer, and in the article, Roy

Herbst, MD, PhD, reviews the use of immunotherapy in squamous non-small cell lung cancer.

We hope that you find this issue to be a rewarding educational experience. As always, we welcome your

comments and suggestions, as well as article and commentary submissions.

Michael J. Hennessy

Chairman and Chief Executive Officer

Chairman’s Note

The content of this publication is for general information purposes only. The reader is encouraged to confirm the information presented with other sources. American Journal of Hema-tology/Oncology makes no representations or warranties of any kind about the completeness, accuracy, timeliness, reliability, or suitability of any of the information, including content or advertisements, contained in this publication and expressly disclaims liability for any errors and omissions that may be presented in this publication. American Journal of Hematology/Oncology reserves the right to alter or correct any error or omission in the information it provides in this publication, without any obligations. American Journal of Hematology/Oncology further disclaims any and all liability for any direct, indirect, consequential, special, exemplary, or other damages arising from the use or misuse of any material or information presented in this publication. The views expressed in this publication are those of the authors and do not necessarily reflect the opinion or policy of American Journal of Hematology/Oncology.

4 www.ajho.com APRIL 2015

Editor-in-ChiefDebu Tripathy, MD

Professor and Chair Department of Breast Medical Oncology The University of Texas MD Anderson Cancer Center Houston, TX

Associate EditorMyron S. Czuczman, MD

Professor of OncologyChief, Lymphoma/Myeloma ServiceHead, Lymphoma Translational Research LaboratoryDepartment of ImmunologyRoswell Park Cancer InstituteBuffalo, NY

Managing EditorDevera Pine [email protected] Art Director Marie Graboso

Editorial OfficesPhysicians’ Education Resource®, LLC666 Plainsboro Road, Ste. 356Plainsboro, NJ 08536(609) 378-3701

Phil TalamoVice President, Independent Medical Education

Medical DirectorMichael Perlmutter, MS, PharmD

Emily ValkoSenior Project Manager

ediToriaL sTaFF

This issue of AJHO brings a wide range of topics, including updates on common cancers and subjects not typically covered in reviews or per-spectives. Few fields have changed as much as that of HER2-positive ad-vanced breast cancer, which began with first randomized trial conducted by Dennis Slamon and colleagues, leading to the approval of trastuzum-ab. This study demonstrated an improvement in overall survival from 20 to 25 months with the addition of trastuzumab to chemotherapy as frontline therapy. Fast forward to this year, with the publication of updated results from Sandra Swain et al from the CLEOPATRA study now showing a median survival of over 56 months with the triplet of docetaxel, trastuzumab, and pertuzumab. These and other advances that constitute the current state of the art for metastatic HER2-positive breast cancer are presented by Drs Drakaki and Hurvitz. Drs Furmark and Pavlick provide us with a synopsis of results from BRAF and MEK kinase inhibition in BRAF-mutated melanoma, reviewing the latest data and discussing the clinical implications of the more frequent and dra-matic responses, with correspondingly rapid relapses, being seeing with these agents. This stands in contrast to the less frequent but longer re-missions seen with immune therapy.

While the less common entity of thyroid cancer is usually curable, few options have existed for less differentiated thyroid cancers that do not take up radioactive iodine (RAI). However, angiogenesis appears to have a critical role in these cancers, and the anti-angiogenic tyrosine kinase inhibitors sorafenib and more recently, levantinib, have now been ap-proved for RAI-resistant thyroid cancer. Underlying molecular biology, predictive factors and new agents under investigation are also reviewed by Dr Tanaka and colleagues. The infrequent “double hit” lymphoma, characterized by two activating genomic alterations in the MYC onco-gene and overexpression of the anti-apoptotic BCL2 or BCL6 proteins, has a correspondingly worse prognosis and mandates aggressive therapy. The recount by Drs Stephens and Sweetenham of the elegant biology and the nuances of differential consequences depending on the type of mutation or translocation serves to remind every oncologist of the need to slowly but surely become familiar with the basic tenets of cancer genomics.

My commentary in this issue represents a plea to the clinical investiga-tive community to ensure that all trial results—positive and negative—are available in press or otherwise in the public domain. This may be the only way to eliminate publication bias in the interpretation and quanti-fication of both benefit and risk, and ultimately affect guidelines and the way we practice clinical oncology.

Our CME article highlights a recent and important set of studies on immunotherapy for squamous cell lung cancer. This is a disease with unmet needs, with lack of responses seen with agents that are effective in adenocarcinoma of the lung, such as bevacizumab and erlotinib. However, immunotherapy has broken this barrier, with the recent ap-proval of the PD-1 checkpoint inhibitor nivolumab based on a phase III trial showing a dramatic 41% improvement in median survival when added to docetaxel after progression on a platinum regimen. A review of the biological differences between squamous and adeno versions of non-small cell lung cancer and our treatment approaches, as well as practical issues of immunotherapy and its toxicities, is pre-sented through an informative interview with Roy Herbst, MD, PhD.

CorporaTe oFFiCers Chairman and CEOMike Hennessy

Vice Chairman Jack Lepping

President Tighe Blazier

Senior Vice President, Operations and Clinical Affairs Jeff Prescott, PharmD, RPh

Vice President, Executive Creative Director Jeff Brown

Debu Tripathy, MD Editor-in-Chief

From the Editor


· thyroid cancer ·

Thyroid Cancer: Molecular Pathogenesis, Tyrosine Kinase Inhibitors, and Other New Therapies

Tiffany N. Tanaka, MD, Sindura K. Alloju, MD, Deborah K. Oh, MD, PhD, and Ezra E.W. Cohen, MD

IntroductionThe discovery of several molecular markers in thyroid cancer heralds an exciting new era of precision medicine, allowing for refined prognostication and therapeutic strategy. The global inci-dence of thyroid cancer is rising rapidly, propelled by the increas-ing incidence of thyroid nodules diagnosed by ultrasonography.1 Although the mortality rate for thyroid cancer is relatively low, persistent and recurrent disease may occur in 20% to 30% of patients affected by this disease2; thus, a deeper understanding of its molecular pathogenesis is needed.

Molecular PathogenesisThyroid cancer originates from 2 types of thyroid endocrine

cells: follicular thyroid cells and parafollicular C cells,3 the for-mer accounting for >90% of thyroid malignancies and including papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), poorly differentiated thyroid cancer (PDTC), and anaplastic thy-roid cancer (ATC). Of note, PTC and FTC are classified as dif-ferentiated thyroid cancer (DTC). We will focus our discussion on the pathobiology of follicular thyroid cell–derived carcinoma and related therapeutic targets.

The progression of thyroid cancer is thought to be the result of an accumulation of genetic and epigenetic lesions that lead to perturbations in classical signaling pathways involved in cell proliferation and survival.4 The discovery of these molecular al-terations has yielded several disease biomarkers that may con-tribute to our ability to diagnose and prognosticate. The Cancer Genome Atlas project recently studied 496 PTC cases, identify-ing driver mutations in all but <4% of cases, and finding that different molecular alterations lead to different pathologic and clinical features.5 In fact, as with many malignancies, classifica-tion of thyroid cancers by molecular rather than histologic sub-type may one day be a more informative approach. These genetic alterations have also been linked to the loss of radioiodine (RAI) avidity in thyroid cancer, and have become the targets of novel drug therapy, suggesting that cure rates beyond conventional sur-gical thyroidectomy and adjuvant RAI ablation may be possible.

At the core of thyroid cancer pathogenesis are 2 classical signaling pathways, the MAPK and the PI3K-AKT pathways.6,7 Both of these pathways are coupled to the receptor tyrosine ki-nase (RTK) at the cell membrane, which transduces an extra-cellular growth stimulus that prompts downstream intracellular signaling (Figure). The MAPK pathway has a fundamental role in the regulation of cell proliferation, differentiation, apoptosis, and survival, and has been linked to tumorigenesis when dis-rupted. Once RTK is activated by an extracellular signal, down-stream activation of RAS, followed by BRAF, MEK, and then ERK, occurs. ERK then enters the nucleus to induce tumor-pro-moting genes and downregulate tumor suppressor genes and thyroid iodide-handling genes. Several oncogenic mechanisms have been identified in association with this pathway, including aberrant genome-wide hypermethylation and hypomethylation,8 and upregulation of oncogenic proteins such as chemokines,

Abstract

Molecular testing in thyroid cancer proposes many novel

approaches to this disease. Traditional histologic diagno-

sis and classification of thyroid cancer may one day soon

be refined by genomic profiling, a common theme in the

era of precision medicine. An increasing understanding

of the molecular pathogenesis of this disease has led

to the discovery of driving somatic genetic alterations,

largely explained by, although not limited to, the MAPK

and PI3K pathways. Identification of these molecular

markers suggests better methods to risk-stratify patients

prior to surgery, reducing the number of thyroidectomies

performed for benign nodules, and also identifying pa-

tients at risk for recurrence, or even dedifferentiation, into

a more aggressive thyroid cancer, thus mandating more

aggressive therapy approaches beyond traditional sur-

gery and radioactive iodine therapy. Molecular profiling

also offers tremendous benefit in the metastatic setting,

as these patients typically do not respond to cytotoxic

chemotherapy, and identification of targetable pathogen-

ic lesions may select for more precise therapeutic op-

tions, such as the small molecular kinase inhibitors.

Key words: Thyroid cancer, molecular testing, genomic

profiling, MAPK, PI3K, precision medicine, small molecu-

lar kinase inhibitors



matrix metalloproteinases, nuclear factor-κB, and vascular endo-thelial growth factor A, among many others.4 Many of these pro-teins have been identified as drivers of cancer cell proliferation, growth, migration, and viability. In thyroid cancer, common activating mutations of the MAPK pathway include BRAF9 and RAS10 mutations, RET-PTC rearrangement,11 and in some cases, ALK rearrangements.12

The PI3K-AKT pathway also plays a significant role in spo-radic thyroid tumorigenesis. As with the MAPK pathway, an extracellular stimulus activates RTK at the cell membrane, and subsequently PI3K, ultimately leading to phosphorylation and activation of AKT.13 Activated AKT then enters the nucleus to upregulate tumor-promoting genes. Within the cytoplasm, acti-vated AKT also activates other signaling molecules, including the mTOR pathway and phosphorylation of glycogen synthase kinase 3β. Common genetic alterations implicated in induction of the PI3K-AKT pathway include RAS and PTEN mutation or deletion, PI3KCA mutation or amplification, AKT1 mutation, and amplifications of the RTK genes.14

BRAF InhibitorsBRAF mutations are the most common genetic alteration found in thyroid cancer and are detected in 50% of patients with PTC and 25% of PTC-derived ATC.15 The BRAFV600E mutation carries prognostic implication and has been correlated with poor clin-icopathological outcomes, including increased tumor invasion, metastasis, recurrence of PTC, and mortality.16-18 A retrospective trial evaluated 2099 patients with PTC and found that recur-rence occurred in 20.9% of patients with BRAFV600E mutations

versus 11.6% of wild-type mutations.19 The BRAFV600E mu-tation is also associated with loss of expression of thyroid iodide-metabolizing genes, elucidating a mechanism for how patients with thyroid cancer lose RAI avidity, resulting in recurrence of their thyroid cancer.20

In the metastatic setting, BRAF inhibitors are part of the armamentarium of novel targeted treatments of DTC. Vemurafenib, a selective BRAFV600E inhibitor approved in BRAF-mutated melanoma, is currently being tested in the phase II setting for thyroid cancer. A study of 3 patients with metastatic PTC treated with vemurafenib found that time to progression (TTP) ranged from 11.4 to 13.2 months.21 These results prompted a larger phase II study that evalu-ated survival outcomes associated with vemurafenib in 51 patients with progressive BRAFV600E-mutated PTC refractory to RAI therapy.22 After 6 months, the best overall response rate (ORR) was 35% in patients naïve to tyrosine kinase inhibitor (TKI) treatment, and 26% in patients previous-ly treated with TKI therapy. While larger cohorts need to be studied, these results are promising in comparison with outcomes achieved with systemic chemotherapy, where du-ration of response is typically <6 months. Additionally, the usage of trametinib, a MEK inhibitor, in conjunction with

dabrafenib—an approach that demonstrated increased survival benefit in patients with BRAF-mutant metastatic melanoma23—is currently under investigation in an ongoing, randomized, phase II trial in patients with recurrent PTC.24

VEGF Receptor InhibitorsHigh levels of vascular endothelial growth factor (VEGF 1,2,3), the dominant growth factor in angiogenesis, have been found in DTC and MTC. In experimental models, interference with VEGF blocked the proliferation of DTC cells.25 VEGFR-2 is of-ten overexpressed in both MTC cells and supporting vasculature. It is thought that simultaneous targeting of both MET and VEG-FR-2 provides an antitumor effect.

Several TKIs that target VEGF receptors have been studied in metastatic RAI-resistant DTC, but only 1 has received FDA approval. Sorafenib, a multikinase inhibitor of VEGFR-1, -2, and -3, RET, BRAF, and platelet-derived growth factor, was approved by the FDA in 2013 based on data from the DECISION trial, a phase III placebo-controlled trial with 417 patients.26 Patients treated with sorafenib showed a significant improvement in me-dian progression free survival (PFS) compared with placebo (10.8 months vs 5.8 months; P <.0001). Overall survival (OS) did not differ significantly between the groups; however, crossover was allowed in this trial. A total of 11 patients discontinued therapy, most commonly due to hand-foot skin reactions.

Lenvatinib, an inhibitor of VEGFR1-3, FGFR1-4, PDGFR-β, RET, and KIT signaling networks, was studied in the random-ized, double-blind, phase III SELECT trial, which evaluated

FIGURE. Signaling Pathways in Thyroid Cancer

Cell Membrane

Nucleus

Growth factor

PTEN PI3K

PDK

AKTAKT

RTK

ERKERK

MEK

RAS

BRAF V600E

ÛTumorpromoting

genes

ÜTumorsuppresor

genes ERKAKT

AxitinibCabozantinib

LenvatinibSorafenibSunitinib

Vandetanib

DabrafenibVemurafenib

Sorafenib

SelumetinibTrametinib


Molecular Pathogenesis, tyrosine Kinase inhibitors, and other new theraPies

392 patients with progressive, RAI-refractory thyroid cancer.27 Patients treated with lenvatinib demonstrated a 64.8% response rate. Additionally, median PFS was 18.3 months in the lenvati-nib group versus 3.6 months in the placebo group (P <.0001). OS was not reached in either group; however, crossover was also allowed in this trial due to significant response rates.

Several TKIs have been studied in phase II trials. In a study of 145 patients with RAI-resistant metastatic DTC, vandetanib, an inhibitor of RET, VEGFR-2, VEGFR-3, and epidermal growth factor receptors, improved PFS compared with placebo (11.1 months vs 5.9 months; P = .0007).28 A total of 24 patients (33%) discontinued treatment due to toxicity, QTc prolongation, and diarrhea. A phase III study is currently under way. Axitinib, a selective inhibitor of VEGFR, was studied in 60 patients with advanced thyroid cancer of any histology. The ORR was 38%.29 Another study of 52 patients with advanced MTC or RAI-resis-tant DTC demonstrated an ORR of 35% and median PFS of 16 months.30 Motesanib, an inhibitor of VEGFR-1, -2, -3, PDGF, and KIT, was studied in 93 patients, and resulted in 49% of patients with either confirmed partial response (PR) or durable stable disease (SD) and an estimated PFS of 40 weeks.31 Five pa-tients developed cholecystitis, which has not been reported with other angiogenesis inhibitors. Pazopanib, an inhibitor of c-KIT, FGFR, PDGFR, and VEGFR, was studied in a single-arm study of 39 patients.32 Treatment led to PR in 49% and a median PFS of 11.7 months.

Sunitinib, which inhibits VEGFR, PDGF, and RET, was test-ed in 29 patients with positron emission tomography (PET)-pos-itive, RAI-refractory DTC,33 and at 6 months, 28% of patients showed a response and 77% had SD. New preliminary data show potential for use of sunitinib as second-line therapy in patients who have failed treatment with sorafenib. In 3 patients with met-astatic RAI-refractory DTC who received sequential treatment of sorafenib followed by sunitinib, there was restoration of antineo-plastic activity as confirmed by biochemical PR and detection of tumor necrosis.34 Cabozantinib, an inhibitor of VEGFR-2, MET, and RET, was recently investigated in a small phase I study of 15 patients with advanced DTC who progressed on standard RAI therapy, finding a similar safety profile to other multitargeted VEGFR inhibitors.35 A National Cancer Institute–sponsored phase II trial is currently open for accrual to evaluate the use of cabozantinib as second-line therapy in patients with refractory DTC.36

RAI Re-Sensitizing AgentsA novel area of development is usage of TKIs as RAI re-sensitiz-ing agents. Survival is significantly lower in patients with non-RAI avid disease, with a 10-year survival rate of only 10% ver-sus 60% in patients with iodine-avid disease.37 Animal studies found that inhibition of BRAF or MAPK allowed RAI-resistant thyroid cancers to regain the ability to take up iodine. A pilot

study evaluated 20 patients with metastatic, RAI-refractory DTC who were treated with selumetinib, a MEK inhibitor.38 Selume-tinib increased iodine uptake in 12 patients, and 8 were retreated with RAI. Of these 8 patients, 5 had confirmed PR and 3 had SD, suggesting that MEK inhibition therapy can lead to RAI re-sensitization. This study has led to the development of the randomized, double-blind, placebo-controlled, phase III ASTRA trial to compare complete response (CR) rates obtained with ad-juvant selumetinib in addition to adjuvant RAI, versus placebo plus RAI in patients with newly diagnosed DTC at high risk for primary treatment failure.39

The use of dabrafenib, a selective BRAF inhibitor, was also evaluated in 10 patients with BRAFV600E mutations.40 Six patients demonstrated new RAI uptake following treatment. These pa-tients were then treated with RAI, and 2 patients experienced PR and 4 patients demonstrated SD at 3 months; additionally, thyroglobulin decreased in 4 of these 6 patients.

SummaryUncovering the molecular pathobiology of thyroid cancer has driven the development of targeted drug therapies that have rev-olutionized the way we approach thyroid cancer—a theme that pervades modern medical oncology in the era of major genomic breakthroughs.41 Additionally, these molecular targets may also serve as practical biomarkers that may be utilized to predict a patient’s risk for developing thyroid cancer, such as in the pre-operative setting, or risk of cancer recurrence. Our understand-ing of the genetic and epigenetic alterations involved in thyroid carcinogenesis undoubtedly provides opportunity to treat each patient more precisely, and in the metastatic setting, identifies targeted therapies that may offer significant survival benefit that rivals our dismal experience with traditional cytotoxic chemo-therapy.

