Part III – Individualizing Therapy in NSCLC Tuesday, June 28, 2011 7:30 PM – 8:30 PM ET RTP TV:...

Part III – Individualizing Therapy in NSCLCTuesday, June 28, 20117:30 PM – 8:30 PM ET

RTP TV: An 8-Part Live CME Webcast Series

Lucian R Chirieac, MD Associate Professor of Pathology, Harvard Medical School Pathologist, Brigham and Women’s Hospital Boston, Massachusetts

Thomas J Lynch Jr, MDJonathan and Richard Sackler Professor of Internal MedicineDirector, Yale Cancer CenterPhysician-in-Chief, Smilow Cancer Hospital at Yale New HavenNew Haven, Connecticut

Neil Love, MDResearch To PracticeMiami, Florida

Lecia V Sequist, MD, MPH Assistant Professor of Medicine, Harvard Medical School Center for Thoracic Cancers Massachusetts General Hospital Cancer Center Boston, Massachusetts

Disclosures for Moderator Neil Love, MD

Dr Love is president and CEO of Research To Practice, which receives funds in the form of educational grants to develop CME activities from the following commercial interests: Allos Therapeutics, Amgen Inc, AstraZeneca Pharmaceuticals LP, Aureon Laboratories Inc, Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals Inc, Biogen Idec, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, Daiichi Sankyo Inc, Dendreon Corporation, Eisai Inc, EMD Serono Inc, Genentech BioOncology, Genomic Health Inc, ImClone Systems, a wholly owned subsidiary of Eli Lilly and Company, Lilly USA LLC, Millennium: The Takeda Oncology Company, Mundipharma International Limited, Myriad Genetics Inc, Novartis Pharmaceuticals Corporation, OSI Oncology, Sanofi and Seattle Genetics.

Disclosures for Lucian R Chirieac, MD

No financial interests or affiliations to disclose

Disclosures for Thomas J Lynch Jr, MD

Board of Directors Infinity Pharmaceuticals Inc

Consulting AgreementsBoehringer Ingelheim Pharmaceuticals Inc, SuperGen Inc

Stock OwnershipBiogen Idec, Infinity Pharmaceuticals Inc

Disclosures for Lecia V Sequist, MD, MPH

Advisory Committee GlaxoSmithKline

Paid Research

Boehringer Ingelheim Pharmaceuticals Inc, Daiichi Sankyo Inc, Genentech BioOncology, Lilly USA LLC, Merrimack Pharmaceuticals

Agenda: Individualizing Therapy for NSCLC

• ASCO 2011: Key presentations

• Histopathology and lung cancer management

• Faculty cases

• Questions & answers

Survey of 100 Practicing OncologistsApril 15-28, 2011

• 51 — Median total number of patients with lung cancer

evaluated in the past year

• Median number of patients evaluated in the following

settings during the past year…

– Adjuvant therapy for NSCLC: 10

– Treatment of locally advanced NSCLC: 10

– Treatment of metastatic NSCLC: 20

– Treatment of SCLC: 6

RTP TV — Individualizing Therapy for NSCLC

Key Papers from ASCO 2011

Molecularly Driven Studies

Rosell et al. EURTAC: Phase III trial of erlotinib vs chemotherapy in EGFR mutant advanced NSCLC

Spigel et al. OAM4558g: Randomized phase II study of MetMAb or placebo in combination with erlotinib in advanced NSCLC

Kris et al. NCI Lung Cancer Mutation Consortium: Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma

Shaw et al. Impact of crizotinib on survival in patients with advanced, ALK+ NSCLC compared with historical controls (Sequist Case #3)

Maintenance Treatment

Paz-Ares et al. PARAMOUNT: Phase III study of maintenance pemetrexed plus best supportive care (BSC) versus placebo plus BSC following induction pemetrexed/cisplatin for advanced nonsquamous NSCLC

Zhang et al. INFORM, C-TONG 0804: Phase III study of maintenance gefitinib in locally advanced or metastatic NSCLC

Adjuvant Treatment

Kreuter et al. TREAT: Randomized, Phase II study of adjuvant cisplatin plus either pemetrexed or vinorelbine (Lynch Case #4)

1. What is your usual initial first-line therapy for a patient with EGFR mutation-positive metastatic NSCLC?

2%

22%

12%

64%

0% 20% 40% 60% 80%

Erlotinib

Gefitinib

Chemotherapy alone or with bevacizumab

Other

Rosell R et al. Proc ASCO 2011;Abstract 7503.

