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Pasi A. Jänne, M.D., Ph.D. Lowe Center for Thoracic Oncology Dana Farber Cancer Institute Novel Strategies for Targeting the EGFR Pathway

EGFR Targeted Therapies First generation TKIs –Erlotinib, gefitinib, lapatinib Second generation TKIs –Neratinib, afatinib (BIBW2992), dacomitinib (PF299804) Third generation –WZ4002 – preclinical only Combinations –Afatinib/cetuximab

Use of Novel EGFR Therapies When erlotinib fails –Afatinib phase III trial –Afatinib/cetuximab Instead of erlotinib –Second line – dacomitinib vs. erlotinib –First line – afatinib or dacomitinib instead of erlotinib

LUX-Lung 1: Trial Design Randomization 2:1 (Double Blind) Oral afatinib 50 mg once daily plus BSC Oral placebo once daily plus BSC Primary endpoint: Overall survival (OS) Secondary: PFS, RECIST response, QoL (LC13 & C30), safety Radiographic assessments at 4, 8, 12 wks and every 8 wks thereafter Exploratory biomarkers: Archival tissue testing for EGFR mutations (optional; central lab) Serum EGFR mutational analysis (all patients) Patients with: Adenocarcinoma of the lung Stage IIIB/IV Progressed after one or two lines of chemotherapy (incl. one platinum-based regimen) and ≥12 weeks of treatment with erlotinib or gefitinib ECOG 0–2 N=585

Primary Analysis: Overall Survival Miller et al. ESMO 2010 OS Placebo, deaths = 114 (58.5%), median = months (95% CI: ) Afatinib, deaths = 244 (62.6%), median = months (95% CI: ) –Hazard ratio (afatinib vs placebo) (0.862, 1.346) –Log-rank test p-value (one-sided) Afatinib RR: 7% PFS: Afatinib 3.3 months; placebo 1.1 months –HR 0.38, 95% CI 0.31 to 0.48, p <

Regales et al. JCI 2009 Combination of BIBW2992 and Cetuximab Is Effective against EGFR T790M "The combination of both agents together induced dramatic shrinkage of erlotinib-resistant tumors harboring the T790M mutation, because together they efficiently depleted both phosphorylated and total EGFR."

Phase Ib Study of Afatinib & Cetuximab 1 EGFR G719X, exon 19 deletion, L858R, L861Q; 2 Progression of disease (Response Evaluation Criteria in Solid Tumors v1.1) on continuous treatment with erlotinib or gefitinib within the last 30 days; 3 Amended from original 14-day interval; 4 Acquisition of tumor tissue after the emergence of acquired resistance was mandated. i.v.=intravenous; MTD=maximum tolerated dose; NSCLC=non-small cell lung cancer; SD=stable disease. Stop erlotinib/ gefitinib for ≥72 hours 3 Disease progression 2 Pathology confirmed NSCLC with EGFR mutation 1 OR SD  6 months on erlotinib/gefitinib OR Partial or complete response to erlotinib/gefitinib MTD cohort expanded up to 80 EGFR mutation-positive patients 4 : 40 T790M+ and 40 T790M– Dose escalation schema 3–6 patients per cohort Afatinib p.o. daily + escalating doses of i.v. cetuximab q 2 weeks Dose levels starting at: afatinib 40 mg + cetuximab 250 mg/m 2 Predefined maximum dose: afatinib 40 mg + cetuximab 500 mg/m 2 ECOG PS 0-2 Age ≥ 18 years

Research To Practice could not obtain permission to reproduce this slide at the time of publication. To access the following abstract, please visit our Select Publications page: Groen JL et al. Proc IASLC 2011;Abstract O19.07.

Randomized Phase 2 Study of Dacomitinib (PF299804) vs. Erlotinib Stratification: Non-smokers vs smokers Adeno vs Non-adeno East Asian vs non-East Asian Primary endpoint: PFS Secondary endpoints: OS, response, safety, patient reported outcomes 128 PFS events to show 45% improvement, with 80% power,  =0.1 (1-sided) Key Eligibility: ­Advanced NSCLC ­1  2 prior chemotherapies  ECOG PS 0 ‒ 2 ­Available tumor tissue ­No prior EGFR TKI Recruited 11/08 – 10/09 47 Centres, 12 countries Treated till PD, death or unacceptable toxicity Erlotinib 150 mg QD N=94 PF mg QD N=94 RANDOMIZEDRANDOMIZED Boyer et al. WCLC 2011

Progression-Free Survival (PFS) PF vs Erlotinib: All and KRAS WT (both 12% Censored) Boyer et al. WCLC 2011 PF299804ErlotinibStratified HR 2-sided p-value PFS, all patients (n=94) 12.4 weeks8.3 weeks 0.66 (95% CI: ) PFS, KRAS WT (n=57) 16.1 weeks8.3 weeks0.50 (95% CI: ) 0.002

Patients clinically selected: Never-* or former light- smoker † ; Asian or KRAS WT non-Asian OR Known EGFR mutation Additional inclusion criteria: Adenocarcinoma histology Chemotherapy naϊve ECOG PS 0/1 First-Line Phase II Trial of PF PF mg QD (amended to 30 mg) *Never-smoker: <100 cigarettes, cigars, or pipes over lifetime, and none in 12 months † Former light-smoker: ≤15 years since last cigarette, and less than 10 pack-years of prior cigarette smoking Endpoints: Primary PFS rate at 4 months Secondary: PFS OS ORR Safety Exploratory: Serial tissue- and blood-based biomarkers (T790M) Data cut-off: July 28, 2010 Mok et al. ESMO 2010

Best Tumor Change in Target Lesions: Overall Population Treated with PF –20 –40 –60 –80 –100 Best change from baseline (%) 45 mg, RDI ≥70% 45 mg, RDI <70% 30 mg, RDI ≥70% 30 mg, RDI <70% N=71 With permission from Mok et al. ESMO 2010

First-Line Therapy with Second- Generation EGFR TKIs Dacomitinib (PF299804) – –High RR (~60% in EGFR mutants) –PFS – ASCO 2012 Afatinib 1 –RR 64%; PFS 14.7 months Afatinib vs. chemotherapy –ASCO Yang et al. ASCO 2010

Saturday, February 11, 2012 Hollywood, Florida Faculty Co-Chairs Rogerio C Lilenbaum, MD Mark A Socinski, MD Co-Chair and Moderator Neil Love, MD Chandra P Belani, MD John Heymach, MD, PhD Pasi A Jänne, MD, PhD Thomas J Lynch Jr, MD Heather Wakelee, MD