Affiliations: Drs Tanaka and Cohen are from the Division of Hematology and Oncology, and Drs Alloju and Oh are from the Division of Endocrinology, Diabetes and Metabolism, Universi-ty of California at San Diego, La Jolla, CA. Disclosures: Drs Tanaka, Sindura, and Oh have no relevant con-flicts of interest to disclose. Dr Cohen has served as a consultant and speaker for Bayer and Eisai.Address correspondence to: Ezra Cohen, MD, UC San Diego Moores Cancer Center, 3855 Health Sciences Dr, Mail Code 0658, La Jolla, CA 92093-0658. Phone: 858-534-6161; fax: 858-822-5754; email: [email protected].

REFEREncES1. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006;295:2164-2167.2. Hundahl SA, Fleming ID, Fremgen AM, et al. A National



Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995. Cancer. 1998;83:2638-2648.3. Tuttle RM, Haddad RI, Ball DW, et al. Thyroid carcinoma, version 2.2014. J Natl Compr Canc Netw. 2014;12:1671-1680.4. Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 2013;13:184-199. 5. The Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159:676-690.6. Kohno M, Pouyssegur J. Targeting the ERK signaling pathway in cancer therapy. Ann Med. 2006;38:200-211.7. Hou P, Liu D, Shan Y, et al. Genetic alterations and their re-lationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer. Clin Cancer Res. 2007;13:1161-1170.8. Hou P, Liu D, Xing M. Genome-wide alterations in gene meth-ylation by the BRAF V600E mutation in papillary thyroid cancer cells. Endocr Relat Cancer. 2011;18:687-697.9. Kimura ET, Nikiforova MN, Zhu Z, et al. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for consti-tutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res. 2003;63:1454-1457.10. Vasko V, Ferrand M, Di Cristofaro J, et al. Specific pattern of RAS oncogene mutations in follicular thyroid tumors. J Clin Endocrinol Metab. 2003;88:2745-2752.11. Ciampi R, Nikiforov YE. RET/PTC rearrangements and BRAF mutations in thyroid tumorigenesis. Endocrinol. 2007;148:936-941.12. Murugan AK, Xing M. Anaplastic thyroid cancers har-bor novel oncogenic mutations of the ALK gene. Cancer Res. 2011;71:4403-4411.13. Fresno Vara JA, Casado E, de Castro J, et al. PI3K/Akt sig-nalling pathway and cancer. Cancer Treat Rev. 2004;30:193-204.14. Wang Y, Hou P, Yu H, et al. High prevalence and mutual exclusivity of genetic alterations in the phosphatidylinositol-3-ki-nase/Akt pathway in thyroid tumors. J Clin Endocrinol Metab. 2007;92:2387-2390.15. Xu X, Quiros RM, Gattuso P, et al. High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tu-mor cell lines. Cancer Res. 2003;63:4561-4567.16. Hou P, Liu D, Xing M. Functional characterization of the T1799-1801del and A1799-1816ins BRAF mutations in papillary thyroid cancer. Cell Cycle. 2007;6:377-379.17. Liu D, Liu Z, Condouris S, et al. BRAF V600E maintains proliferation, transformation and tumorigenicity of BRAF mutant papillary thyroid cancer cells. J Clin Endocrinol Metab. 2007;92:2264-2271.18. Xing M, Alzahrani AS, Carson KA, et al. Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA. 2013;309:1493-1501.19. Xing M, Alzahrani AS, Carson KA, et al. Association be-tween BRAF V600E mutation and recurrence of papillary thy-

roid cancer. J Clin Oncol. 2015;33:42-50.20. Liu D, Hu S, Hou P, et al. Suppression of BRAF/MEK/MAP kinase pathway restores expression of iodide-metabolizing genes in thyroid cells expressing the V600E BRAF mutant. Clin Cancer Res. 2007;13:1341-1349.21. Kim KB, Cabanillas ME, Lazar AJ, et al. Clinical responses to vemurafenib in patients with metastatic papillary thyroid cancer harboring BRAF(V600E) mutation. Thyroid. 2013;23:1277-1283.22. Brose MS, Cabanillas ME, Cohen EE, et al. An open-label, multi-center phase 2 study of the BRAF inhibitor vemurafenib in patients with metastatic or unresectable papillary thyroid cancer positive for BRAF V600 mutation and resistant to ra-dioactive iodine (NCT01286753, NO25530). Presented at: the European Cancer Congress (ECCO-ESMO-ESTRO); September 27-October 1, 2013; Amsterdam, The Netherlands. Eur J Cancer. 2013;49(suppl 3):S1-S19.23. Robert C, Karaszewska B, Schacter J, et al. Improved over-all survival in melanoma with combined dabrafenib and trame-tinib. N Engl J Med. 2014;372:30-39.24. Dabrafenib with or without trametinib in treating patients with recurrent thyroid cancer. ClinicalTrials.gov. https://clini-caltrials.gov/ct2/show/NCT01723202. Clinical Trials Identifi-er: NCT01723202.25. Perri F, Pezzullo L, Chiofalo MG, et al. Targeted therapy: a new hope for thyroid carcinomas. Crit Rev Oncol Hematol. 2015;94:55-63. 26. Brose MS, Nutting C, Jarzab B, et al. Sorafenib in locally advanced or metastatic patients with radioactive iodine-refracto-ry differentiated thyroid cancer: the phase III DECISION trial. Lancet. 2014;384:319-328.27. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib ver-sus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372:621-630.28. Leboulleux S, Bastholt L, Krause T, et al. Vandetanib in lo-cally advanced or metastatic differentiated thyroid cancer: a ran-domized, double-blind, phase 2 trial. Lancet Oncol. 2012;13:897-905.29. Locati LD, Licitra L, Agate L, et al. Treatment of advanced thyroid cancer with axitinib: phase 2 study with pharmacoki-netic/pharmacodynamic and quality-of-life assessments. Cancer. 2014;120:2694-2703.30. Cohen EE, Tortorici M, Kim S, et al. A phase II trial of axitinib in patients with various histologic subtypes of ad-vanced thyroid cancer: long-term outcomes and pharmacoki-netic/pharmacodynamics analyses. Cancer Chemother Pharmacol. 2014;74:1261-1270.31. Sherman SI, Wirth LJ, Droz J-P, et al. Motesanib diphos-phate in progressive differentiated thyroid cancer. N Engl J Med. 2008;359:31-42.32. Bibile C, Suman VJ, Molina JR, et al. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated


Molecular Pathogenesis, tyrosine Kinase inhibitors, and other new theraPies

thyroid cancers: results of a phase 2 consortium study. Lancet Oncol. 2010;11:962-972.33. Carr LL, Mankoff DA, Goulart BH, et al. Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differ-entiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res. 2010;16:5260-5268. 34. Marotta V, Di Somma C, Rubino M, et al. Second-line suni-tinib as a feasible approach for iodine-refractory differentiated thyroid cancer after the failure of first-line sorafenib [published online October 11, 2014]. Endocrine. 2014. 35. Cabanillas ME, Brose MS, Holland J, et al. A phase I study of cabozantinib (XL 184) in patients with differentiated thyroid cancer. Thyroid. 2014;24:1508-1514.36. Cabozantinib-S-malate in treating patients with refractory thyroid cancer. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01811212?term=cabozantinib&rank=17. Clinical Tri-als Identifier: NCT01811212.37. Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab. 2006;91:2892-2899.38. Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med. 2013;368:623-632.39. Study comparing complete remission after treatment with selumetinib/placebo in patient with differentiated thyroid can-cer (ASTRA). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01843062. Clinical Trials Identifier: NCT01843062.40. Rothenberg MS, McFadden DG, Palmer EL, et al. Redif-ferentiation of iodine-refractory BRAF V600E-mutant meta-static papillary thyroid cancer with dabrafenib. Clin Cancer Res. 2015;21:1028-1035. 41. Salama JK, Golden DW, Yom SS, et al. ACR Appropriateness Criteria® thyroid carcinoma. Oral Oncol. 2014;50:577-586.


· lymphoma ·

Clinical Controversies of Double-Hit Lymphoma

Deborah M. Stephens, DO, and John W. Sweetenham, MD

IntroductionDouble-hit lymphomas (DHLs), as currently defined by the World Health Organization classification, are those lymphomas express-ing the co-occurrence of MYC and BCL2 or BCL6 rearrange-ment as detected by fluorescence in situ hybridization (FISH) or standard cytogenetics.1 DHLs are not restricted to any particular histologic subtype of lymphoma, although most of the available data are restricted to diffuse large B-cell lymphoma (DLBCL). The presence of cytogenetic abnormalities in addition to MYC rearrangement, such as BCL2 or BCL6 rearrangements, general-ly excludes the diagnosis of Burkitt lymphoma. Aberrant MYC expression is associated with uncontrolled cell growth, division, and metastasis.2 BCL2 is an anti-apoptotic gene, which when dysregulated can lead to extended cell survival.3 BCL6 normal-ly encodes a transcriptional repressor, and when overexpressed can downregulate several other genes, including the p53 tumor suppressor gene, which subsequently allows DNA-damaged cells to escape from apoptosis.4 Theoretically, lymphomas that harbor mutations that lead to both uncontrolled cell growth and an-ti-apoptotic activity demonstrate enhanced survival of malignant cells.5

Clinical data support the predicted aggressive behavior of DHLs. Nineteen patients (4.8%) in the Adult Lymphoma Treat-ment Study Group with de novo DLBCL with both MYC and BCL2 translocations were identified. The dual translocation was observed more frequently in patients with high lactate dehy-

drogenase (LDH), B symptoms, bone marrow involvement, and advanced stage. Progression-free survival (PFS; 0%) and overall survival (OS; 23.3%) rates were significantly lower in patients with the dual translocation than in those with other transloca-tion (compared with PFS rates 36.1% to 69.8% and OS rates 65.2% to 83.7%; P =.001 for all comparisons).6

A single-center analysis of 53 patients with DLBCL identified 17 cases of DHL by FISH or metaphase karyotyping. Median OS was significantly shorter for DHL compared with non-DHL (8.2 vs 56.8 months; P <.001).7 Another study identified 54 (4%) of 1260 patients with lymphoma with dual translocation by FISH. This group was more likely to have bone marrow involvement, a high International Prognostic Index (IPI) score, and to have demonstrated a median OS of less than 1 year.5 MD Anderson reported its experience with 129 cases of DHLs. The 2-year event-free survival (EFS) was much lower than reported outcomes in patients with DLBCL and was reported as 25%, 67%, and 32% in patients who received R-CHOP (rituximab, cyclophospha-mide, doxorubicin, vincristine, and prednisone), R-EPOCH (rit-uximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), and R-Hyper-CVAD/MA (rituximab-hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate-cytarabine), respectively.8

As a result of the poor clinical outcomes in this subset of DLBCL, much research interest has been directed at DHL in the past few years. Many clinical controversies in diagnosis and treat-ment surround this subtype of lymphoma, and this article’s aim is to review and provide our input regarding these controversies.

Controversy #1: Is the current definition of “double-hit” lym-phoma adequate?We argue that the current definition of “double-hit” lymphoma does not encompass all clinically or pathologically distinct sub-types. MYC, BCL2, and BCL6 rearrangements can be detected by FISH or cytogenetics; however, the genes can also be amplified, mutated, or overexpressed as detected by immunohistochemis-try (IHC) or comparative genome hybridization. Many studies have investigated the clinical impact of “double-protein”-ex-pressing lymphoma as detected by IHC, and also found neg-ative clinical implications (Table)9-14 as observed in “double-hit”

Abstract

Double-hit lymphoma (DHL) has been identified as a

subset of diffuse large B-cell lymphoma with poor clin-

ical outcomes. Because minimal data about this subtype

of lymphoma have been published, many controversies

in diagnosis and treatment surround DHL. In this article,

we review the current definition, proper diagnosis, cen-

tral nervous system prophylaxis, current treatment reg-

imens, and potential novel therapeutic options for DHL.

Key words: double-hit lymphoma, double-protein ex-

pressing lymphoma, diffuse large B-cell lymphoma


CliniCal Controversies of Double-Hit lympHoma

lymphoma (as detected by FISH). The use of IHC is an appealing alternative to FISH, as FISH is not always readily available, and is costly and time-consuming. However, traditional IHC tech-niques and scoring are performed visually by pathologists and have been reported to be quite variable. Additionally, optimal cutoff points between positive and negative IHC stains have not been firmly established.

In published data of the double-protein-expressing DLBCL, most studies have considered the sample to be MYC-positive if the IHC stains demonstrate ≥40% MYC-expressing cells. However, the cutoff point is more discordant for BCL2 positiv-ity with studies reporting values of ≥30% to ≥70% BCL2-pos-itive cells (Table).5,9,10,12-14 We consider ≥40% MYC-positive cells with ≥70% BCL2-positive cells to be a double-protein-ex-pressing DLBCL. The Figure depicts a representative pathology sample of a double-protein-expressing DLBCL.

Controversy #2: Should all patients with DLBCL be tested to determine whether they have DHLs?We argue that all DLBCL patient pathology samples should be tested for MYC, BCL2, and BCL6 translocations and by IHC because there are adverse clinical implications for these patients that will require alternate or targeted treatment approaches (See “Controversy #4”). We have described the adverse clinical im-plications for patients with both traditional double-hit DLBCL and double-protein-expressing DLBCL in the Introduction. Emerging evidence shows that although these 2 patient groups have lower PFS and OS, a patient with double-protein-expressing DLBCL may not have DHL. In a combined data set of 290 pa-tients with DLBCL initially treated with RCHOP, 14 cases (5%) of DHL were detected. These patients had worse 5-year PFS and OS rates (18% and 27%, respectively) than the remaining pa-tients who were double-protein-expressing (n = 55; 5-year PFS =

Table. Retrospective Studies Detailing Methods of Diagnosis and Outcomes for Patients With Double-Protein-Expressing Lymphoma

DE indicates double protein expressor; EFS, event-free survival; IHC, immunohistochemistry; OS, overall survival; PFS, progression-free survival; R-ACVBP, rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-EPOCH, rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin.

aCompared with patients without double protein expression.bValidation cohort.cR-CHOP/R-miniCHOP: n = 433; R-ACVBP: n = 237.

authors IHC Cutoff MYC+ (%)

IHC Cutoff bCl2+ (%)

N De (%) Regimen De Impact on PFSa

De Impact on OSa

Green et al9 ≥40 ≥70 193 29 R-CHOP 3-yr PFS 39% vs 75%

(P <.001)

3-yr OS 43% vs 86%

(P <.001)

Hu et al10 ≥40 ≥70 466 34 R-CHOP 5-yr PFS 27% vs 73%

(P <.001)

5-yr OS 30% vs 75%

(P <.001)

Johnson et al11 ≥40 ≥50 167 21 R-CHOP 5-yr PFS 21% vs 63%

(P = .020)b

5-yr OS 30% vs 70%

(P = .018)b

Molina et al12 ≥40 ≥70 670 21 R-CHOP/ R-miniCHOPor R-ACVBPc

Decreased PFS (P = .003)

Decreased OS(P = .005)

Perry et al13 ≥50 ≥30 106 44 CHOP+/-R Independent pre-dictor of EFS (P = .0017)

Independent predictor of OS

(P <.001)

Dunleavy et al14 ≥40 Same or more intense staining as T-cell control

66 20 R-EPOCH 10-yr PFS = 67.5%; 10-yr PFS not infe-rior to other groups

(P = .5)

10-yr OS = 75%; 10-yr OS not

inferior to other groups (P = .8)


· lymphoma ·

32%; 5-year OS = 36%; P <.05). Additionally, both groups had lower 5-year PFS and OS when compared with patients with-out double-hit or double-protein-expressing disease (n = 236; 5-year PFS = 65%; 5-year OS = 71%; P 0.05).11 These data in-dicate that there may be a difference in these 2 patient groups that may require different targeted treatment strategies, as described below.

Some proponents of limiting the amount of patients evalu-ated for DHL have suggested restricting evaluation to patholo-gy samples that have a high Ki67 index (or MiB-1 IHC stain-ing), based on an initial study that demonstrated patients with MYC-aberrant DLBCL were more likely to have a Ki67 index >80%.15 However, subsequent studies have found that Ki67 in-dex cannot be used as a baseline predictive factor for double-hit status.7, 11 One study found that only 1 out of 14 confirmed cases of double-hit lymphoma had a Ki67 index >90%.11 These data suggest that testing for double-hit or double-protein-expressing lymphoma should not be limited to those DLBCL samples with high-proliferation indices.

Another argument has been to limit testing for double-hit or double-protein-expressing DLBCL to those samples that have a germinal center B-cell–like (GCB) cell of origin as initial stud-ies reported that MYC-rearranged DLBCL16,17 and FISH-defined double-hit DLBCL18 were strongly associated with GCB deriva-tion. However, a large study of 893 patients demonstrated that double-protein-expressing lymphomas were more likely to have activated B-cell (ABC) cell of origin.10 Therefore, until a clear-cut way to predict which DLBCL sample will be a double-hit or double-protein-expressing lymphoma, we feel that all DLBCL samples should be closely scrutinized for rearrangements and protein expression.

Controversy #3: Should all patients receive intrathecal prophy-laxis for central nervous system disease?A clinical dilemma is whether these patients require central ner-vous system (CNS) prophylaxis. Multiple cases of an increased in-cidence of CNS involvement have been reported. A small study described 40 patients with DLBCL with leukemic-phase disease, 14 of whom had CNS disease. Eight of these patients had FISH-confirmed double-hit lymphoma. In logistic regression analysis, double-hit status was found to be the one independent factor correlated with CNS involvement.19 In the MD Anderson experience, the incidence of CNS involvement at diagnosis was 4%, with a cumulative incidence of CNS involvement of 13% at 3 years. In patients who did not have documented CNS disease at the time of diagnosis, the incidence of eventual CNS involve-ment was lower in those receiving prophylactic intrathecal ther-apy (5% at 3 years) than in those who did not (15% at 3 years; P =.017).8 At this time, secondary to the paucity of data, we can make no firm recommendations about using CNS prophylaxis in this set of patients, but feel that these data indicating a potential

higher risk of CNS disease should be discussed with the patient, along with the risks of intrathecal chemotherapy administration.

Controversy #4: What are the best treatment options for pa-tients with double-hit or double-protein-expressing lymphoma?As described in the Introduction, prognosis for this patient group when treated with standard DLBCL therapy of R-CHOP is guarded, and novel approaches are needed to improve survival in this group. Strategies previously investigated for this patient group include intensification of induction regimens and/or im-mediate consolidation with autologous or allogeneic stem cell transplantation (SCT). From the start, this strategy is hampered by the typical demographics of this group, in which elderly pa-tients—the majority with comorbid conditions—are heavily over-represented.11 Additionally, published data to guide treatment options for this group is limited to mostly small retrospective studies, the majority with a focus on FISH-defined DHL. Many of these studies have contradictory findings.