Erlotinib vs Chemotherapy (CT) in Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients (p) with Epidermal Growth Factor Receptor (EGFR) Activating Mutations: Interim Results of the European Erlotinib vs Chemotherapy (EURTAC) Phase III Randomized Trial

With permission, Rosell R et al. Proc ASCO 2011;Abstract 7503.

Primary Endpoint: PFS in ITT Population(Updated Analysis January 26, 2011)

Erlotinib (n = 86)Chemotherapy (n = 87)

HR = 0.37 Log-rank p < 0.0001

Best Overall Response in ITT Population

Clinical parameterErlotinib(n = 88)

Chemotherapy(n = 87)

Best overall response rate Complete response Partial response

58%2%

56%

15%0%

15%

Disease control rate 79% 66%

Rosell R et al. Proc ASCO 2011;Abstract 7503.

EURTAC Conclusions

• EURTAC met its primary PFS endpoint at the interim analysis.

• Study results confirm significant PFS benefit of first-line erlotinib over standard chemotherapy for patients with EGFR mutation-positive NSCLC:– 63% reduction in risk of progression or death

Is Erlotinib a Standard First-Line Therapy for Patients with EGFR Mutation?

Study Response rate PFS

EURTAC 58% vs 15% 9.7 vs 5.2 mos

OPTIMAL 83% vs 36% 13.1 vs 4.6 mos

NEJ002 74% vs 31% 10.8 vs 5.4 mos

WJTOG 3405 62% vs 31% 9.2 vs 6.3 mos

Mok T. Proc ASCO 2011;Discussant.

Final Efficacy Results from OAM4558g, a Randomized Phase II Study Evaluating MetMAb or Placebo in Combination with Erlotinib in Advanced NSCLCSpigel DR et al.Proc ASCO 2011;Abstract 7505.

MetMAb + Erlotinib in Patients with MetDx+ NSCLC

With permission from Spigel DR et al. Proc ASCO 2011;Abstract 7505.

Pro

bab

ility

of

Pro

gre

ssio

n F

ree

Pro

bab

ilit

y o

f S

urv

ival

1.0

0.8

0.6

0.4

0.2

0.0

PFS: HR = 0.53, p = 0.04 OS: HR = 0.37, p = 0.002

Time to Progression (months)

0 3 6 9 12 15 18

Overall Survival (months)

1.0

0.8

0.6

0.4

0.2

0.0

0 3 6 9 12 15 18 21

Placebo + erlotinib

MetMAb +

erlotinibMedian (mo) 1.5 2.9

Placebo + erlotinib

MetMAb +

erlotinibMedian (mo) 3.8 12.6

Spigel DR et al. Proc ASCO 2011;Abstract 7505.

MetMAb + Erlotinib versus Placebo + Erlotinib for 2nd/3rd-Line NSCLC (n = 128)

• In patients with NSCLC and positive c-MET

immunohistochemistry the addition of MetMAb to

erlotinib resulted in a twofold reduction in the risk of

progression (HR = 0.53, p = 0.04) and a

near-threefold reduction in the risk of death

(HR = 0.37, p = 0.002).

• EGFR mutation or FISH status does not drive the

benefit from MetMAb.

• MetMAb + erlotinib was well tolerated.

Kris MG et al.

Proc ASCO 2011;Abstract CRA7506.

Identification of Driver Mutations in Tumor Specimens from 1,000 Patients with Lung Adenocarcinoma: The Lung Cancer Mutation Consortium (LCMC)

Kris MG et al. Proc ASCO 2011;Abstract CRA7506.

Lung Cancer Mutation Consortium: Patients and Study Plan

Use data to selecttherapy

(erlotinib with EGFRmutation)

Use data to selecttherapy

(erlotinib with EGFRmutation)

Recommended clinicaltrial of agent

specific for target

Recommended clinicaltrial of agent

specific for target

Report toLCMCvirtual

database

Report toLCMCvirtual

database

Mutational analysisCLIA-certified lab at LCMC site:

KRAS, EGFR, EML4-ALK, BRAF,HER2, PIK3CA, NRAS, MEK1,

AKT1, MET amplification

Mutational analysisCLIA-certified lab at LCMC site:

KRAS, EGFR, EML4-ALK, BRAF,HER2, PIK3CA, NRAS, MEK1,

AKT1, MET amplificationReport tophysicianReport tophysician

1,000 patientsStage IV

ECOG PS 0-2Lung adenocarcinoma

Sufficient tissue (paraffin)Informed consent

1,000 patientsStage IV

ECOG PS 0-2Lung adenocarcinoma

Sufficient tissue (paraffin)Informed consent

Centralconfirmation of

adenocarcinomadiagnosis(1 slide)

Centralconfirmation of

adenocarcinomadiagnosis(1 slide)


Lung Cancer Mutation Consortium: Incidence of Single Driver Mutations

NO MUTATIONDETECTED

KRAS22%

EGFR17%

EML4-ALK7%

DOUBLE MUTANTS 3%

BRAF 2%

PIK3CA

HER2

MET AMP

MEK1

NRAS

AKT1

Mutation found in 54% (280/516) of tumors completely tested (CI 50-59%)

Lung Cancer Mutation Consortium:LCMC Protocols Linked to Specific Molecular Lesions Detected (I)

Target Agent(s) LCMC Lead

EGFRErlotinib + OSI 906Erlotinib + MM 121

C RudinL Sequist

KRASTivantinib + Erlotinib

GSK1120212J SchillerP Jänne

MET Amplification

EML4-ALK Crizotinib R Camidge

NRAS GSK1120212 P Jänne

Lung Cancer Mutation Consortium:LCMC Protocols Linked to Specific Molecular Lesions Detected (II)

Target Agent LCMC Lead

MEK1 GSK1120212 P Jänne

BRAF (V600E) GSK2118434 B Johnson

BRAF (not V600E) GSK1120212 P Jänne

HER2 Afatinib M Kris

PIK3CA BKM120 J Engelman

AKT1


Lung Cancer Mutation Consortium: Using LCMC Data to Guide Care – MSKCC Patients

121Enrolled

121Enrolled

102Multiplex mutation testingand/or FISH completed

102Multiplex mutation testingand/or FISH completed

60 (59%)Driver mutations found

60 (59%)Driver mutations found

31 (30%)Received therapy

targeted tospecific mutation

31 (30%)Received therapy

targeted tospecific mutation

19 – Erlotinib as initial therapy16 – Clinical trial of agent for identified mutation

19 – Erlotinib as initial therapy16 – Clinical trial of agent for identified mutation

Conclusions

• In 516 tumor samples analyzed by IHC and FISH, 54% were positive for a driver mutation.

• Mutational status information is being used in real time to select erlotinib as initial therapy and direct patients to linked trials.

Paz-Ares LG et al. Proc ASCO 2011;Abstract CRA7510.

PARAMOUNT: Phase III Study of Maintenance Pemetrexed (Pem) plus Best Supportive Care (BSC) versus Placebo plus BSC Immediately Following Induction Treatment with Pem plus Cisplatin for Advanced Nonsquamous Non-Small Cell Lung Cancer

Edelman MJ. Proc ASCO 2011;Discussant.

EGFR Mutations and Maintenance

• EGFR mutations predict substantial and sustained benefit for EGFR TKIs.

• All studies that involve patients with EGFR mutations and EGFR TKIs demonstrate substantial PFS advantage.

• Almost no benefit is observed in EGFR mutation- negative patients.


Who Should Receive Maintenance?

• Everybody?

• Patients who responded and are doing well?

• Patients who had stable disease/not doing so well?

• Performance status?