Data evaluating the need for a more intensive induction che-motherapy are described by several small retrospective analyses. In a single-center analysis, 33 patients with DHL received thera-py with R-CHOP (n = 15), R-EPOCH (n = 12), or R-CODOX-M/IVAC (n = 6; rituximab-cyclophosphamide, vincristine, doxoru-bicin with methotrexate/ifosfamide, etoposide, and cytarabine). Although this was a small retrospective analysis, the median PFS

FIGURe. Representative Pathology Sample Depicting Double Protein Expressing Diffuse Large B Cell Lymphoma

A. Hematoxylin and eosin stainingB. MYC immunohistochemical (IHC) staining (~70% positive

in this sample)C. MIB-1 IHC staining (~90% positive in this sample)D. BCL2 IHC staining (~80% positive in this sample)

A

C

B

D



and OS for patients who received R-EPOCH were 21 and 34 months, respectively, compared with 6 and 8 months for pa-tients who received RCHOP, and 6 and 7 months for patients who received R-CODOX-M/IVAC. This small study indicated a possible improvement in clinical outcomes for patients with DHL who receive therapy with R-EPOCH.20 In another small single-center analysis, 31 patients with DHL received therapy with R-CHOP (n = 15), R-EPOCH (n = 8), R-Hyper-CVAD (n = 6), or other (n = 2). This study demonstrated no statistical difference in PFS or OS when comparing R-CHOP with the oth-er regimens. However, this study was small and restricted by the low number of patients.21

Additional small retrospective studies have attempted to an-swer the question of whether consolidation with SCT should be required for patients with DHL. One small study supporting the use of SCT for this population included 36 patients with DHL where 24 patients (66%) were treated with a dose-intense (DI) induction regimen (R-Hyper-CVAD, R-EPOCH, or R-CO-DOX-M/IVAC) and 12 patients (33%) received a standard-dose (SD) induction regimen (R-CHOP or R-CHOP–like). The group found a statistically significant increase in the PFS of patients treated with a DI (46 months) versus SD regimen (8 months; HR = .26; P =.005). Within the DI group, 42% of the patients underwent SCT (73% allogeneic). Of the patients who received DI and SCT, there was additional increase in OS compared with patients who received SD; this was not seen in the patients who received DI and did not receive SCT. However, this study is likely limited by small numbers and generally favorable patient char-acteristics in those patients selected for intensive induction and SCT.22

In contrast, other small studies do not support a survival ad-vantage for the patients who receive SCT as a frontline therapy for DHL. A retrospective study of 52 patients with DHL was reported with 19 patients who received R-CHOP and 30 pa-tients who received aggressive therapy with the R-Hyper-CVAD regimen. Eleven patients went on to autologous SCT. There was no statistically significant difference in PFS or OS between the patients who received R-Hyper-CVAD or other treatments and those who underwent SCT versus no SCT.18 In a retrospective review of 27 patients with DHL, 20 patients received treatment with an aggressive regimen of R-CODOX-M/IVAC, with the remainder receiving R-CHOP–like regimens. Fourteen patients went on to receive SCT (7 autologous and 7 allogeneic). Over-all, the 2-year EFS was 35%. For patients who received R-CO-DOX-M/IVAC and those who received this regimen followed by SCT, the 2-year EFS was 37% and 43%, respectively.23 These pa-tients were likely highly selected for good performance status but did not have improved survival despite the aggressive therapy.

In a retrospective study of 54 patients with DHL, 6 patients received high-dose chemotherapy with or without SCT; howev-er, this group had similar poor outcomes compared with those

patients (n = 14) treated with palliative care (median survival, 3 months vs 1 month, respectively; P >.05).5

Two large retrospective studies support the notion that regard-less of induction regimen or SCT, achieving a complete response (CR) to induction therapy is a more accurate prognostic factor than the choice of therapy. In MD Anderson Cancer Center’s experience of 129 patients with DHL, CR rates in response to frontline R-EPOCH (68%) or R-Hyper-CVAD/M (68%) were higher than those observed among patients who received R-CHOP (40%; P ~.01 for both comparisons). Interestingly, despite a higher CR rate after R-Hyper-CVAD/M, the clinical outcomes were similar between these patients and those who received R-CHOP. In contrast, patients receiving R-EPOCH demonstrated a longer EFS (P =.004) and OS (P =.057) than those patients who received R-CHOP. In patients who achieved a CR with induction therapy (n = 71), the 2-year OS rates were 70% and not statistically different between patients who did (n = 23) or did not (n = 48) receive SCT.8

The largest retrospective study of patients with DHL described 311 patients treated at 23 academic centers. Of the patients, 32% (n = 100) received R-CHOP, 21% (n = 64) R-EPOCH, 21% (n = 65) R-Hyper-CVAD, 14% (n = 42) R-CODOX-M/IVAC, 3% (n = 9) RICE (rituximab, ifosfamide, carboplatin, etoposide), and 10% (n = 31) other. After achieving CR, 53 patients (17%) went on to receive SCT (autologous, n = 39). Although PFS was pro-longed for patients who received any intensive induction regi-men compared with R-CHOP (P =.001), OS was not statistically different between the 2 groups (P =.564). Among patients who achieved CR to frontline therapy, median OS was similar for those who were observed (103 months) and those who under-went consolidation SCT of any type (OS not reached; P =.14). This study concluded that achievement of CR with induction therapy, a measure of chemotherapy sensitivity, was a more im-portant predictive factor of outcome than type of induction ther-apy or whether or not a patient received SCT.24 In summary, data gleaned from these retrospective studies indicate that:

• A more-intensive induction regimen than R-CHOP is likely needed to induce CR in patients with DHL

• CR appears to be a more predictive factor of outcome than choice of initial therapy

• Patients with DHL do not necessarily need to proceed di-rectly to consolidation with SCT, especially those who can achieve CR with induction therapy

In limited prospective data, the R-EPOCH regimen has come forth as a promising frontline treatment for patients with dou-ble-hit or double-protein-expressing DLBCL. The NIH analyzed 2 prospective studies of 59 patients with DLBCL who received R-EPOCH at their institution (10% with MYC rearrangement). They found no difference in 4-year EFS between patients with and without MYC rearrangement (83% vs 76%, respectively; P


· lymphoma ·

=.46).25 The same group reviewed 66 patients with DLBCL who received R-EPOCH (20% double-protein-expressing) and found no difference in 10-year OS between double-protein-expressing patients versus all others.14 The NIH group led a multicenter prospective phase II study including 52 patients with MYC-re-arranged DLBCL (BCL2 was rearranged in 14/31 and overex-pressed by IHC in 24/43 cases tested). With a median follow-up of 14 months, this preliminary report described PFS and OS of 79% and 77%, respectively. PFS was 87% and 64%, respectively, in cases that were FISH-positive and IHC-positive for BCL2.26

With a paucity of data using standard regimens, attention has turned to evaluation of these patient groups in clinical tri-als. Intuitively, drugs that directly or indirectly interfere with MYC function are attractive therapeutic targets. Preclinical data showed that mammalian target of rapamycin (mTOR) complex 1–dependent evasion of senescence is critical for cellular trans-formation and tumor maintenance by MYC in B-lymphocytes.27 In mouse models of MYC-associated lymphoma, mTOR inhibi-tion demonstrated promising activity.28 In a phase II study, temsi-rolimus (an mTOR inhibitor) demonstrated single-agent activity in DLBCL.29 Although preclinical data showed that an aurora A kinase inhibitor in combination with a histone deacetylase inhibitor enhanced lymphoma cell death through repression of C-MYC and C-MYC-responsive microRNAs,30 in a small clinical trial of this combination, the 3 patients with DHL developed progressive disease.31 MLN9708, a second-generation protea-some inhibitor, degraded MYC and induced cell death at nano-molar concentrations in preclinical lymphoma models32; howev-er, a phase I trial in relapsed/refractory lymphoma showed only modest single-agent activity.33 Bromodomain and extraterminal proteins have demonstrated selective sensitivity toward MYC in-hibition, and small-molecule inhibitors of this pathway may pres-ent a future therapeutic option for MYC-associated lymphomas.

Another obvious druggable target is BCL2. ABT-199 is a platelet-sparing BCL2 inhibitor that has shown early success in chronic lymphocytic leukemia. As a single agent, a very prelimi-nary report described responses to ABT-199 in 3 of the 8 patients with relapsed/refractory DLBCL treated in the higher-dose co-horts.34 Recently published preclinical data showed that ABT-199 may enhance the antitumor activity of chemotherapy agents including doxorubicin, cytarabine, and bortezomib in DHL cell lines.35 These data have prompted clinical investigation of ABT-199 combinations; however, the trials are still in early stages.

Other potentially interesting therapies for double-hit or double-protein-expressing lymphomas under early investigation include small-molecule inhibitors of BCL636 and chimeric anti-gen receptor modified T-cells directed against CD19+ B-cells.37

As there are no definitive data to describe the best treat-ment for these patients, our practice is to enroll these patients in a clinical trial if available. Outside of a clinical trial, dose-ad-justed R-EPOCH is our preferred regimen. We do not routine-

ly refer patients for consolidation to SCT, especially those who achieve CR with induction chemotherapy. ConclusionIn summary, many diagnostic and clinical controversies surround double-hit and double-protein-expressing DLBCL. In our opin-ion, although both double-hit and double-protein expressing lymphomas appear to have poor prognosis, these groups should be classified separately as they appear to have different clinical outcomes. We feel that all DLBCL should be tested for both dual translocation and dual protein-expressing status as treatment rec-ommendations may differ from other DLBCL. Our practice is to enroll these patients in clinical trials when available; we prefer dose-adjusted R-EPOCH for treatment off-study. We do not rou-tinely refer patients for consolidation to SCT, especially those who achieve CR with induction chemotherapy. Secondary to the increased incidence of CNS involvement of these lymphomas, CNS prophylaxis should at least be discussed with the patient. We strongly support investigation of new agents in this patient population.

Acknowledgment: The authors would like to thank Dr Rodney Miles from the University of Utah Hematopathology Depart-ment for preparation of the Figure.Affiliations: Drs Stephens and Sweetenham are from the Divi-sion of Hematology, Department of Internal Medicine, Univer-sity of Utah, Salt Lake City.Disclosures: Drs Stephens and Sweetenham report no relevant conflicts of interest to disclose. Address correspondence to: Deborah M. Stephens, DO, Hunts-man Cancer Institute, The University of Utah, 2000 Circle of Hope, Room 4246, Salt Lake City, UT 84112. Phone: 801-587-4354; fax: 801-581-4136; email: [email protected].

ReFeRenCeS1. Swerdlow SH, Campo E, Harris NL, et al. World Health Orga-nization Classification of Tumours of Haematopoietic and Lymphoid Tissue, 4th Edition. Lyon, France: International Agency on Re-search for Cancer; 2008.2. Adhikary S, Eilers M. Transcriptional regulation and transfor-mation by Myc proteins. Nat Rev Mol Cell Biol. 2005;6:635-645.3. Korsmeyer SJ. Bcl-2 initiates a new category of oncogenes: reg-ulators of cell death. Blood. 1992;80:879-886.4. Phan RT, Dalla-Favera R. The BCL6 proto-oncogene sup-presses p53 expression in germinal-centre B cells. Nature. 2004;432:635-639.5. Johnson NA, Savage KJ, Ludkovski O, et al. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood. 2009;114:2273-2279.6. Niitsu N, Okamoto M, Miura I, Hirano M. Clinical features and prognosis of de novo diffuse large B-cell lymphoma with



t(14;18) and 8q24/c-MYC translocations. Leukemia. 2009;23:777-783.7. Landsburg DJ, Nasta SD, Svoboda J, et al. ‘Double-hit’ cytoge-netic status may not be predicted by baseline clinicopathological characteristics and is highly associated with overall survival in B cell lymphoma patients. Br J Haematol. 2014;166:369-374.8. Oki Y, Noorani M, Lin P, et al. Double hit lymphoma: the MD Anderson Cancer Center clinical experience. Br J Haematol. 2014;166:891-901.9. Green TM, Young KH, Visco C, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclo-phosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30:3460-3467.10. Hu S, Xu-Monette ZY, Tzankov A, et al. MYC/BCL2 pro-tein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The Interna-tional DLBCL Rituximab-CHOP Consortium Program. Blood. 2013;121:4021-4031; quiz 4250.11. Johnson NA, Slack GW, Savage KJ, et al. Concurrent expres-sion of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30:3452-3459.12. Molina TJ, Briere J, Copie-Bergman C, et al. Overexpression of MYC, BCL2, MYC/BCL2, IGM, and non-germinal centre B cell-like immunophenotype predicts a worse progression-free sur-vival and overall survival in a series of 670 de novo diffuse large B-cell lymphomas: S Lysa Study. Hematol Oncol Clin North Am. 2013;31(suppl 1):151-200. Abstract 178.13. Perry AM, Alvarado-Bernal Y, Laurini JA, et al. MYC and BCL2 protein expression predicts survival in patients with dif-fuse large B-cell lymphoma treated with rituximab. Br J Haematol. 2014;165:382-391.14. Dunleavy K, Pittaluga S, Shovlin M, et al. Concurrent expres-sion of MYC/BCL2 protein in newly diagnosed DLBCL is not associated with an inferior survival following EPOCH-R therapy. Presented at: the 2013 American Society of Hematology Annual Meeting; December 7-10, 2013; New Orleans, LA. Blood. 2013. Abstract 3029.15. Savage KJ, Johnson NA, Ben-Neriah S, et al. MYC gene rear-rangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood. 2009;114:3533-3537.16. Horn H, Ziepert M, Becher C, et al. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood. 2013;121:2253-2263.17. Valera A, Lopez-Guillermo A, Cardesa-Salzmann T, et al. MYC protein expression and genetic alterations have prognos-tic impact in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Haematologica. 2013;98:1554-1562.

18. Li S, Lin P, Fayad LE, et al. B-cell lymphomas with MY-C/8q24 rearrangements and IGH@BCL2/t(14;18)(q32;q21): an aggressive disease with heterogeneous histology, germinal center B-cell immunophenotype and poor outcome. Mod Pathol. 2012;25:145-156.19. Shuhua Y, Zhong S, Zou D et al. BCL2 and MYC rearrange-ments in leukemic phase of diffuse large B-cell lymphoma pre-dicts central nervous system involvement. Presented at: the 2014 American Society of Hematology Annual Meeting; December 5-8, 2014; San Francisco, CA. Blood. 2014. Abstract 2958.20. Abramson JS, Barnes JA, Feng Y, et al. Double hit lympho-mas: evaluation of prognostic factors and impact of therapy. Presented at: the 2012 American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 1619.21. Tsai J, Greer JP, Morgan DS, et al. Role of aggressive che-motherapeutic regimens in double hit lymphoma: can alternate aggressive induction regimens overcome the poor prognosis of diffuse large B cell lymphoma? Presented at: the 2013 American Society of Hematology Annual Meeting; December 7-10, 2013; New Orleans, LA. Blood. 2013. Abstract 4361.22. Howlett C, Goy A, Zielonka T, et al. Dose intensive induc-tion followed by allogeneic stem cell transplantation more than doubles progression-free and overall survival in “double-hit’ lym-phoma. Presented at: the 2013 American Society of Hematology Annual Meeting; December 7-10, 2013; New Orleans, LA. Blood. 2013. Abstract 2141.23. Sun H, Savage KJ, Karsan A, et al. Outcome of patients with double-hit lymphomas treated with CODOX-M/IVAC + R fol-lowed by hematopoietic stem cell transplantation in British Co-lumbia. Presented at: the 2013 American Society of Hematology Annual Meeting; December 7-10, 2013; New Orleans, LA. Blood. 2013. Abstract 1788.24. Petrich AM, Cassaday RD, Press OW, et al. Impact of in-duction regimen and consolidative stem cell transplantation in patients with double hit lymphoma: a large multicenter retro-spective analysis. Presented at: the 2013 American Society of He-matology Annual Meeting; December 7-10, 2013; New Orleans, LA. Blood. 2013. Abstract 640.25. Dunleavy K, Pittaluga S, Wayne A. MYC+ aggressive B-cell lymphomas: novel therapy of untreated Burkitt lymphoma and MYC+ diffuse large B-cell lymphoma with DA-REPOCH. Ann Oncol. 2011;22(suppl 4):71.26. Dunleavy K, Fanale M, LaCasce A, et al. Preliminary report of a multicenter prospective phase II study of DA-EPOCH-R in MYC-rearranged aggressive B-cell lymphoma. Presented at: the 2014 American Society of Hematology Annual Meeting; Decem-ber 5-8, 2014; San Francisco, CA. Blood. 2014. Abstract 395.27. Wall M, Poortinga G, Stanley KL, et al. The mTORC1 inhibi-tor everolimus prevents and treats Emu-Myc lymphoma by restor-ing oncogene-induced senescence. Cancer Discov. 2013;3:82-95.28. Pourdehnad M, Truitt ML, Siddiqi IN, et al. Myc and mTOR


· lymphoma ·

converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. Proc Natl Acad Sci U S A. 2013;110:11988-11993.29. Smith SM, van Besien K, Karrison T, et al. Temsirolimus has activity in non-mantle cell non-Hodgkin’s lymphoma subtypes: The University of Chicago phase II consortium. J Clin Oncol. 2010;28:4740-4746.30. Kretzner L, Scuto A, Dino PM, et al. Combining histone deacetylase inhibitor vorinostat with aurora kinase inhibitors en-hances lymphoma cell killing with repression of c-Myc, hTERT, and microRNA levels. Cancer Res. 2011;71:3912-3920.31. Fanale MA, Hagemeister FB, Fayad L, et al. A phase I trial of alisertib plus romidepsin for relapsed/refractory aggressive B- and T-cell lymphomas. Presented at: the 2014 American Society of Hematology Annual Meeting; December 5-8, 2014; San Fran-cisco, CA. Blood. 2014. Abstract 1744.32. Evens AM, Dashnamoorthy R, Kandela I, Mazar A. The novel 2nd generation proteasome inhibitor MLN9708 induces redox- and MAPK-related cell death in T-cell lymphoma and Hodgkin lymphoma cell lines and human lymphoma xenograft models. Hematol Oncol Clin North Am. 2013;31(suppl 1):96-150. Abstract 030.33. Assouline S, Chang JE, Cheson BD, et al. Results of a phase 1 dose-escalation study of once-weekly MLN9708, an investiga-tional proteasome inhibitor, in patients with relapsed/refractory lymphoma. Presented at: the 2012 American Society of Hema-tology Annual Meeting; December 8-11, 2012; Atlanta, GA. Ab-stract 3646.34. Davids MS, Seymour JF, Gerecitano JF, et al. Phase I study of ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL): responses observed in diffuse large B-cell (DLBCL) and follicular lymphoma (FL) at higher co-hort doses. J Clin Oncol. 2014;32(15 suppl; abstr 8522).35. Johnson-Farley N, Veliz J, Bhagavathi S, Bertino JR. ABT-199, a BH3 mimetic that specifically targets Bcl-2, enhances the antitumor activity of chemotherapy, bortezomib, and JQ1 in “double hit “ lymphoma cells. Leuk Lymphoma. 2014:1-12.36. Cerchietti LC, Ghetu AF, Zhu X, et al. A small-molecule in-hibitor of BCL6 kills DLBCL cells in vitro and in vivo. Cancer Cell. 2010;17:400-411.37. Sauter CS, Riviere I, Bernal YJ, et al. Interim safety analysis: a phase I trial of high dose therapy and autologous stem cell trans-plantation followed by infusion of chimeric antigen receptor modified T-cells (19-28z CAR-T) directed against CD19+ B-cells for relapsed and refractory aggressive B-cell non-Hodgkin lym-phoma. Presented at: the 2014 American Society of Hematology Annual Meeting; December 5-8, 2014; San Francisco, CA. Blood. 2014. Abstract 677.