Maintenance Therapy: Rationale Behind Continuation vs Switch

• Continuation maintenance– Continual suppression of malignancy will be more

effective than intermittent use

• Switch maintenance (planned sequential)– Transition to proven second-line therapy before

the emergence of resistance– Early use assures exposure to second-line therapy

(ie, “no one falls off the cliff”)

PARAMOUNT: Select Grade 3 and 4 Drug-Related Toxicities

Adverse eventPemetrexed

(n = 359)Placebo(n = 180)

Fatigue* 4.2% 0.6%

Anemia* 4.5% 0.6%

Neutropenia* 3.6% 0

Leukopenia 1.7% 0

Sensory neuropathy 0.3% 0.6%

Mucositis/stomatitis 0.3% 0

ALT (SGPT) 0.3% 0

* Statistically significant between arms (p ≤ 0.05)



PARAMOUNT: PFS – Independent Review

Pem + BSC (n = 316)

Placebo + BSC (n = 156)

Median PFS* (months) 3.9 2.6

Hazard ratio: 0.64, p = 0.0002

* 88% of patients were independently reviewed (472/539).

PARAMOUNT Conclusions

• The trial met its primary PFS endpoint with pemetrexed continuation maintenance therapy resulting in a significant benefit compared to placebo for patients with advanced nonsquamous NSCLC.

• Pemetrexed maintenance was well tolerated.

• Mature OS data are pending.

Zhang L et al.

Proc ASCO 2011;Abstract LBA7511.

Efficacy and Tolerability Data from a Randomized, Placebo-Controlled, Parallel-Group Study of Gefitinib as Maintenance Therapy in Patients with Locally Advanced or Metasatic NSCLC (INFORM) (C-TONG 0804)

Progression-Free Survival (ITT Population)

Zhang L et al. Proc ASCO 2011;Abstract LBA7511.

Gefitinib(n = 148)

Placebo (n = 148)

Median PFS (months) 4.8 2.6

6-month PFS rate (%) 47.3 15.0

12-month PFS rate (%) 33.2 2.9

HR = 0.42; p < 0.0001

Progression-Free Survival by EGFR Mutation Status (N = 79)

Zhang L et al. Proc ASCO 2011;Abstract LBA7511.

EGFR mutation-positive

EGFR wild-type

Gefitinib (n = 15)

Placebo (n = 15)

Gefitinib (n = 25)

Placebo (n = 24)

Median PFS (months)

16.6 2.8 2.7 1.5

Hazard ratio = 0.17 Hazard ratio = 0.86

INFORM Conclusions

• The trial met its primary PFS endpoint and demonstrated a statistically significant benefit with gefitinib compared to placebo for Asian patients with advanced NSCLC.

• The greatest magnitude of effect on PFS was observed in patients with EGFR mutation-positive tumors.

Top-Line Results of Single Agent Maintenance Trials

Study Agent PFS (mos) OS (mos)

PARAMOUNT PemetrexedControl

3.9*2.6

NRNR

INFORM GefitinibControl

4.8*2.6

18.716.9

FIDIAS Docetaxel Control

5.7*2.7

12.39.7

IMFN PemetrexedControl

4.3*2.6

13.410.6

SATURN Erlotinib Control

12.3 wk*11.1 wk

12.0*11.0

Belani 2010 GemcitabineControl

7.47.7

8.09.3

IFCTGemcitabine

ErlotinibControl

3.8* 2.9*1.9

12.111.410.8

* Statistically significant (p < 0.05).


2. Which maintenance treatment do you generally recommend after completion of induction therapy for patients with advanced NSCLC and stable disease or better?

6%

15%

23%

17%

39%

0% 10% 20% 30% 40% 50%

Pemetrexed

Bevacizumab

Pemetrexed with bevacizumab

Erlotinib

Other


• 82% — Fraction of oncologists who recommend maintenance treatment after completion of induction therapy for patients with advanced NSCLC and stable disease or better

• Maintenance therapy used:– Pemetrexed: 43%– Bevacizumab: 29%– Bevacizumab plus pemetrexed: 20%– Erlotinib: 8%

Acinar Pattern

Bronchioloalveolar PatternSolid Pattern

Papillary Pattern

Lung Adenocarcinoma Subtypes

Bronchioloalveolar CarcinomaNon-mucinous Type

Mucinous Bronchioloalveolar Carcinoma

Dr Sequist (Case 1)

• A 44 yo mother of two who works at the local elementary school presents with an EGFR-mutant adenocarcinoma of the lung with metastases to the brain, bones and liver – Erlotinib response x 13 months followed by

progression• Repeat biopsy: T790M adenocarcinoma• Next treatment — on or off protocol?

Case 1: Initial Response

Case 1: Acquired Drug Resistance

Sequist LV et al.

Sci Transl Med 2011;3(75):75ra26.

Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors

Frequency of Observed Acquired Mechanisms of Resistance to EGFR TKIs in 37 EGFR Mutant Patients

Sequist LV et al. Sci Transl Med 2011;3(75):75ra26.

PIK3CA(5%)

SCLCtransformation(14%)

Unknownmechanism

(30%)

T790M(49%)

WithEGFRamp

METamp(5%)

PIK3CA + SCLC(5%)

LUX-Lung 1: Afatinib plus BSC vs BSC Alone in Patients with NSCLC Progressing on Chemo and Erlotinib/Gefitinib

Miller VA et al. Proc ESMO 2010;Abstract LBA1.

Afatinib + BSC(n = 390)

Placebo + BSC(n = 195)

Hazard ratio p-value

Efficacy

Median overall survival 10.78 months 11.96 months 1.08 NS

Median progression-free survival 3.3 months 1.1 months 0.38 <0.0001

Disease control rate at 8 weeks 58% 19% — <0.0001

Overall response rate 7.4% 0.5% — <0.01

NS = not significant

Janjigian YY et al.Proc ASCO 2011;Abstract 7525.

Activity and Tolerability of Afatinib (BIBW 2992) and Cetuximab in NSCLC Patients with Acquired Resistance to Erlotinib or Gefitinib

Dr Lynch (Case 2)

• A 64 yo man with a primary lung cancer presents with neck pain– PET/CT and MRI– Oligometastatic disease to the C6/C7 spine

• Carbo/pemetrexed/bevacizumab tolerated well– Maintenance pemetrexed/bevacizumab initiated

• Lung mass beginning to progress, SOB– Radiation therapy?

Case 2


• In general, which doublet chemotherapy regimen (either alone or with a biologic agent) is your first-line treatment choice for a patient with metastatic nonsquamous cell NSCLC and a good performance status?– Carboplatin or cisplatin/pemetrexed: 61%– Carboplatin/paclitaxel: 28%– Carboplatin/gemcitabine: 5%– Carboplatin or cisplatin/docetaxel: 6%

Dr Sequist (Case 3)

• A 64 yo man who works for the state of New York and is a life-long nonsmoker with resected EGFR wildtype adenocarcinoma of the lung 5 years previously presents with a RUL pulmonary nodule. It is initially hoped to be resectable but upon thoracotomy there are innumerable pleural nodules– Biopsy:

Adenocarcinoma, ALK translocation

• Clinical trial of crizotinib– Near CR maintained for 22 months– Decreased WBC without neutropenia– Rash after 1 yr, which resolved w/o intervention

Case 3

Lung Adenocarcinoma with ALK Rearrangements Cytologic Features

Lung Adenocarcinoma with ALK Rearrangements FISH Testing

ALK Rearrangement in NSCLC

or

• Present in ~4% of NSCLC cases• Enriched in younger never or light smokers with adenocarcinoma histology• Rarely overlaps with EGFR and KRAS mutations• Potent oncogenic driver in cell line and animal models

TranslocationInversion

With permission, Shaw AT et al. Proc ASCO 2011;Abstract 7507.

Tumor Responses to Crizotinib for Patients with ALK-Positive NSCLC

60

40

20

0

–20

–40

–60

–80

–100

Progressive disease

Stable disease

Confirmed partial response

Confirmed complete response

Max

imu

m C

han

ge

in T

um

or

Siz

e (%

)

–30%

*Partial response patients with 100% change have non-target disease present *

Kwak EL et al. N Engl J Med 2010;363(18):1693-703. Copyright © 2011 Massachusetts Medical Society. All rights reserved.