· breast cancer ·

HER2-Positive Breast Cancer: Update on New and Emerging Agents

Alexandra Drakaki, MD, and Sara A. Hurvitz, MD

IntroductionBreast cancer remains the most common cancer diagnosed in women, and in spite of significant improvements in treatment, it is still the second leading cause of cancer-related deaths.1 Re-search in the last several decades has led to a better understand-

ing of the complex molecular heterogeneity of this malignancy. One such discovery was the identification of the HER2 gene, which encodes a tyrosine kinase receptor that is a potent media-tor of cellular growth and proliferation in normal and malignant epithelial cells. Amplification of this gene is observed in up to 25% of breast cancers and has been shown to be a driving force of tumor biology.2,3

This discovery led to the development and approval of the first HER2-targeted therapy, trastuzumab.4 Since that time, sev-eral other HER2-targeted therapeutics have been successfully de-signed and approved for the treatment of HER2-positive breast cancer. It is now clear that the routine use of trastuzumab and other HER2-targeted agents has dramatically improved the prog-nosis associated with HER2-driven breast cancer. This article will briefly review the current available therapies for HER2-positive breast cancer, describe several newly approved agents, and pro-vide a concise consideration of novel therapies currently under investigation.

Trastuzumab or Lapatinib in the Early- and Late-Stage SettingsTrastuzumab is a recombinant humanized monoclonal antibody (mAb) that inhibits ligand-independent HER2 and HER3 signal-ing5 and may trigger antibody-dependent cellular cytotoxicity.6,7 Multiple trials have studied its role in the adjuvant, neoadjuvant, and metastatic settings. The addition of trastuzumab to chemo-therapy in patients with previously untreated metastatic breast cancer (MBC) led to a significantly higher objective response rate, prolonged time to progression (TTP; 7.4 vs 4.6 months; P <.001), and improved overall survival (OS; 25 vs 20 months; P = .01) compared with chemotherapy alone.4 Furthermore, in patients with early-stage breast cancer, the addition of tras-tuzumab to chemotherapy significantly improved disease-free survival (DFS) and OS in multiple clinical trials in the early and locally advanced settings.8-12

Abstract

The most common malignancy and second leading

cause of cancer-related death in women is breast cancer.

An improved understanding of breast cancer pathobiolo-

gy has led to the development of novel therapies that are

directed at proteins uniquely expressed on tumor cells.

One such targeted approach is trastuzumab for HER2-am-

plified/overexpressing breast cancer. Since the approval

of trastuzumab for HER2-positive metastatic breast can-

cer in 1998, outcomes for patients diagnosed with this

innately aggressive form of cancer have vastly improved.

Subsequently, several new therapies have been devel-

oped for HER2-positive breast cancer, including lapatinib

(a small-molecule inhibitor of HER1 and HER2 tyrosine

kinase), pertuzumab (a HER2-directed monoclonal anti-

body), and trastuzumab emtansine (T-DM1; the first an-

tibody-drug conjugate approved for breast cancer). In

addition, several emerging agents are currently being

evaluated in clinical trials for HER2-positive breast can-

cer. In this review, the current available therapies for

HER2-positive breast cancer will be described, and inno-

vative HER2-directed approaches that are currently under

investigation will be explored.

Key words: Breast cancer, HER2-targeted therapy, tras-

tuzumab, pertuzumab, lapatinib, T-DM1, trastuzumab

emtansine


· breast cancer ·

While evidence consistently shows that in the absence of HER2-directed therapy, HER2-positive disease has a poor-er prognosis compared with HER2-normal cancer, recent studies are now indicating that the prognosis associated with trastuzumab-treated HER2-positive breast cancer is better than that for HER2-normal breast cancer, thus indicating that trastu-zumab has altered the natural history of HER2-driven cancer.13,14

Lapatinib is a dual tyrosine kinase inhibitor (TKI) of HER2 and epidermal growth factor receptor (EGFR or HER1). Pa-tients with advanced breast cancer or MBC who have already progressed on regimens that included trastuzumab, an anthracy-cline, and a taxane had a better TTP (8.4 vs 4.4 months; P <.001) when they received lapatinib in combination with capecitabine compared with those who received capecitabine alone.15 These were the first results to show that continuing HER2-targeted therapy after progression on a HER2-targeted regimen improves outcomes. Moreover, these data led to the FDA approval of lapa-tinib in 2007.

Trastuzumab and lapatinib have each been combined with chemotherapy16 or endocrine therapy17,18 in clinical trials for HER2-positive MBC, and have demonstrated acceptable safety profiles and improved outcomes compared with sin-gle-agent chemotherapy or endocrine therapy. While data sup-port the use of trastuzumab- or lapatinib-based therapy in the trastuzumab-pretreated advanced disease setting,19 a head-to-head study of paclitaxel plus trastuzumab or lapatinib in the frontline setting showed improved progression-free survival (PFS) in the trastuzumab arm.20 Thus, trastuzumab-based therapy remains the optimal choice in the first-line setting.

Trastuzumab has been evaluated in several studies in the neo-adjuvant setting and has been shown to improve outcomes com-pared with chemotherapy alone.11,12 However, when lapatinib was compared with trastuzumab in combination with neoadjuvant anthracycline-taxane–based chemotherapy in the GeparQuinto trial,21 the pathologic complete response (pCR) rate at the time of surgery was significantly lower in the lapatinib group (93 of 307 patients [30.3%] in the trastuzumab group and 70 of 308 patients [22.7%] in the lapatinib group; P =.04). Therefore, the use of lapatinib alone or in combination with chemotherapy is not supported by evidence in the neoadjuvant setting.

Dual Receptor Blockade: Lapatinib Plus TrastuzumabPreclinical studies have demonstrated synergy in vitro and in vivo by combining lapatinib with trastuzumab.22,23 Based on these data, clinical evaluation of dual HER2 targeting was undertaken, and ultimately showed that in heavily pretreated, trastuzumab-re-sistant HER2-positive MBC, PFS and OS were improved with trastuzumab plus lapatinib compared with lapatinib alone.24,25 These data therefore support the use of trastuzumab in combina-

tion with lapatinib in trastuzumab-pretreated MBC.Dual HER2 targeting with lapatinib and trastuzumab has also

been evaluated in the early-stage setting but has demonstrated conflicting results. In the phase II CHER LOB trial,26 paclitaxel was combined with trastuzumab, lapatinib, or their combina-tion, followed by an anthracycline-based regimen. Patients in the lapatinib-trastuzumab combination arm had a 46.7% pCR rate compared with 25% in the trastuzumab arm and 26.3% in the lapatinib arm.

Similarly, in the phase III NeoALTTO study,27 paclitaxel was given in combination with lapatinib or trastuzumab or both. While the pCR rate (with pCR defined as no invasive cancer in breast and no cancer metastases in lymph nodes, or American Joint Committee on Cancer stage ypT0/is ypN0) was signifi-cantly higher in the group receiving both HER2-targeted drugs (46.8% for lapatinib plus trastuzumab vs 27.6% for trastuzumab vs 20.0% for lapatinib; P = .007), the event-free survival (EFS) and OS were no different in the combination arm compared with single-agent HER2-targeted therapy.28 In contrast to these 2 studies, the phase III NSABP B-41 trial,29 in which patients received paclitaxel plus lapatinib and/or trastuzumab after doxo-rubicin/cyclophosphamide, showed no significant difference be-tween treatment arms in terms of pCR.

In addition to these data in the neoadjuvant setting, the ALT-TO study30 revealed that adjuvant lapatinib plus trastuzumab did not improve DFS compared with trastuzumab alone, underscor-ing the lack of data to support the use of lapatinib in the curative setting.

What’s Neu With HER (HER2/neu): Pertuzumab and T-DM1Pertuzumab is a novel humanized mAb directed at the dimeriza-tion domain (domain 2) of HER2. Specifically, it inhibits li-gand-dependent signaling between HER2 and HER3, which is known to activate a potent cell-survival signal. Because of the different binding sites, trastuzumab and pertuzumab have dif-ferent but similar and complementary mechanisms of action.31

The combination of pertuzumab with trastuzumab was evaluated in a large phase III randomized trial in the first-line HER2-positive MBC setting.32,33 The results of this study showed that the addition of pertuzumab to trastuzumab and docetaxel significantly prolonged both PFS and OS compared with tras-tuzumab and docetaxel alone. Based on these data, in 2012 the FDA approved pertuzumab in combination with trastuzumab and docetaxel for HER2-positive MBC in patients who had re-ceived no prior HER2-directed therapy.

Two phase II trials have evaluated pertuzumab-plus-trastuzum-ab–based therapy in the neoadjuvant setting. In the randomized, multicenter phase II NeoSphere trial,34 pertuzumab and/or tras-tuzumab with or without docetaxel were given for 4 cycles prior


HER2-PositivE BREast CanCER

to surgery. In this trial, the use of dual HER2-targeted therapy with pertuzumab and trastuzumab combined with docetaxel was associated with a significantly improved pCR (45.8%) compared with pertuzumab or trastuzumab plus docetaxel (24% and 29%, respectively).34

The cardiac safety of pertuzumab plus trastuzumab combined with chemotherapy was evaluated in the phase II, randomized neoadjuvant TRYPHAENA study.35 In 2 of the treatment arms, trastuzumab (H) and pertuzumab (P) were given concurrently or sequentially with an anthracycline-based (5-fluorouracil, epiru-bicin, cyclophosphamide [FEC] followed by docetaxel [T]) che-motherapy regimen (FECHP-THP and FEC-THP). A third arm evaluated the safety of concurrent docetaxel and carboplatin with trastuzumab and pertuzumab (TCHP). Low rates of symp-tomatic systolic dysfunction were noted in all 3 arms in this rel-atively small study, and there was no evidence that pertuzumab increased the rate of cardiac dysfunction. Although the primary endpoint of this trial was cardiac safety, the secondary endpoint was pCR. The pCR rates were high in all 3 treatment arms (61.6% vs 57.3% vs 66.2%).

Based on the results of these 2 studies, in September 2013 the FDA approved 3 neoadjuvant regimens for HER2-positive breast cancer (THP x 4 cycles; FEC x 3 cycles followed by THP x 3 cycles; and TCHP x 6 cycles). Subsequently, National Com-prehensive Cancer Network (NCCN) guidelines supported the use of pertuzumab with trastuzumab in the adjuvant setting; however, the use of pertuzumab in the adjuvant setting is still be-ing evaluated in the APHINITY trial (NCT01358877), in which patients with HER2-positive breast cancer are randomized to re-ceive adjuvant chemotherapy and trastuzumab with or without pertuzumab for 1 year.

Ado-trastuzumab emtansine (T-DM1) is another novel an-ti-HER2 therapy. Specifically, it is an antibody-drug conjugate (ADC) in which trastuzumab is stably linked to a potent micro-tubule inhibitor, which is a derivative of maytansine (DM1). T-DM1 was compared with lapatinib and capecitabine in the second-line, advanced-disease setting in the EMILIA study.36 Patients with HER2-positive MBC whose disease progressed on trastuzumab and taxane-based therapy had an OS of 30.9 months in the T-DM1 arm compared with 25.1 months in the control group. Importantly, T-DM1 is associated with improved tolerability compared with standard therapy.

In the TH3RESA trial,37 a heavily pretreated patient popula-tion with advanced HER2-positive breast cancer was randomized to receive T-DM1 compared with physician’s choice therapy. The PFS was significantly improved with T-DM1 compared with physician’s choice (median, 6.2 months vs 3.3 months; P <.001), providing further evidence of the relative activity and tolerability of this agent against the current standard therapy.

These findings led to the FDA approval of the first ADC for breast cancer in 2013. T-DM1 has been compared with docetaxel plus trastuzumab in first-line MBC in a phase II study, and demonstrated a significant 5-month improvement in PFS com-pared with the control arm.38 The use of T-DM1 in the front-line setting is being more definitively evaluated in the phase III MARIANNE study (NCT01120184), the results of which are pending. In that study, patients with MBC or recurrent, locally advanced HER2-positive breast cancer receive T-DM1 with or without pertuzumab compared with a taxane and trastuzumab. A global press release on December 18, 2014, indicated that the MARIANNE study met the noninferiority endpoint, showing similar PFS among the 3 arms; however, it did not meet the PFS superiority endpoint for T-DM1–containing regimens. The full results have not been presented publicly as of the date of this publication.

As an adjuvant treatment, T-DM1 is being compared with tras-tuzumab in the phase III KATHERINE trial (NCT01772472), while in the KAITLIN trial (NCT01966471), taxanes will be given postoperatively with either T-DM1 plus pertuzumab or trastuzumab plus pertuzumab in patients who have already re-ceived anthracycline-based chemotherapy. In the neoadjuvant setting, KRISTINE (TRIO-021; NCT02131064) is an ongoing trial in which patients are randomized to receive T-DM1 with pertuzumab compared with TCHP.

Emerging Agents for HER2-Positive Breast CancerNeratinib is a potent pan-TKI that irreversibly inhibits HER2. An ongoing phase III study (NALA; NCT 01808573) is compar-ing neratinib plus capecitabine to lapatinib plus capecitabine for patients with HER2-positive MBC that progressed on 2 prior HER2-targeted regimens. In the ExteNET trial (NCT00878709), patients with early-stage HER2-positive breast cancer who re-ceived adjuvant trastuzumab for a year were randomized to re-ceive neratinib or placebo for an additional year. A press release in 2014 indicated that neratinib was associated with a 33% im-provement in DFS compared with placebo; however, these re-sults have not been peer-reviewed or publicly presented to date. Given the increased rate of diarrhea from neratinib, preemptive use of antidiarrheal drugs is being evaluated in ongoing clinical trials.

MM-302 is a novel ADC that offers targeted delivery of pe-gylated liposomal doxorubicin to cancer cells overexpressing the HER2 protein. Based on a phase I monotherapy study, MM-302 is well tolerated with promising activity, especially in patients with anthracycline-naïve breast cancer.39 In the phase II random-ized HERMIONE trial (NCT02213744), the investigational drug MM-302 plus trastuzumab will be compared with chemotherapy of physician’s choice plus trastuzumab in anthracycline-naïve patients


· breast cancer ·

with locally advanced breast cancer or MBC that has progressed on pertuzumab and T-DM1 in the advanced-disease setting.

ONT-380, also known as ARRY-380, is a small-molecule selec-tive inhibitor of HER2. Given that it is associated with highly po-tent inhibition of HER2 without significant inhibition of HER1, ONT-380 may have a better side-effect profile with less skin rash and GI toxicity compared with other dual inhibitors. Currently, there are 2 ongoing phase Ib clinical trials with ONT-380 in wom-en with HER2-amplified breast cancer. In the first trial, ONT-380 is given with capecitabine and/or trastuzumab in patients whose disease progressed after trastuzumab and T-DM1 (NCT02025192). In the second study, ONT-380 is given with T-DM1 in patients who were previously treated with trastuzumab and taxanes (NCT01983501). Results are eagerly awaited from these 2 studies.

Small HER2-Positive TumorsThe biological aggressiveness of HER2-positive breast cancer leads many clinicians to recommend trastuzumab-based che-motherapy even for tumors smaller than 2 cm in size. Howev-er, randomized studies evaluating the benefit of this approach for small, lymph node–negative tumors are lacking, and the proportion of patients with tumors smaller than 1 cm in size enrolled in the large adjuvant studies is very small. Moreover, trastuzumab-based regimens can lead to considerable side effects, owing mainly to the cytotoxic chemotherapy used. Therefore, giv-en the efficacy and tolerability profile of T-DM1 in the metastatic and neoadjuvant settings, a phase II study is being conducted (the ATEMPT trial; NCT01853748) for patients with stage I HER2-positive tumors. In this randomized trial, patients will receive T-DM1 or paclitaxel in combination with trastuzumab, with both HER2-targeting drugs given for 1 full year, in the adju-vant setting in order to compare the effectiveness of the 2 treat-ment arms, and to assess symptoms and changes in quality of life.

Management of HER2-Positive Breast Cancer Brain MetastasesTreating patients with brain metastases is definitely more chal-lenging due to the lack of effective therapies that cross the blood–brain barrier, as well as the poor prognosis associated with this condition. Although randomized studies to indicate the thera-py or therapies associated with optimal outcomes are lacking, in 2014 the American Society of Clinical Oncology published clinical practice guidelines for the management of patients with HER2-positive breast cancer with brain metastases, indicating that patients should receive appropriate systemic therapy for ex-tracranial disease as well as appropriate local therapy, which may include surgery, whole-brain radiotherapy, and/or stereotactic radiosurgery.40 The major determinants of the choice of treat-ment are a patient’s performance status, multifocality, and size of the lesions. The consensus indicates that patients should not undergo screening imaging of the brain unless they are symptom-

atic, because doing so has not been shown to improve long-term outcomes for patients.

What Obstacles Are We Facing With HER2 Targeting?HER2-targeted approaches have revolutionized the treatment and outcomes associated with HER2-overexpressing breast can-cer. However, de novo and acquired resistance to HER2-directed approaches remains a clinical challenge. Several resistance mech-anisms have been described, including mutations in other sig-naling pathways, such as the insulin-like growth factor receptor, receptor crosstalk, and autophagy.41

Another mechanism of resistance is the presence of a short form of HER2 that is constitutively active and missing the p95 extracellular domain. This short-form HER2 does not respond to trastuzumab therapy because the trastuzumab-binding domain is lacking.42 The presence of PI3K mutations may also play a role in resistance to anti-HER2 therapy, thus providing rationale for targeting the PI3K/mTOR pathway.43 Interestingly, these pre-clinical data are confirmed by the findings of the BOLERO-3 trial,44 in which the addition of everolimus (an mTOR inhibitor) to trastuzumab and vinorelbine significantly prolonged PFS in patients with trastuzumab- and taxane-resistant disease. In the BOLERO-1 trial, patients with HER2-positive MBC were ran-domized in the first-line setting to receive trastuzumab and pacl-itaxel with or without everolimus.

While uncommon in breast cancer, HER2 somatic mutations may also play a role in breast carcinogenesis in tumors lacking HER2 amplification. Therefore, tumors with those mutations may be resistant to reversible HER2 inhibitors but sensitive to irreversible ones.45 More than 12 different HER2 mutations have been described, and identification and targeting of those muta-tions may prove to be beneficial in the treatment of this disease.

ConclusionsThe discovery of the HER2 alteration as a driver of disease biol-ogy in up to one-quarter of breast cancers led to a paradigm shift in the way this malignancy was understood, such that it is now recognized and accepted that breast cancer comprises heteroge-neous subtypes that are each best treated with molecularly target-ed approaches. The successful development of trastuzumab, the first drug targeting HER2-positive cancer, validated the concept that we can improve disease biology by treating the underlying molecular driver. In the past decade, 3 more HER2-directed ther-apies—lapatinib, pertuzumab, and T-DM1—have earned regulato-ry approval based on data in the metastatic and early-stage set-tings. While the outcomes associated with this disease have been dramatically improved with the use of these agents, resistance to these approaches remains an unmet clinical need. Understand-ing the mechanism of resistance to HER2-directed therapy will hopefully lead to the development of novel therapeutic agents



aimed at preventing or circumventing resistance, thus turning an otherwise terminal disease into a chronic condition.

Acknowledgment: Both authors contributed equally to the writ-ing of this article. Affiliations: Drs Drakaki and Hurvitz are from the Division of Hematology/Oncology, University of California, Los Angeles.Disclosures: Dr Hurvitz receives research funding relevant to the content of this article (paid to the University of California, Los Angeles) from Boehringer-Ingelheim, Genentech, GlaxoSmith-Kline, Merrimack Pharmaceuticals, Novartis, Puma Biotechnol-ogy, and Roche. Dr Drakaki reports no relevant conflicts of in-terest to disclose.Source of funding: Dr Hurvitz receives support from the Nation-al Cancer Institute of the National Institutes of Health (NIH) under Award Number P30CA016042, and from the STOP CANCER Marni Levine Memorial Seed Grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.Address correspondence to: Sara A. Hurvitz, MD, FACP, As-sociate Professor of Medicine, University of California, Los Angeles, Department of Medicine, Division of Hematology/On-cology, 2825 Santa Monica Blvd, Suite 211, Santa Monica, CA 90404; phone: 310-829-5471; fax: 310-829-6192; email: [email protected].

REFERENCES1. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. Cancer. 2014;64:9-29.2. Slamon DJ, Clark GM, Wong SG, et al. Human breast can-cer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177-182.3. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian can-cer. Science. 1989;244:707-712.4. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemo-therapy plus a monoclonal antibody against HER2 for met-astatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783-792.5. Junttila TT, Akita RW, Parsons K, et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell. 2009;15:429-440.6. Clynes RA, Towers TL, Presta LG, et al. Inhibitory Fc recep-tors modulate in vivo cytoxicity against tumor targets. Nat Med. 2000;6:443-446.7. Junttila TT, Parsons K, Olsson C, et al. Superior in vivo effica-cy of afucosylated trastuzumab in the treatment of HER2-ampli-fied breast cancer. Cancer Res. 2010;70:4481-4489.

8. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adju-vant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673-1684.9. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Tras-tuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659-1672.10. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365:1273-1283.11. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastu-zumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375:377-384.12. Buzdar AU, Ibrahim NK, Francis D, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemother-apy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005;23:3676-3685.13. Dawood S, Broglio K, Buzdar AU, et al. Prognosis of wom-en with metastatic breast cancer by HER2 status and trastu-zumab treatment: an institutional-based review. J Clin Oncol. 2010;28:92-98.14. Musolino A, Ciccolallo L, Panebianco M, et al. Multifacto-rial central nervous system recurrence susceptibility in patients with HER2-positive breast cancer: epidemiological and clini-cal data from a population-based cancer registry study. Cancer. 2011;117:1837-1846.15. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733-2743.16. Hurvitz SA, Kakkar R. Role of lapatinib alone or in combi-nation in the treatment of HER2-positive breast cancer. Breast Cancer (Dove Med Press). 2012;4:35-51.17. Kaufman B, Mackey JR, Clemens MR, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol. 2009;27:5529-5537.18. Johnston S, Pippen J Jr, Pivot X, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009;27:5538-5546.19. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer. J Clin Oncol. 2009;27:1999-2006.


· breast cancer ·

20. Gelmon KA, Boyle F, Kaufman B, et al. Open-label phase III randomized controlled trial comparing taxane-based chemo-therapy (Tax) with lapatinib (L) or trastuzumab (T) as first-line therapy for women with HER2+ metastatic breast cancer: Inter-im analysis (IA) of NCIC CTG MA.31/GSK EGF 108919. J Clin Oncol. 2012;30. Abstract LBA671.21. Untch M, Loibl S, Bischoff J, et al. Lapatinib versus trastuzum-ab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol. 2012;13:135-144.22. Konecny GE, Pegram MD, Venkatesan N, et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-over-expressing and trastuzumab-treated breast cancer cells. Cancer Res. 2006;66:1630-1639.23. Scaltriti M, Verma C, Guzman M, et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxici-ty. Oncogene. 2009;28:803-814.24. Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28:1124-1130.25. Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall sur-vival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-posi-tive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012;30:2585-2592.26. Guarneri V, Frassoldati A, Bottini A, et al. Preoperative che-motherapy plus trastuzumab, lapatinib, or both in human epi-dermal growth factor receptor 2-positive operable breast cancer: results of the randomized phase II CHER LOB study. J Clin On-col. 2012;30:1989-1995.27. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with tras-tuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379:633-640.28. Piccart-Gebhart M, Holmes AP, de Azambuja E, et al. The as-sociation between event-free survival and pathological complete response to neoadjuvant lapatinib, trastuzumab, or their combi-nation in HER2-positive breast cancer. Survival follow-up analy-sis of the NeoALTTO study. Cancer Res. 2013;73. Abstract S1-01.29. Robidoux A, Tang G, Rastogi P, et al. Lapatinib as a compo-nent of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14:1183-1192.30. Piccart-Gebhart MJ, Holmes AP, Baselga J, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapati-nib alone (L), trastuzumab alone (T), their sequence (T�L), or their combination (T+L) in the adjuvant treatment of HER2-pos-

itive early breast cancer (EBC). J Clin Oncol. 2014;32(suppl; abstr LBA4).31. Nahta R, Hung MC, Esteva FJ. The HER-2-targeting anti-bodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res. 2004;64:2343-2246.32. Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastu-zumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.33. Swain SM, Kim SB, Cortes J, et al. Pertuzumab, trastu-zumab, and docetaxel for HER2-positive metastatic breast can-cer (CLEOPATRA study): overall survival results from a ran-domised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461-471.34. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with local-ly advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 tri-al. Lancet Oncol. 2012;13:25-32.35. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant an-thracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24:2278-2284.36. Verma S, Miles D, Gianni L, et al. Trastuzumab emtan-sine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783-1791.37. Krop IE, Kim SB, Gonzalez-Martin A, et al. Trastuzumab emtansine versus treatment of physician’s choice for pretreat-ed HER2-positive advanced breast cancer (TH3RESA): a ran-domised, open-label, phase 3 trial. Lancet Oncol. 2014;15:689-699.38. Hurvitz SA, Dirix L, Kocsis J, et al. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2013;31:1157-1163.39. Munster P, Krop IE, Miller K, et al. Assessment of safety and activity in an expanded phase 1 study of MM-302, a HER2-target-ed liposomal doxorubicin, in patients with advanced HER2-pos-itive (HER2+) breast cancer. Cancer Res. 2013;73.Abstract PA-12-29.40. Ramakrishna N, Temin S, Chandarlapaty S, et al. Recom-mendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32:2100-2108.41. Hurvitz SA, Hu Y, O’Brien N, et al. Current approaches and future directions in the treatment of HER2-positive breast can-cer. Cancer Treat Rev. 2013;39:219-229.42. Arribas J, Baselga J, Pedersen K, et al. p95HER2 and breast



cancer. Cancer Res. 2011;71:1515-1519.43. O’Brien NA, McDonald K, Tong L, et al. Targeting PI3K/mTOR overcomes resistance to HER2-targeted therapy in-dependent of feedback activation of AKT. Clin Cancer Res. 2014;20:3507-3520.44. Andre F, O’Regan R, Ozguroglu M, et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, place-bo-controlled phase 3 trial. Lancet Oncol. 2014;15:580-591.45. Bose R, Kavuri SM, Searleman AC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 2013;3:224-237.


· melanoma ·

BRAF Inhibitors and the “Lazarus Syndrome”An Update and Perspective

Lena Furmark, MD,and Anna C. Pavlick, MD

State of the Art UpdateThe identification of BRAF as a therapeutic target has changed the landscape of melanoma therapy and impacted many patient lives. Since this driver mutation is expressed in approximately 50% of all melanomas, many patients will receive therapeutic benefit from targeted agents. Response rates to these therapies range between 20% and 50%, which is truly impressive consid-ering that chemotherapy response rates are less than 15%. These responses, however dramatic, have a tendency to be of limited duration, and therein lies our challenge.

Pathways for Melanoma MetastasisThe Figure shows pathways for melanoma metastasis. Vemu-rafenibis an oral, highly selective inhibitor of the oncogenic V600E mutant BRAF kinase, which showed promising results in early clinical studies. In a dose-finding phase I trial, 11 of 16 patients (68%) with BRAF-mutated metastatic melanoma achieved a par-tial response (PR) and 4 patients had minor responses, leading to a progression-free survival (PFS) of 8 to 9 months.1 A dose-ex-tension phase I trial with 32 patients demonstrated an objective response rate of 81% (2 complete responses [CRs], 24 PRs). The median PFS among these patients was more than 7 months. Ve-murafenib was generally well tolerated, with the most common side effects being rash, photosensitivity, arthralgia, and nausea. Of note, 31% of patients developed grade 3 squamous cell carci-noma (SCC), keratoacanthoma (KA) type. The median time to the appearance of a cutaneous SCC was 8 weeks with no report-ed involvement of other organs. Treatment with vemurafenib was not interrupted by the appearance of these skin lesions, and the majority of them were resected.2

The phase II trial of vemurafenib 960 mg orally twice daily administered to patients with previously treated melanoma (BRIM 2) demonstrated an overall survival (OS) of 16.9 months, which is unprecedented in melanoma trials.3 The phase III trial (BRIM 3) comparing vemurafenib 960 mg orally twice daily to dacarbazine 1000 mg/m2 IV in untreated patients with BRAF V600E-mutant metastatic melanoma demonstrated improvement in PFS and OS for patients receiving vemurafenib. Due to the significant advantage of vemurafenib, the trial was amended to allow patients randomized to dacarbazine to crossover to the ve-murafenib arm.4

The data from the previously treated patients in the phase II trials mirrored the results of the untreated patients in the phase III trial, confirming that order of therapy does not impact re-sponse rate or survival.3 The robust data generated in this phase III trial was the basis for FDA approval of vemurafenib in pa-tients with BRAF V600E-mutated metastatic melanoma in 2011.4

Dabrafenib is another oral, highly potent, and selective BRAF V600E/K/D inhibitor that has shown similar effectiveness to vemu-rafenib. In a phase I/II study, treatment with dabrafenib 150

Abstract

Identification of the BRAF mutation as an effective thera-

peutic target in approximately 50% of patients with met-

astatic melanoma has dramatically impacted the land-

scape of melanoma treatment. These therapies have not

only impacted progression-free survival, but overall sur-

vival as well. They are, however, not without flaws. While

these drugs have a very rapid onset of action and can

quickly reverse a clinical decline of a patient with met-

astatic melanoma, their flaw lies in the limited duration

of activity. Although there have been cases of long dura-

ble responses, the majority of tumors will develop resis-

tance within months of treatment, and tumors will again

progress. Combining dual targets such as BRAF and MEK

inhibitors has improved the time to progression and sur-

vival, but has not demonstrated consistent long-term du-

rability of responses. Continued research with multiple

targeted therapies and targets with immunotherapy are

under way. These agents have salvaged patients from im-

pending death, which is revolutionary in the treatment of

melanoma; however, this comes with new psychological

impacts for the patient, family, and healthcare team, as

patients are transiently resurrected but ultimately suc-

cumb to this disease within a few short months.

Key words: Metastatic melanoma, BRAF inhibitors, MEK

inhibitors, targeted therapy


BRAF InhIBItoRs And the “LAzARus syndRome”

mg orally twice daily led to a decrease in FDG-PET metabolic uptake, with 11 of 14 patients (79%) with melanoma showing a decrease from baseline (range, 5% to 100%) and 18 of 30 pa-tients (60%) demonstrating a greater than 20% tumor decrease by RECIST at first restaging (8-9 weeks).5 Most of the side ef-fects, including low-grade nausea, pyrexia, vomiting, fatigue, and headaches, were predominantly transient and mild in severity, making dabrafenib very well tolerated. Similar to vemurafenib, patients also experienced increased rates of low-grade SCC le-sions; however, this side effect was found to be much less prev-alent with dabrafenib. A phase III study of dabrafenib as initial therapy in patients with unresectable stage III or metastatic dis-ease demonstrated improved PFS compared with chemotherapy.6 Although confounded by crossover, this study was later updated to show improved OS with dabrafenib, 18.2 months versus 15.6 months.7 Following these results, the FDA added dabrafenib to the melanoma treatment repertoire in 2013.

One of the factors that initially set dabrafenib apart from ve-murafenib was the extensive data regarding its effects on brain metastases. Dabrafenib was first found to have activity in a phase I dose escalation trial, in which a small subgroup of 10 patients with brain metastases had a significant reduction in the size of their brain lesions.8 This was further supported by a phase II multicenter, open-label trial that evaluated dabrafenib therapy in 172 patients with melanoma with both previously treated and untreated brain metastases. Dabrafenib therapy resulted in a 31% and 39% response rate, respectively.9 Recently, similar out-comes were found with vemurafenib. A small open-label pi-lot study involving 24 patients with previously treated brain metastases showed a PR in 10 patients and stable disease in 9 patients with vemurafenib therapy.10

MEK Inhibitors Trametinib is a potent and selective inhibitor of the MEK1/2 enzymes, which are found downstream from BRAF. A phase I clinical trial resulted in a response rate greater than 70% in patients with advanced melanoma with known BRAF mutations, including 1 patient who was previously treated with vemurafenib.11 A phase II study further supported the activity of trametinib in patients with BRAF-mutated dis-ease, with the greatest effect observed in patients who were BRAF-inhibitor naïve.12 This was followed by a phase III open-label trial that compared chemotherapy (dacarbazine or paclitaxel) with trametinib and found improved median PFS and OS in the trametinib group; median PFS was 4.8 months in the trametinib group versus 1.5 months in the chemotherapy group.13 The study revealed that even though 74% of patients had some tumor regression with trametinib, only 22% had a response that met RECIST. Although these

results are not as robust as with BRAF inhibitors, it still provides significant benefit to patients when compared with previous che-motherapy treatment options. Similar to other targeted thera-pies, trametinib is well tolerated; however, the side effect profile is different from BRAF inhibitors and includes papulopustular rash, diarrhea, and peripheral edema.

Dual Targeted TherapyEmerging data at the time of these studies disappointingly re-vealed that the dramatic responses to single-agent BRAF inhi-bition were of limited duration. Research has shown none of the mechanisms of resistance to be through the MAPK pathway, making the idea of dual blockade an intuitive option to pursue. Dabrafenib and trametinib were combined in a phase I dose es-calation trial, and the phase II recommended dosages of these medications were identified at 150 mg orally twice daily for dab-rafenib and 2 mg orally daily for trametinib.14

The phase II trial published in 2012 demonstrated that this combination provided improved PFS and increased the propor-tion of patients alive at 1 year compared with dabrafenib mono-therapy.15 The subsequent phase III trial published in The New

Practical Application

• DifferentiatingbetweenbothBRAFinhibitorsandMEKinhibitors• RealizingthedifferentpotentialadverseeffectsofBRAF,MEK,and

dual-targetedtherapy• Understandingthebenefitsandlimitationsoftargetedtherapy

FIGURE. Pathways For Melanoma Metastasis

Cobemetinib

Tramatenib

TranscriptionFactors

Bcl-2

MAPK

MEK

Raf

Ras PI3K

mTOR

IF4E

Tumor Cell Survival, Proliferation, Invasion and/or Metastasis

p70S6K

MMP-2

AKT

PTEN

Vemurafenib

Dabrafenib

Cell Membrane


· melanoma ·

England Journal of Medicine in 2014 additionally demonstrated improved PFS in the combination group of 9.3 months versus 8.8 months. In addition to increased PFS, combination thera-py significantly decreased the development of SCC.16 There are, however, a small group of patients who will achieve complete or partial responses that are sustained for greater than 12 months. While these prolonged responses do occur, we cannot predict which patients will derive this benefit de novo. This long-term follow-up data of the phase I and II trials was recently presented at the 2014 American Society of Clinical Oncology Annual Meet-ing, with updated results showing a median OS of 23.8 months with the combination treatment.25

Concurrently, trials evaluating vemurafenib combined with cobimetinib were being conducted. A phase III trial published in The New England Journal of Medicine evaluated 495 patients who were randomly assigned to either the combination group or sin-gle-agent vemurafenib group. Results not only showed improved PFS, but revealed an OS benefit in the combination group. There was an 81% survival rate at 9 months in the combination group versus 73% in the single-agent group. Although the com-bination did show increased grade 3 adverse events, similar to previous combination studies, there was a significant decrease in SCC rates.17 Tables 1 and 2 detail single-agent versus dual-agent efficacy and toxicity.