Dr Lynch (Case 4)

• A 47-year-old man who works as an auto insurance adjuster with early-stage EGFR mutant NSCLC (exon 20)– Cisplatin/pemetrexed/bevacizumab on Intergroup

E1505– Hypertension– Quickly relapsed

• Received erlotinib on the standard arm of a clinical trial– Progressed without response

• Enrolled on a trial of the anti-PD-1 antibody MDX-1106– Too early to determine if he is responding

Case 4: Pre-surgery

Case 4: Post-surgery

ECOG-E1505: Phase III Study of Chemo with or without Bevacizumab in Patients with Resected NSCLC

• Trial Identifier: NCT00324805

• Target accrual: 1,500 patients

• Study arms: Chemotherapy alone (cisplatin and either docetaxel,

gemcitabine, pemetrexed or vinorelbine)

Chemotherapy + bevacizumab

• Eligibility:

– Stage IB (tumor size ≥4 cm) to IIIA NSCLC

– Resection within past 6-12 weeks

– Only nonsquamous histology for patients assigned to pemetrexed or cisplatin as chemotherapy

www.clinicaltrials.gov, June 2011.

Randomized Phase II Trial on Refinement of Early-Stage NSCLC Adjuvant Chemotherapy with Cisplatin and Pemetrexed (CPx) versus Cisplatin and Vinorelbine (CVb): TREATKreuter M et al.

Proc ASCO 2011;Abstract 7002.

Cisplatin/Vinorelbine (CVb) versus Cisplatin/Pemetrexed (CPx) in Early NSCLC

• CPx was safe and feasible (met primary endpoint):– Less toxicity compared to CVb– Superior dose delivery compared to CVb– Mean cisplatin dose higher for CPx versus CVb

• Dose delivery failure in CVb was due mostly to Vb (delivery d15, d22)

Kreuter M et al. Proc ASCO 2011;Abstract 7002.

Safety and Antitumor Activity of Biweekly MDX-1106 (anti-PD-1, BMS-936558/ONO-4538) in Patients with Advanced Refractory MalignanciesSznol M et al.

Proc ASCO 2010;Abstract 2506.

Dr Sequist (Case 5)

• 65 yo bartender with a 100 pack-year smoking history is referred from his surgeon with chest wall pain and a mass on the edge of his lung extending to rib

• Mediastinoscopy and VATS show T3N2M0 squamous cell – Stage IIIB squamous cell carcinoma– PIK3CA mutation

• Receiving EP 50/50 + RT and will be evaluated for surgery after pre-op dose of 50.4 Gy

Case 5

Mutation Adenocarcinoma Squamous cell carcinoma

EGFR 5-15%* <5%†

ALK 5-15% <5%

HER2 <5% 0

BRAF <5% 0

KRAS >15% <5%

PIK3CA <5% <5%

AKT1 0 <5%

MAP2K1 <5% 0

MET <5% <5%

* Mainly EGFR kinase domain mutations. † Mainly EGFR VIII mutations, which result from deletion of exons 2-7.

Pao W, Girard N. Lancet Oncol 2011;12:175-80.

Frequency of Driver Mutations in NSCLC

Schedule of Events

Tuesday, July 5Multiple MyelomaNikhil C Munshi, MDA Keith Stewart, MBChB

Tuesday, July 12Gastric CancerCharles S Fuchs, MD, MPHDavid H Ilson, MD, PhDLaura H Tang, MD, PhD

Tuesday, July 19Triple-Negative Breast Cancer: Current Clinical Management

Harold J Burstein, MD, PhDCharles E Geyer Jr, MD

Tuesday, July 26Non-Hodgkin’s Lymphoma/Chronic Lymphocytic LeukemiaStephanie A Gregory, MDJohn P Leonard, MD

Tuesday, August 2Chronic Myeloid LeukemiaSusan M O’Brien, MDNeil P Shah, MD, PhD

Part III – Individualizing Therapy in NSCLC Tuesday, June 28, 2011 7:30 PM – 8:30 PM ET RTP TV:...

Documents

Transcript of Part III – Individualizing Therapy in NSCLC Tuesday, June 28, 2011 7:30 PM – 8:30 PM ET RTP TV:...