Future Research on Combination TherapyAlthough targeting the MAPK pathway is a promising new ther-apeutic approach for the treatment of melanoma, and treatment with selective BRAF and MEK inhibitors can induce high re-sponse rates, the limited duration of these responses in most patients, most likely because of emerging resistance to these inhibitors, represent a significant clinical challenge. Molecular redundancy, in part due to the existence of RAF isoforms and signaling through alternative oncogenic pathways such as PI3K/

AKT/mTOR pathway,18,19 receptor tyrosine kinase (PDGFRβ)-de-pendent pathway,20 and COT (MAP3K8),21 may provide the mel-anoma cells escape mechanisms to specific pathway inhibitors, and underscore their ability to adapt to pharmacologic challeng-es. In preclinical models, it has been reported that acquired resis-tance of melanoma cells to the BRAF inhibitors was associated with rebound activation of the RAF/MEK/ERK pathway.19 In line with this finding, activating signals to downstream MEK/ERK has been shown to switch to ARAF22 or CRAF22,23 via N-RAS upregulation20 to overcome the effect of BRAF inhibi-tion. Moreover, the majority of melanoma cells harboring the BRAFV600E mutation retained the wild-type BRAF allele, which could be rescued from the effects of BRAF knock-down by ex-tracellular growth factors such as basic fibroblast growth factor, hepatocyte growth factor, or endothelin-1.24 These mechanisms of resistance may not apply to immunotherapy with checkpoint inhibitors, which may lead to less frequent responses, but can be of longer duration compared with BRAF and MEK inhibition.

Continued research exploring multi-targeted inhibitors and immunotherapy is currently under way. These trials will explore important questions of drug sequencing and scheduling.

Clinical PerspectiveDespite the majority of significant responses lasting several months, there is a subset of patients who experience what we have termed the “Lazarus Syndrome.” I have coined this term be-cause Lazarus was raised from the dead simply by God calling his name, and these drugs resurrect deathly ill patients with melano-ma this quickly. It is an unbelievable feeling for the patient, their family, and the medical staff—a sense of vindication occurs, and patients and families stop planning funerals and start planning vacations. Unfortunately, some of the most miraculous respons-es in deathly ill patients are also the shortest-lived, with most responses lasting no more than months.

TablE 1. Efficacy of Combination BRAF and MEK Inhibitors

AE indicates adverse event; NR, not reported; PFS, progression-free survival.

Endpoint Vemurafenib17 Vemurafenib and Cobimetinib17

Dabrafenib16 Dabrafenib and Tramatenib16

Objectiveresponse(%) 45 68 51 67

Completeresponse(%) 4 10 9 10

MedianPFS(months) 6.2 9.9 8.8 9.3

Survivalat6months(%) NR NR 77 85

Survivalat9months(%) 73 81 NR NR

AEsleadingtotreatmentdiscontinuation(%) 12 13 5 9



Clinical Cases of the “Lazarus Syndrome”A 26-year-old Hispanic female with BRAF-mutated metastatic melanoma status post-4 cycles of ipilimumab with no response and rapid progression of disease presented to the clinic via ambu-lance transport on a stretcher. Physical examination demonstrat-ed an extremely cachectic young woman in moderate distress, with multiple massive subcutaneous masses over trunk and ex-tremities, severe abdominal distention due to liver metastases, bilateral 4+ pitting, and weeping lower-extremity edema and shal-low breathing due to bilateral pleural effusions.

She was treated with vemurafenib 960 mg orally twice daily and was instructed to return for follow-up in 1 week.

Her response was dramatic. One week after initiating vemu-rafenib, her leg edema resolved, her abdomen was no longer dis-tended, and she was eating normally. She walked into the clinic 1 week later modeling her size 4 jeans with a pair of platform shoes! It was a wonderfully emotional day for the patient, family, and staff.

She did extremely well for 8 weeks until she called to report a new “lump” on the right side of her neck, which appeared “overnight.” It was the beginning of the end. Within 2 weeks, she became severely debilitated and bedridden with recurrent abdominal distention and leg edema. She died 10 weeks after that dramatic response.

Another such case was that of a 57-year-old male who devel-oped a large necrotic mass on his right posterior shoulder. A biopsy was nondiagnostic due to the extensive necrosis. He had a distant history of stage I melanoma 12 years prior. Magnetic reso-nance imaging (MRI) demonstrated extensive necrotic tumors in the right shoulder, liver, lungs, subcutaneous nodes, and brain. His brain lesions were treated with gamma knife surgery. The pa-thology returned, identifying his tumor as a BRAF-mutated mela-noma. On the same day the information regarding his pathology was revealed, he was hospital-ized for progressive shortness of breath that required CPAP ventilation. Within 72 hours of starting vemurafenib, he was discharged from the ICU and was sent home 24 hours later. Within 1 week, he also had a notable improvement in the large, right-shoulder mass.

He did well for approximate-ly 9 weeks, but required dose delays and dose reductions due to liver function test eleva-tions. Reimaging demonstrat-ed stable treated brain metas-tases and 75% reduction in his disease burden. Since he was having difficulty tolerating the

targeted therapy but had dramatically improved clinically and was neurologically stable, his therapy was changed to immuno-therapy with ipilumumab. He received 1 dose of ipilimumab and 14 days later developed mental status changes and headaches. MRI revealed innumerable, hemorrhagic brain metastases and leptomeningeal disease. Systemic scans also documented rapid progression in visceral organs.

He was immediately started on dabrafenib and trametinib, but had no response to treatment and became severely debilitated from the rapid progression of disease complicated by his whole-brain radiation therapy. He died 12 weeks after the initiation of dual-targeted therapy.

These cases represent the “roller coaster” that some patients and their families endure with this disease. They prepare for death, then a “miracle drug” salvages them and gives them hope that survival is possible. Unfortunately, far too often and far too quickly, this hope is crushed with the rapid progression of disease and demise of the patient. The mental anguish that pa-tients, families, and healthcare professionals experience during this time needs to be acknowledged. This roller coaster of hope deceives patients, family members, and health care providers into believing that “everything is going to be okay.” This period of hope must be tempered with the reality that it may only be a transient hiatus and that the patient is going to die from their disease. It is an area where psychosocial support can have a tre-mendous impact.

We must always keep in mind our limitations as well as the limitations of these drugs. These are life-changing drugs whose impact has been felt worldwide, but now we are faced with the challenge to make these responses durable. We have to approach our patients by hoping for the best, but always being prepared for the worst. Most important, we have to continue to enroll pa-

TablE 2. Toxicity Associated With BRAF Inhibitors

adverse Event(grade 3-4)

Vemurafenib17 Vemurafenib and Cobimetinib17

Dabrafenib16 Dabrafenib and Trametinib16

Pyrexia (%) 0 2 34 32

Fatigue (%) 3 4 2 6

Rash (%) 5 6 1 0

Peripheral edema (%) 0 0 1 1

Elevated LFT (%) 8 19 5 3

Myalgia/arthralgia (%) 5 2 1 0

SCC (%) 11 2 4 2

Retinopathy (%) 0 1 0 0

Photosensitivity (%) 0 2 0 0

LFT indicates liver function test; SCC, squamous cell carcinoma.


· melanoma ·

tients onto clinical trials so that we can continue to improve on our successes and work to resolve the “Lazarus Syndrome,” and provide all of our patients with long-term durable responses. We have made huge strides in combating this disease, but more work still needs to be done.

Affiliations: Lena Furmark, MD, is from the Division of Medical Oncology, Department of Medicine, and Anna C. Pavlick, MD, is from the Division of Medical Oncology, Departments of Der-matology and Medicine, New York University Perlmutter Cancer Center, New York City.Disclosures: Drs Furmark and Pavlick have no relevant conflicts of interest to disclose.Address correspondence to: Anna C. Pavlick, MD, NYU Perlmutter Cancer Center, 160 East 34th Street, 9th Floor, New York, NY 10016. Phone:212-731-5431; fax: 212-731-6017; email: [email protected].

REFEREnCES1. Flaherty K, Puzanov I, Sosman J, et. al. Phase I study of PLX4032: proof of concept for V600E BRAF mutation as a ther-apeutic target in human cancer. J Clin Oncol. 2009;27(15s;abstr 9000).2. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma, activated BRAF in met-astatic melanoma. N Engl J Med. 2010;363:809-819.3. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012;366(8):707-714.4. Chapman PB, Hauschild A, Robert C, et al. BRIM-3 study group. Improved survival with vemurafenib in melanoma patients with BRAF V600E mutations. N Engl J Med. 2011;364(26):2507-2516.5. Kefford R, Arkenau H, Brown MP, et al. Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors. J Clin Oncol. 2010;28(15s; abstr 8503). 6. Hauschild A, Grob J, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicenter, open-label, phase 3 randomized controlled trial. Lancet. 2012;380:358-365.7. Hauschild A, Grob J, Demidov LV, et al. An update on BREAK-3, a phase III, randomized trial: dabrafenib (DAB) ver-sus dacarbazine (DTIC) in patients with BRAF V600E-positive mutation metastatic melanoma (MM). J Clin Oncol. 2013;31(sup-pl;abstr 9013).8. Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012;379:1893-1901.9. Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients

with Val600Glu or Val600lys BRAF-mutant melanoma metastat-ic to the brain (BREAK-MB): a multicenter, open-label, phase 2 trial. Lancet Oncol. 2012;13:1087-1095.10. Dummer R, Goldinger SM, Turtschi CP, et al. Vemurafenib in patients with BRAF (V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer. 2014;50(3):611-621.11. Infante JR, Fecher LA, Nallapareddy S, et al. Safety and effi-cacy results from the first-in-human study of the oral MEK 1/2 inhibitor GSK 1120212. J Clin Oncol. 2010;28(15s;abstr 2503).12. Kim KB, Kefford R, Pavlick AC, et al. Phase II study of MEK1/MEK2 inhibitor trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor.J ClinOncol. 2013;31(4):482-489.13. Flaherty, KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107-114.14. Infante JR, Falchook GS, Lawrence DP, et al. Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK1/2 inhibitor GSK1120212 dosed in combination with the oral BRAF inhibitor GSK2118436. J Clin Oncol. 2011;29(sup-pl;abstr 8503). 15. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694-1703.16. Long GV, Stroyakovskiy H, Gogas E, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melano-ma. N Engl J Med. 2014;371:1877-1888.17. Larkin J, Ascierto P, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867-1876.18. Jiang CC, Lai F, Thorne RF, et al. MEK-independent survival of BRAF V600E melanoma cells selected for resistance to apop-tosis induced by the RAF inhibitor PLX4720. Clin Cancer Res. 2011;17(4):721-730.19. Paraiso KH, Fedorenko IV, Cantini LP, et al. Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy. Br J Cancer. 2010;102(12):1724-1730.20. Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resis-tance to B-RAF (V600E) inhibition by RTK or N-RAS upregula-tion. Nature. 2010;468(7326):973-977.21. Johannessen CM, Boehm JS, Kim SY, et al. COT drives resis-tance to RAF inhibition through MAP kinase pathway reactiva-tion. Nature. 2010;468(7326)968-972.22. Villanueva J, Vultur A, Lee JT, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell. 2010;18(6): 683-695.23. Montagut C, Sharma SV, Shioda T, et al.Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008;68(12):4853-4861.



24. Christensen C, Guldberg P. Growth factors rescue cutaneous melanoma cells from apoptosis induced by knockdown of mutat-ed (V600E) B-RAF. Oncogene. 2005;24(41):6292-630225. Flaherty K, Daud A, Weber JS, et al. Updated overall survival (OS) for BRF113220, a phase 1-2 study of dabrafenib (D) alone versus combined dabrafenib and trametinib (D+T) in pts with BRAF V600 mutation-positive (+) metastatic melanoma (MM). J Clin Oncol. 2014;32(suppl 5s; abstr 9010).


· CliniCal Controversies ·

Negative Is Positive: A Plea to Publish All Studies Regardless of Outcome

Debu Tripathy, MD

Positive results from clinical trials naturally get the headlines in the media and are published in more prestigious and higher-im-pact journals. But what about negative results? They also get pub-lished, but less frequently and with more delays.1 In fact, many investigators abandon negative studies and focus their time else-where, leaving these bodies of work in the dark and unavailable, even in cyberspace. Worse yet, the omission of critical informa-tion such as safety data could be harmful to the general public, as has been documented in several noncancer areas.2-4 There are no firm estimates on the imbalance of publication of positive versus negative cancer trials.

So why is it important to publish negative studies? There are many ways that the dissemination of trials that do not meet their primary endpoints can still help science advance and ultimately benefit patients. For one, ineffective and dangerous therapies that are often “tailored” in desperate situations would be avoid-ed. Even animal studies cannot get approved by most Institution-al Animal Care and Use Committees (IACUCs) without a litera-ture search to show that the proposed experiments have not been conducted in the past; oddly enough, the same is not required of clinical trials. Secondly, when studies are pooled, or formal

meta-analyses are conducted to obtain more definitive estimates of efficacy and safety, publication bias resulting from the omis-sion of negative studies may artificially inflate the results.5 This can lead to inappropriate guidelines and widespread adoption of costly and potentially harmful therapies. Finally, science builds on previous results—new directions require that all data be avail-able. Biological hypotheses that lead to clinical investigations can develop from both positive and negative results.

In 2000, a federal law was passed that stipulated the develop-ment of the ClinicalTrials.gov website to provide information about clinical trials for serious medical conditions, with specific information about trial access and other details. In 2007, Con-gress enacted the Food and Drug Administration Amendments Act (FDAAA), in which Section 801 directed clinical trial spon-sors to report primary outcomes of trial results within 1 year of final data collection, and to make this publicly available on ClinicalTrials.gov.6 A recent analysis of 13,327 trials completed between 2008 and 2012 that met FDAAA criteria showed that only 13.4% of trials reported summary results within 12 months of trial completion.7 However, it is possible that data quality checks and regulatory requirements have delayed reports, and it is hoped that this number will rise as trial sponsors become familiar with this process.

The library sciences have advanced with electronic searches and online availability of virtually all published material. The new field of “big data”—the use of artificial intelligence and data mining applied to vast archives of information—promises to yield new clues to the challenges of cancer biology and discovery of vulnerabilities that can be exploited for clinical gains. Therefore, this may be a perfect time for a public plea to publish every study ever conducted, regardless of results.

Is this achievable? Absolutely. While high-profile journals may elect to publish only positive findings (or highly relevant and large negative studies), smaller negative trials can be published in a growing number of specialty journals. The Journal of Negative Results in BioMedicine, launched in 2002, is dedicated to negative (as well as provocative and paradigm-changing) results and en-courages such submission for peer review and publication.8 In addition, there could be a publicly funded repository of negative

Abstract

Negative results from trials can be just as important as

those which are positive. The results of all trials need to

be made easily available to avoid biases when compil-

ing the totality of the data. This is critical to ensure that

guidelines and treatment standards are reflective of the

“the truth, the whole truth, and nothing but the truth.” Ad-

ditionally, negative trial results avoid duplicative studies

and may also contain important safety information that

would otherwise be lost. Several outlets now exist for

negative trials, but investigators and trial sponsors need

to be encouraged or mandated to post the results of all

trials, regardless of results, in the public domain.

Key words: Negative results, clinical trials, publication

bias, clinicaltrials.gov


Negative is Positive: a Plea to Publish all studies RegaRdless of outcome

trials that is searchable. This may be challenging because of the time and expense involved in expert peer review and editing, but even a collection of deposited articles that are not peer-reviewed could be helpful.

Academic credit hinges on peer-reviewed articles, but clinical investigators should also be given credit for their work if it can only be published in this setting. Just as the FDAAA mandates the publication of results of key trials, private, nonprofit, and governmental funding agencies can similarly stipulate that all funded trials eventually be published in a publicly searchable da-tabase. Institutional Review Boards (IRBs) can likewise impose such requirements as a condition for protocol approval. These policies are clearly justified, as they are for the public good. They avoid the repetition of unproductive trials and create more ro-bust literature archives that actually protect future patients and clinical trial subjects.

Bringing negative prospective clinical trials to light will require a “carrot-and-stick” approach. However, the payoffs are great. We will be able get a more realistic and rapid sense of what works and what does not. Clinical investigators will have more ample and reliable preliminary data and background to support their new concepts. Reviewers of protocols will likewise be able to meet their obligations to properly evaluate studies and only ap-prove safe and promising protocols, or to suggest evidence-based modifications. The real winner is the public, and specifically our patients, who are understandably impatient with the time it takes to expand our knowledge and introduce meaningful inno-vations in cancer care.

Affiliation: Debu Tripathy, MD, is professor and chair, Depart-ment of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, and is editor-in-chief of The American Journal of Hematology/Oncology.Disclosure: Dr Tripathy has received grant/research support from Genentech/Roche, Pfizer, Puma Inc, and Novartis (clinical trial support contracted to the University of Southern California and MD Anderson Cancer Center) and has been a consultant for Eisai, Oncoplex Diagnostics, Merck and Novartis.Address correspondence to: Debu Tripathy, MD, Professor and Chair, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Unit 1354, Houston, TX 77030. Phone: 713-792-2817; fax: 713-563-0903; email: [email protected]

RefeRences1. Gordon D, Taddei-Peters W, Mascette A, et al. Publication of trials funded by the National Heart, Lung, and Blood Institute. N Engl J Med. 2013;369:1926-1934.2. Kesselheim AS, Mello MM. Confidentiality laws and secrecy in medical research: improving public access to data on drug safe-

ty. Health Aff (Millwood). 2007;26:483-491.3. Turner EH, Matthews AM, Linardatos E, et al. Selective pub-lication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008;358:252-260.4. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457-2471.5. Dwan K, Altman DG, Clarke M, et al. Evidence for the selec-tive reporting of analyses and discrepancies in clinical trials: a systematic review of cohort studies of clinical trials. PLoS Med. 2014;11(6):e1001666.6. Food and Drug Administration Amendments Act of 2007. Public Law No. 110-85 § 801;2007. Available at: http://www.gpo.gov/fdsys/pkg/PLAW-110publ85/pdf/PLAW-110publ85.pdf#page=82. Accessed March 14, 2015.7. Anderson ML, Chiswell K, Peterson ED, et al. Compli-ance with results reporting at ClinicalTrials.gov. N Engl J Med. 2015;372:1031-1039.8. Journal of Negative Results in BioMedicine. Available at: http://www.jnrbm.com/about. Accessed March 14, 2015.


CME

Dates of Certification: April 20, 2015- April 20, 2016

Medium: Print with online posttest, evaluation, and request for credit

Medical Writer Allison A. Muller, PharmD, DABAT Disclosure: No relevant financial relationships with commercial inter-ests to disclose. The American Journal of Hematology/ Oncology Editorial Board Debu Tripathy, MD Professor of Medicine and Chair Department of Breast Medical OncologyThe University of Texas MD Anderson Cancer CenterHouston, TX Disclosure: Grant/research support from Genentech/Roche, Pfizer, Puma Inc, and Novartis (clinical trial support contracted to the Univer-sity of Southern California and MD Anderson Cancer Center); consul-tant for Eisai, Oncoplex Diagnostics, Merck, and Novartis.

Myron Czuczman, MD Professor of OncologyChief, Lymphoma/Myeloma Service Department of Medicine Head, Lymphoma Translational Research Laboratory Department of Immunology Roswell Park Cancer Institute Buffalo, NY Disclosure: Other support: Advisory Board: Algeta, Celgene Corpora-tion, Teva, Boehringer Ingelheim, Mundipharma

Faculty Roy S. Herbst, MD, PhD Ensign Professor of Medicine (Medical Oncology)Professor of PharmacologyChief of Medical OncologyAssociate Director for Translational ResearchYale Cancer CenterYale School of MedicineNew Haven, CT Disclosure: Consultant: SAB, Kolltan, N-of-One, Inc, DiaTech Oncology, Quintiles Inc, Biothera.

Staff/Planner Disclosures and Conflict of Interest ResolutionThe staff of Physicians’ Education Resource (PER®), LLC (Ann C. Lichti, CCMEP, Beth Cameron, PhD, Michael Perlmutter, MS, PharmD, and Kerry Clayton) as well as the editorial staff of The American Journal of Hematology/Oncology (Devera Pine) have no relevant financial relationships with commercial interests to disclose.

In accordance with Accreditation Council for Continuing Medical Edu-cation (ACCME) Standards for Commercial SupportSM, PER® resolved all conflicts of interest (COI) prior to the release of this CME activity using a multistep process.

Overview This activity is designed to aid physicians in assessing new data in immunotherapy for lung cancer, including patient-specific treatment regimens and monitoring for adverse events during therapy, and applying these data to their practices.

Target Audience

This activity is directed toward medical oncologists who manage and treat patients with lung cancer. Surgical oncologists, radiation oncol-ogists, pathologists, pulmonologists, fellows, nurses, nurse practi-tioners, physician assistants, and other healthcare providers interested in the treatment of lung cancer are also invited to participate.Learning Objectives

After participating in this CME activity, learners should be better prepared to:

• Identify current treatment challenges in the treatment of squamous cell lung cancer.

• Describe the currently available immunotherapy options for the treatment of squamous cell lung cancer.

• List the most frequent adverse events associated with available immunotherapy agents for squamous cell lung cancer.

Accreditation/Credit Designation

Physicians’ Education Resource®, LLC, is accredited by the Accredita-tion Council for Continuing Medical Education to provide continuing medical education for physicians.

Physicians’ Education Resource®, LLC, designates this enduring ma-terial for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity is funded by Physicians’ Education Resource®. Instructions for Participation/How to Receive AMA PRA Category 1 CreditTM

1. Read the article in its entirety.2. Use the QR Code or type http://www.gotoper.com/link/158 into your Web browser to access the posttest.3. Complete and pass the posttest with a score of 70% or higher.4. Complete the evaluation and request for credit. Participants may immediately download a CME certificate upon successful completion of these steps.

Off-Label Disclosure and Disclaimer

This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options for a specif-ic patient’s medical condition.

Disclaimer

The opinions expressed in the content are solely those of the individu-al faculty members and do not reflect those of PER®.

Contact information for questions about the activity:Physicians’ Education Resource®, LLC666 Plainsboro Road, Suite 356Plainsboro, NJ 08536Phone: (888) 949-0045E-mail: [email protected]



SquamouS NSCLC

Checkpoint InhibitorsPatients with advanced, refractory squamous cell NSCLC have poor outcomes. With the scarcity of approved or efficacious treatments for refractory squamous NSCLC, up until recently, supportive care or clinical trials were the primary treatment options for patients with this disease.8 Immune checkpoint inhibitors (including CTLA-4, PD-1, and PD-L1) have become the focus of research for NSCLC, particularly the squamous cell type.9 Nivolumab, a PD-1 checkpoint inhibitor, was recently FDA-approved for the treatment of metastatic squamous NSCLC with progression on or after platinum-based che-motherapy.10,11

Nivolumab’s approval followed results of a phase III trial (Check-Mate-017), an open-label, randomized trial comparing nivolumab with docetaxel in 272 pretreated patients with advanced, squamous NSCLC. The trial excluded patients with active autoimmune disease or symptomatic interstitial lung disease, and all patients received ≥2 prior systemic treatments.10 The study was stopped early once the pri-mary endpoint of improved OS was reached.11 The results of this trial showed that patients who received nivolumab for their squamous cell NSCLC lived 3.2 months longer (41% reduced risk of death), on average, than patients receiving docetaxel.

Checkpoint inhibitors are associated with immune-related toxici-ties not encountered with established chemotherapy treatments for lung cancer, including pneumonitis, colitis, hepatitis, thyroiditis, rashes, neuropathies, and other less-common immune-mediated tox-icities. Many of the toxicities associated with these agents are low grade. However, for AEs such as pneumonitis, there is a potential for

serious or fatal outcomes if not recognized promptly.10,12 Nivolumab was discontinued in 27% of patients in the nivolumab arm of the CheckMate-017 trial due to AEs, and 29% of patients had a drug delay for an AE. Serious AEs occurred in 59% of patients receiving nivolumab. Serious AEs occurring in at least 2% of patients were: dyspnea, pneumonia, chronic obstructive pulmonary disease exacer-bation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.10

Dr. Roy Herbst, Chief of Medical Oncology, Yale Cancer Center, New Haven, Connecticut, shares his clinical insight into the approval of nivolumab, and how it can change the landscape of squamous NSCLC treatment:

Moderator: What are the clinical implications of the data from the nivolumab trials for NSCLC?Dr. Herbst: I think the data on nivolumab are quite impressive. With 40-plus percent improvement in survival in refractory squamous cell lung cancer, I think it’s likely to become the standard of care in the second-line setting in squamous cell lung cancer. At this point, we’ve seen median improvement in survival of over 3 months, even with-out yet incorporating biomarker work, which is still ongoing. So I think it’s going to change the way we treat squamous cell lung cancer.

Moderator: What can we take from any clinical experience with nivolumab in melanoma? How similar or different would your expec-tations be for a patient with lung cancer?Dr. Herbst: Well, I think we’re seeing equally strong data in melano-

Lung cancer is the leading cause of cancer death, accounting for about 27% of all cancer deaths each year.1 A total of 221,200 new cases of all types of lung cancer and over 158,000 deaths are expected in 2015.1

Non-small cell lung cancer (NSCLC) makes up about 85% to 90% of lung cancers, with 3 main subtypes: squamous cell (epidermoid) carcinoma (25%-30% of cases), adenocarcinoma (40% of cases), and large cell (undifferentiated) carcinoma (10%-15% of cases).1 The overall survival (OS) for patients with NSCLC is low, with a 5-year OS of only 4% to 6% in advanced stages of the disease.2 Epidermal growth factor receptor (EGFR) overexpression is most commonly encountered with squamous (84%), large cell (68%), and adenocarcinoma (65%).3 The increased vascular endothelial growth factor (VEGF) expression in squamous NSCLC can lead to resistance to anti-EGFR drugs (independent of EGFR signaling) and bevacizumab (Table). With a limited number of immunotherapy options for lung cancer to begin with, squamous NSCLC becomes even more challenging to treat.

Traditional chemotherapy agents for the treatment of lung cancer are associated with severe adverse effects (AEs) on the patient’s immune system. Immunotherapeutic agents enhance the immune response to tumors with hopes of avoiding immunosuppressive AEs, as well as prolonging responses and improving survival compared with chemotherapeutic agents.4,5 Immunotherapeutic agents for lung cancer fall into 4 main categories: monoclonal antibodies, checkpoint inhibitors, therapeutic vaccines, and adoptive T cell transfer (Table).6 These agents treat lung cancer via passive immunotherapy (eg, cytokines or immunomodulating monoclonal antibodies) or active immunotherapy (eg, antitumor vaccines or cellular therapies).7

This article will focus on checkpoint inhibitors approved for use in advanced NSCLC.



CME

ma, though given the unmet need and the large number of patients in lung cancer, this will benefit an even larger number of patients. I believe the drug has shown itself to be well tolerated in patients with lung cancer; there were some early issues with severe pneumonitis have been dealt with via early treatment with steroids and other ini-tiatives. So I think it’s really a paradigm shift now for lung cancer. Immunotherapy is here to stay in lung cancer treatment. Who would have thought this 10 years ago? It is great for patients!

Moderator: When evaluating an individual patient, how should the clinical team define response—is the evaluation of response and progression different than other types of systemic therapy for lung cancer? Dr. Herbst: Only a little different. In immunotherapy, you will usu-

ally allow patients who are clin-ically stable to progress through one assessment because some-times the tumor grows before it shrinks (we call this pseudo progression). That only occurs about 10% to 15% of the time, but that’s one thing that’s a lit-tle bit different, and you might wait a little bit longer to see a benefit. But still, if someone is progressing with symptoms, they have to come off the ther-apy.

Moderator: Could you go into a little more detail about that? Would you let it go for any case or only if the patient was asymp-tomatic? Dr. Herbst: Only if a patient had few, if any, symptoms of clinical significance. One also has to carefully evaluate the presence of any immune-related toxcities.

Moderator: How does nivolum-ab differ from other checkpoint inhibitors, such as anti-CTLA-4 agents and/or alternative an-ti-PD-1/PD-L1 agents? Dr. Herbst: Nivolumab is a PD-1 inhibitor. There are a couple of other drugs that are similar but slightly different.

There’s another PD-1 inhibitor that is still in clinical trials. There are also several PD-L1 agents, too. PD-L1 is thought to be theoretically, less toxic, as it targets PD-L1 only, leaving PD-L2 intact to interact with PD-1, which is thought to be involved in normal inflammatory responses. It’s still too early to say that PD-L1 is less toxic than PD-1 inhibitors, but that’s a different approach. Most feel that the agents are all quite similar in efficacy. Some of the biomarker work and se-lection criteria might separate them, but there aren’t any data for that yet. Perhaps the data will be coming at future meetings.

Moderator: Do the responses and progressions of those agents seem very similar to ipilimumab?Dr. Herbst: Not really. Ipilimumab never showed that much sin-gle-activity in lung cancer, so that’s one thing to separate the 2 drugs.

TAbLe. Antibodies and Immunotherapeutic Agents Approved or in Phase III Trials for Lung Cancer6,13

CTLA-4 indicates cytotoxic T-lymphocyte-associated protein 4; EGFR, epidermal growth factor receptor; HER3, human epidermal growth factor receptor 3; HGF, hepatocyte growth factor; NSCLC, non-small cell lung cancer; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand-1; SCLC, small-cell lung cancer; VEGF, vascular endothelial growth factor.

Agent Name Category Target Approval Status/Indication(s)FDA-Approved: AClinical Trial: C

Bevacizumab Monoclonal antibody VEGF A: first-line advanced/metastatic nonsquamous NSCLC

Bavituximab Monoclonal antibody Phosphatidylserine C: advanced/metastatic nonsquamous NSCLC

Cetuximab Monoclonal antibody EGFR C: advanced NSCLC

Patritumab Monoclonal antibody HER3 C: recurrent advanced/metastatic NSCLC

Rilotumumab Monoclonal antibody HGF C: second-line therapy for advanced/metastatic squamous NSCLC

Ipilimumab Checkpoint inhibitor CTLA-4 C: metastatic squamous NSCLC; extensive-stage SCLC

Nivolumab Checkpoint inhibitor PD-1 A: squamous NSCLC that has failed chemotherapyC: advanced/metastatic NSCLC

Pembrolizumab Checkpoint inhibitor PD-1 C: PD-L1+ NSCLC

MEDI4736 Checkpoint inhibitor PD-L1 C: NSCLC

GV1001 Therapeutic vaccine C: inoperable stage III NSCLC

INGN Therapeutic vaccine C: extensive-stage SCLC

Tergenpumatucel-L Therapeutic vaccine C: second-line advanced/metastatic NSCLC

TG4010 Therapeutic vaccine C: first-line metastatic MUC1+ NSCLC


SquamouS NSCLC

Ipilimumab works more in T-cell early development, the priming of T-cells, that is, the T-cells as they’re developing in the lymph node, whereas PD-1 and PD-L1 checkpoint inhibition function more in the tumor microenvironment. They specifically work at the site of the tumor cells, in the primary or metastatic site. I think the com-bination of the two offers some promise, though we will need to dose carefully and monitor for combined immunotoxicity (increased autoimmunity).

Moderator: Are there any data you can give us about patient selec-tion for nivolumab? Are there any criteria you use to identify a pa-tient who might be more appropriate, or less appropriate, for this?Dr. Herbst: This is the million dollar question! This is an amazing advance in patient care, but we’re not where we need to be yet. Still only 15% or so of patients respond, and the median survival is still only 9 months, so there’s still a lot of room to go. So many patients still don’t benefit. Some patients don’t benefit and have some side effects, so that’s certainly even worse than nothing at all. Some pa-tients benefit and then they become refractory, so I feel there is room to raise the bar further. Clinical trials with biomarker endpoints will help this process.

Moderator: Are there any patient or tumor characteristics that make nivolumab an agent of choice?Dr. Herbst: No. I think there are some data that are emerging that the number of mutations in these patients’ tumors makes a differ-ence, and we’re more likely to see activity in smokers versus non-smokers—but it is still very early.

Moderator: What are the clinical data for other immunotherapeutics in lung cancer? Is nivolumab likely the beginning of the trend?Dr. Herbst: All of the agents have about a 15% to 20% response rate, similar to nivolumab in the unselected population. I think they’ll generate similar data, some a little bit better, and some a little bit worse. But I think the whole class is looking like it’s going to be a winner. Biomarker discovery and their use could differentiate among the agents.

Moderator: Is there anything that a clinician who doesn’t have expe-rience with nivolumab might need to know in order to successfully adopt this drug into their practice?Dr. Herbst: Primarily, it’s to understand that the toxicities are a little bit different from standard chemotherapy. You don’t see neurotox-icity and neutropenia with nivolumab, but we’re dealing with more unique inflammatory situations—pneumonitis, hepatitis, gastritis, colitis, dermatologic rashes, and endocrine issues, such as thyroid, pituitary, adrenal. For the most part, if recognized early, they’re all manageable and treatable, but they’re rather new to lung cancer.

Moderator: What should clinicians tell their patients to be aware of when taking nivolumab, and how can they successfully monitor their

patients for toxicities?Dr. Herbst: Patients should know to report any possible side effects with nivolumab, as with any drug. Clinicians should check thyroid hormone levels and adrenal function and think about consulting either a pulmonologist or an endocrinologist for advice and man-agement.

REFEREnCES1. American Cancer Society. Lung cancer (Non-Small Cell). 3/4/2015. http://www.cancer.org/acs/groups/cid/documents/web-content/003115-pdf. Accessed March 23, 2015.2. National Cancer Institute. SEER Cancer Statistics Review, 1975-2011. http://seer.cancer.gov/csr/1975_2011/ Accessed March 23, 2015.3. Shanker M, Willcutts D, Roth JA, et al. Drug resistance in lung cancer. Lung Cancer:Targets and Therapy. 2010;1:23–26.4. Sundar R, Cho B, Brahmer JR, et al. Nivolumab in NSCLC: latest evidence and clinical potential. Ther Adv Med Oncol. 2015;7(2):85–96.5. Madureira P, de Mello RA, de Vasconcelos A, et al. Immunothera-py for lung cancer: for whom the bell tolls? [published online March 4, 2015]. Tumour Biol. 2015. 6. Cancer Research Institute. Cancer Immunotherapy: Lung Can-cer. http://www.cancerresearch.org/cancer-immunotherapy/impact-ing-all-cancers/lung-cancer. Accessed March 23, 2015.7. Domingues D, Turner A, Silva MD, et al. Immunotherapy and lung cancer: current developments and novel targeted therapies. Immunotherapy. 2014;6(11):1221-1235.8. Rizvi, Mazières J, Planchard D, et al. Activity and safety of nivolum-ab, an anti-PD-1 immune checkpoint inhibitor, for patients with ad-vanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16:257-265.9. de Mello RA, Pousa I, Pereira D. Nivolumab for advanced squamous cell lung cancer: what are the next steps? Lancet Oncol. 2015;16(3):234-235.10. Opdivo [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015. 11. CheckMate-017, a phase 3 study of Opdivo (nivolumab) compared to docetaxel in patients with second-line squamous cell non-small cell lung cancer, stopped early. http://news.bms.com/press-release/checkmate-017-phase-3-study-opdivo-nivolumab-compared-docetaxel-patients-second-line-s. Accessed March 25, 2015.12. Howell M, Lee R, Bowyer S, et al. Optimal management of im-mune-related toxicities associated with checkpoint inhibitors in lung cancer [published online February 16, 2015]. Lung Cancer. 2015. 13. National Institutes of Health. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/home. Accessed March 26, 2015.

iNSTRUCTiONS FOR AUTHORS

The rapid pace of discovery in the field of oncology presents practicing oncologists with the difficult challenge of implementing novel research findings into clinical practice. In order to accelerate the translation of academic advances to community-based practice, The American Journal of Hematology/Oncology aims to provide practical interpretations of the latest advances in medical and hematologic oncology and to help practicing oncologists gain a better understanding of how these advances have changed the treatment landscape for both solid and hematologic malignancies. The editors are pleased to consider manuscripts on a wide range of topics related to the journal’s mission. Articles of interest include:• Original research• Reviews

- State of the Art Updates- On the Horizon- Emerging Guidelines

• Editorials and perspectives- Clinical Controversies - Looking Forward- Brief Reports- Pivotal Trials- New Technologies- Meeting Updates - Case Reports- Survivorship Issues- Team Approaches (Allied Health/Care Extenders)

- Pharmacology Updates- Oncology Practice Issues: Evolving

Detailed descriptions of each category can be found in the Instructions for Authors at www.ajho.com.

T h e

TH

E O

FFICIAL J

OU

RN

AL O

F o f

LYMPHOMAThe Role of PET Imaging in the Management of Patients With Hodgkin Lymphoma Craig Moskowitz, MD

LEUKEMIAA Primer on Molecular Testing in Chronic Myeloid Leukemia (PCR for Poets)Jerald P. Radich, MD

OVARIAN CANCERGenomic (“Precision”) Medicine in the Management of Ovarian CancerMaurie Markman, MD PER: 9TH ANNUAL INTERNATIONAL SYMPOSIUM ON OVARIAN CANCER AND GYNECOLOGIC MALIGNANCIES®

What Would Clinicians Do If BRCA or Lynch Positive?Medical Management, Insurance Discrimination, and Confidentiality

A m e r i c a n

J o u r n a l

H e m a t o l o g y /

O n c o l o g y ®

A Peer-Reviewed Resource

for Oncology Education

CMEMedical Crossfire: Recent Advances in the Treatment of Metastatic Melanoma A CME-certified enduring material sponsored by Physicians’ Education Resource®, LLC

ajho

www.AJHO.com

All manuscripts will undergo peer review, and authors of accepted articles will receive an honorarium and will be required to sign an authorship form disclosing any possible conflicts of interest. To submit an article to The American Journal of Hematology/Oncology or if you wish to speak to an editor, please e-mail Devera Pine at [email protected].

Call for Papers

AJHO_CallForPapers_08'14.indd 5 10/7/14 10:53 AM



Mission & ScopeThe American Journal of Hematology/Oncology is a monthly peer-re-viewed publication that provides original research, reviews, and editorial/commentaries that address cutting-edge developments in genomics, targeted therapies, molecular diagnostics, and pathways related to oncological science and clinical practice. As the official publication of Physicians’ Education Resource® (PER®), the Jour-nal’s mission is to advance cancer care through professional educa-tion.

The Journal aims to provide practical interpretations of the latest advances in medical and hematologic oncology and to help practic-ing oncologists gain a better understanding of how these advances have changed the treatment landscape for both solid and hemato-logic malignancies. Articles published in the Journal will illustrate successes and failures in clinical practice and will provide practical insights into the myriad decisions that oncologists face in everyday clinical practice.

ReadershipThe American Journal of Hematology/Oncology circulates to 10,000 prac-ticing oncologists across the country. Our audience includes medical oncologists, hematologists, pathologists, dermatologists, radiation oncologists, and surgical oncologists.

Submitting ManuscriptsRequirements for all submissions generally conform to the Uniform Requirements for Manuscripts Submitted to Biomedical Journals from the International Committee of Medical Journal Editors.1 Our peer-review process is blinded, so all identifying information (eg, au-thor names, affiliations) is removed from the manuscript file before submission to peer review.

Manuscripts submitted for publication in The American Journal of Hematology/Oncology must not have been published previously (either in whole or in part), nor currently be submitted elsewhere in either

identical or similar form. Material posted on the Internet or dis-seminated in any other electronic form constitutes prior publication and may not be considered. Previous publication of a small portion of the content of a manuscript does not necessarily preclude its being published in the Journal, but the editors require information regarding previous publication when deciding how to use space in the Journal efficiently.

These restrictions on prior publication, however, do not apply to abstracts or poster presentations published in connection with sci-entific meetings, or to working papers that have been posted online to facilitate peer feedback.

Authors must indicate in the cover letter whether any portion of the manuscript has been previously published, and are required to submit copies of related publications (either published, in prepara-tion, or submitted), as well as any manuscripts cited as “in press,” to the editors for review. Duplicate, redundant, and/or fragmented publications are not permitted. Refer to Chapter 5 of the American Medical Association (AMA) Manual of Style for further information on duplicate publication.2 Authors of original research should also in-clude a statement in the body of the paper that indicates whether the study was approved by an institutional review board. For all original research (when appropriate), a statement confirming that the in-formed consent of study subjects was obtained should be included with the manuscript.

Types of Manuscripts The editors are pleased to consider manuscripts on a wide range of topics related to the Journal’s mission.

Authors should write for a sophisticated general audience and rec-ognize that many of The American Journal of Hematology/Oncology read-ers are not researchers. In addition to evaluating articles for scientific merit, the editors will assess the overall relevance of the work to the Journal’s audience.

If you are uncertain of an article’s appropriateness for The

iNSTRUCTiONS FOR AUTHORSiNSTRUCTiONS FOR AUTHORS


American Journal of Hematology/Oncology, we encourage authors to send an abstract or outline of an article to the editorial office ([email protected]) to facilitate a pre-submission review by the edi-tor-in-chief.

Submissions generally fall into one of the following categories: (1) original research; (2) reviews; or (3) editorials or commentaries.

Original research articles should employ a clear hypothesis-driven research question and an appropriate research design and analysis to report clinically relevant outcomes. Articles should be 2000-2500 words (excluding abstract, references, tables, etc) and contain no more than 5 graphic elements. Supplemental data (extra tables, fig-ures, or appendices) will be made available on the Journal’s website at the time of publication. Authors should indicate what material is intended as online-only content, and include the appropriate refer-ence or callout to these Web-exclusive elements in the text.

• Ethical Considerations: Authors must abide by the rules of a formally constituted research ethics committee, and/or their Institutional Review Board (IRB), and the tenets of the World Medical Association’s Declaration of Helsinki. Investigators are asked to explain in detail how the ethics of their study were justified. Any relevant information must be provided in the cover letter or included as a supplemental file when submitting the article. This information will be made available to peer reviewers and editorial committees. Peer reviewers are asked to consider and comment on the ethics of submitted work. (The editor-in-chief—contact via [email protected]—will provide more detailed information on ethical considerations for original research that is submitted.) All trials involving an active intervention, either treatment or diagnostic, must be accompanied by a statement of approval by the local IRB or similar ethics committee and a statement guaranteeing that all patients gave written informed consent Non-intervention studies, including survey studies regard-ing patient opinion, quality of life, or attitudes toward cancer, should also be accompanied upon submission by a statement verifying that the study has been approved, or determined exempt, by an independent ethics committee, that informed consent has been obtained even if documentation of in-formed consent has been waived, and that the information contained is kept confidential and all identifiers have been removed prior to submission for publication.

• Animal Welfare: Manuscripts reporting on studies that involve experiments with animals must include a statement verifying that the care of animals was in accordance with institutional guidelines.

Review articles should provide concise, up-to-date reviews of the literature on novel therapies and treatment strategies or other clini-cally relevant overviews. Authors should present real-world exam-

ples and discussion of the inherent challenges of incorporating new therapeutics, new treatment strategies, and new diagnostic tools into clinical practice. Articles should be 1500-2000 words, with at least 1 graphic element to illustrate a key concept. The Journal’s graphic design staff is available to develop original figures based on a sketch provided by authors. Types of review articles are as follows:

• State-of-the-Art Update: Reviews of the evidence support-ing recent key developments in the treatment of cancer, with a particular focus on information essential and applicable to clinical practice. Please illustrate key points with tables and/or figures (assistance is available from the Journal staff for the development of figures).

• On the Horizon: Reviews of translational research, therapies, and technology that are in development but that clinicians will need to be aware of within the next few years. If applicable, please illustrate key points with figures (assistance is available from the Journal staff).

• Emerging Guidelines: Highlights of the key points of the most recent clinical practice guidelines, with expert perspec-tives/opinions on the changes to the guidelines. This can be 1000 words or less, without graphic elements.

Editorials and perspectives can employ several formats that pro-vide concise and lively discussions on timely and relevant topics. These would typically involve areas of rapid change, controversy, or new areas that have the potential for major future clinical impact in oncology. These should be brief (<1500 words), with appropriate citations. Examples include:

• Clinical Controversies: Opinion pieces that discuss relevant and controversial issues in oncology (eg, maintenance ritux-imab and its role in indolent lymphoma; should DCIS be con-sidered a cancer?; when to intervene in prostate cancer; what is the quality-of-life impact of PFS vs OS improvements?)

• Looking Forward: New areas of research or clinical care that are not well known to many oncologists, but may in the future impact cancer care or research directions. The perspective would be a “thought piece” without significant amounts of data or citations.

• Brief Reports: Brief and topical perspectives and updates on new concepts, treatments, and diagnostic assays (less than 1000 words).

• Pivotal Trials: Summaries of clinical trials of interest. Should include the background/rationale, eligibility, treatment sche-ma, contact information, and NCT link (up to 1000 words).

• New Technologies: Discussions of topics such as imaging and tissue-based technologies, genomics, bioinformatics (up to 1000 words).

• Meeting Updates: Summaries of presentations at key CME meetings, conferences, and congresses, with expert perspec-



tives on the reported findings. (Please query the editor-in-chief first to avoid duplication of coverage of meetings.)

• Case Reports: Unusual cases, situations, exceptional respond-ers, including histology and imaging.

• Survivorship: Discussions of survivorship topics and symp-tom management (1000-1500 words).

• Allied Health/Care Extenders: Topics can include discus-sions of how best to use a team approach, eg, in a case report format, such as a discussion of how an individual team met and overcame a challenge or streamlined a process to improve patient care using allied health professionals/care extenders (1000-1500 words). The Journal’s editors encourage allied health professionals on the oncology care team to author or coauthor these articles.

• Pharmacology Updates: Brief overview of new drugs—mechanisms, dosing, side effects, drug interactions (1000-1500 words). These could be contributed by a RPh or PharmD, and may have the look of a write-up typical of a Pharmacy & Therapeutics Committee formulary application.

• Oncology Practice Issues: Evolving aspects of oncology practice such as insurance coverage, electronic medical records, quality assurance, accelerated drug approvals, survi-vorship, and patient education/communication that presents new perspectives and useful information for oncologists (1000-1500 words).

• Letters to the Editor: Letters commenting on articles pub-lished in the Journal will be considered for publication.

AuthorshipOnly persons who have made a direct contribution to the content of a paper should be listed as authors.

The number of authors listed with the manuscript should not exceed 10; more than 10 requires written justification and approval from the editor-in-chief.

The American Journal of Hematology/Oncology uses the criteria pro-vided by the Uniform Requirements for Manuscripts Submitted to Biomedical Journals1 to determine authorship. Each author should have participated sufficiently in the work to take public responsi-bility for the content. Authorship credit should be based only on substantial contributions to the following conditions: (1) conception and design, or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; and (3) final approval of the version to be published. All 3 conditions must be met.1

Individuals who have contributed to a paper but who do not meet the criteria for authorship can be acknowledged.

DisclosuresIt is the Journal’s policy to require that all authors disclose rela-tionships with any commercial interest that may present a real or perceived conflict of interest if: (a) the relationship is financial and

occurred within the past 12 months; and (b) the author discusses products or services of that commercial interest. Relevant financial relationships are those relationships in which the author (and/or the author’s spouse or partner) benefits receiving a salary, royalty, intel-lectual property rights, consulting fee, honoraria, ownership interest (eg, stocks, stock options, or other ownership interests, excluding di-versified mutual funds), or other financial benefit. Financial benefits are typically associated with such roles as employment, management position, independent contractor (including contracted research), consulting, speaking and teaching, membership on advisory com-mittees or review panels, board membership, and/or other activities for which remuneration is received or expected. In addition, authors are required to report all financial and material support for their research, which includes (but is not limited to) grant support and funding sources and any provision of equipment or supplies. To this end, all authors must read and sign the Journal’s “Author Disclosure Form.”

The name of the organization funding or initiating a research project should be made explicit on the title page (eg, “This study was funded by the XYZ Corporation.”). Relevant financial relationships (whether direct to the authors or through a third party) for research and/or writing, including funding, grants, honoraria, etc, must also be named on the title page. If the funding organization had any role in the collection of data, its analysis and interpretation, and/or in the right to approve or disapprove publication of the finished manuscript, this must be noted in the cover letter and described in the text. The editorial staff may inquire further about financial dis-closure after the manuscript is submitted. If the manuscript is ac-cepted for publication, disclosure statements will be printed with the published article.

ManuscriptSpecificationsManuscript components (eg, cover letter, text, tables, figures, related papers) must be included as a part of the submission process. All manuscripts must include the following components:

Cover Letter: A cover letter must accompany each submission and include any background information about the submission (eg, how it contributes to the existing literature, whether any portion has been previously presented or published) that would aid in the editors’ initial evaluation. Include a statement that the manuscript has been read and approved by all authors.

Titles. Titles should be concise (fewer than 10 words) and stimulate reader interest. Provide a brief running title on the general topic area in addition to the main article title.

The title page should include the following information:• Complete manuscript title and subtitle, if any • Full names of all authors, followed by their highest academic

degrees • Name, address, telephone, fax, and e-mail information for the

iNSTRUCTiONS FOR AUTHORSiNSTRUCTiONS FOR AUTHORS


corresponding author • Institutional affiliations for each author at the time the work

was completed • Concise summary of the article for the Table of Contents (up

to 25 words) • Practical application of your work (ie, a bulleted list that high-

lights the real-world impact of your work) • Indication of the source of funding (including grant numbers,

grant agencies, corporations, and sponsors) • Number of pages, references, figures, and tables • Word count (excluding references, tables, and figures) • Key words

Abstract. A paragraph (unstructured) abstract is required for all re-view manuscript submissions. The abstract should not exceed 150 words and should summarize the salient data and the principal con-clusion of the piece. A structured abstract should accompany all original research with headings such as Background, Patients, Methods, Results, and Conclusions.

Text. All text should be in Times New Roman 12-point type, in-cluding acknowledgments, references, tables, and legends. Cite ref-erences, tables, and figures in sequential order in the body of the paper. Measurements of length, height, weight, and volume should be reported in metric units. Temperature should be given in degrees Celsius. Blood pressure should be listed in millimeters of mercury. Except for units of measure, abbreviations are discouraged.

All abbreviations and acronyms must be spelled out in full when it first appears in the text, followed by its abbreviation in parenthe-ses. State the generic name (not the trade name) for all drugs.

Permissions. Data and/or figures reproduced from another pub-lished source must be properly cited and credited. Authors are re-quired to obtain written permission from the appropriate author and/or copyright holder to reproduce previously published or copy-righted material. Authors must also obtain permission from at least 1 author when citing unpublished data, “in-press” articles, and/or personal communication. Copies of permission statements must be included with manuscript submission.

Acknowledgments. Include a list of acknowledgments, if appro-priate. Refer to the “Authorship” section for an explanation of what constitutes authorship and for guidance in distinguishing contribu-tions that warrant an acknowledgment. The corresponding author must affirm that he/she has received permission to list the indi-viduals in the acknowledgment section (see bottom of “Authorship Form”).

References. Begin the reference section on a new page and double-space between reference citations. Number references sequentially in the order cited in the text; do not alphabetize by author names.

Provide the names of all authors when there are 4 or fewer; if there are more than 4 authors, list only the first 3 authors followed by “et al.” All references must be verified by the authors and should con-form to the AMA Manual of Style.2 If using EndNote, please format in JAMA style.

References cited only in tables or figure legends should be num-bered in accordance with the sequence established by the first men-tion of the particular table or figure in the text.

References to papers accepted but not yet published should be designated as “in press” and included in the reference section. In-formation from manuscripts submitted but not accepted should be cited in the text as “unpublished observations” with written permis-sion from the source. (Include copies of any “in press” and “submit-ted” manuscripts [ie, papers under consideration at other journals] for the editors’ evaluation as a part of your submission.)

Avoid citing “personal communication” unless it provides essen-tial information not available from a published source, in which case the name of the person, her/his degree, and the date of commu-nication should be cited in parentheses in the text. Authors should obtain written permission and confirmation of accuracy from the source of a personal communication (see “Permissions” section). Note the format and punctuation in the following sample references:

1. Cortes JE, Kim DW, Kantarjian HM, et al. Bosutinib versus ima-tinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial [published online September 4, 2012]. J Clin Oncol. 2012;30(28):3486-3492. 2. Wierda WG, O’Brien S. Chronic lymphoblastic leukemia. In: De-Vita VT Jr, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. 3. American Cancer Society. Cancer facts and figures 2014. http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfig-ures2014. Accessed March 18, 2015.

Graphic Elements. Use of graphic elements is strongly encour-aged, and each article can contain up to 5 graphic elements. All supplemental data (eg, appendices and lengthy tables) will be posted on the Journal’s website at the time of publication. Authors should indicate what material is intended for Web-exclusive content and in-clude the appropriate reference or callout in the text to these Web-exclusive elements.

Tables. Place each table on a new page. Number tables sequen-tially in the order in which they are cited in the text. Include a title for each table. Special characters, abbreviations, and symbols must be explained in the table key in the following format: “OS indi-cates overall survival; PFS, progression-free survival.” Footnoted material in tables should be indicated with superscript, lowercase letters: “a,” “b,” “c,” and so on. Footnotes are listed at the bottom of the table, each on its own line.



Figures. The Journal’s production team is available to create figures from sketches provided by the authors. Avoid the use of shading in bar graphs or pie charts—use color or crosshatch pat-terns instead. Number all figures in the order in which they are mentioned in the text. Any previously published figures must be accompanied by written permission from the publisher and/or copyright holder (see “Permissions” section). Any payment associated with repro-ducing figures is the responsibility of the author(s).

Legends. Legends should include the figure number and a brief description of the graphic. Identify all abbreviations used in the figure at the end of each legend.

Peer Review ProcessEach manuscript is sent to the editor-in-chief for an internal evalua-tion to determine its appropriateness. Manuscripts that do not meet the Journal’s criteria for overall appropriateness, relevance, original-ity, and scientific merit will be returned promptly (usually within 2 weeks) so that authors may pursue alternate avenues for publication.

Although reviewer selection is ultimately the decision of the editors, authors may provide the names and e-mail information of preferred and nonpreferred peer reviewers. Manuscripts deemed appropriate for The American Journal of Hematology/Oncology will be sent to external peer reviewers via a double-blinded review process. Typically, a manuscript will be sent to a minimum of 2 reviewers to provide feedback on the scientific merit of the paper.

Reviewers are requested to complete their evaluation of a manu-script within 2 weeks. They are asked to treat manuscripts as confi-dential communications and not to share their content with anyone (except colleagues whom they ask in confidence to assist in review-ing) or to use the content for their own purposes. The Journal does not send manuscripts to any reviewers who are affiliated with the same institution as any of the authors, and requires that reviewers declare any potential conflicts of interest, such as personal ties to an organization with a vested interest in the content of the manuscript.

Editorial DecisionsThe editors and peer reviewers judge manuscripts on the interest and importance of the topic, the intellectual and scientific strength, the clarity of the presentation, and relevance to readers. We also con-sider the strength of the paper compared with other papers under review, as well as the number of accepted and previously published articles in the same category. Authors of original research and re-view articles should clearly describe how their findings add to the existing literature.

The editorial office is committed to providing prompt processing times and to communicating timely decisions to authors. While the editorial office makes every effort to notify authors and keep them informed of any delays, most authors can expect a first decision on their manuscript in approximately 4-6 weeks. The editors will

communicate editorial decisions on acceptance or rejection to the corresponding author only.

Accepted ManuscriptsPage proofs (PDFs) are e-mailed to the corresponding author before publication. Authors can expect to receive proofs approximately 3-4 weeks before the scheduled issue date. All proofs should be returned to the editorial office within 48 hours.

References1. International Committee of Medical Journal Editors. Uniform re-quirements for manuscripts submitted to biomedical journals: writ-ing and editing for biomedical publication. www.icmje.org/urm_full.pdf. Accessed March 18, 2015. 2. Iverson C, ed. Ethical and legal considerations. In: American Medi-cal Association Manual of Style. 10th ed. New York, NY: Oxford Uni-versity Press; 2007:125-300.

Editorial Offices:The American Journal of Hematology/OncologyOffice Center at Princeton Meadows, Bldg 400Plainsboro, New Jersey 08536E-mail: [email protected]

Documents

American Journal - Amazon S3 · BreasT CanCer HER2-Positive Breast Cancer: Update on New and Emerging Agents ... American Journal Hematology/ ... Not an official event of the 2015