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

EGFR Targeted Therapies • First generation TKIs – Erlotinib, gefitinib, lapatinib • Second generation TKIs – Neratinib, afatinib (BIBW 2992), dacomitinib (PF 299804) • Third generation – WZ 4002 – 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 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 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, Qo. L (LC 13 & C 30), 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)

Primary Analysis: Overall Survival OS • Placebo, deaths = 114 (58. 5%), median = 11. 96 months (95% CI: 10. 15 -14. 26) • Afatinib, deaths = 244 (62. 6%), median = 10. 78 months (95% CI: 9. 95 -11. 99) – Hazard ratio (afatinib vs placebo) - 1. 077 (0. 862, 1. 346) – Log-rank test p-value (one-sided) - 0. 7428 • Afatinib RR: 7% • PFS: Afatinib 3. 3 months; placebo 1. 1 months – HR 0. 38, 95% CI 0. 31 to 0. 48, p < 0. 0001 Miller et al. ESMO 2010

Combination of BIBW 2992 and Cetuximab Is Effective against EGFR T 790 M "The combination of both agents together induced dramatic shrinkage of erlotinib-resistant tumors harboring the T 790 M mutation, because together they efficiently depleted both phosphorylated and total EGFR. " Regales et al. JCI 2009

Phase Ib Study of Afatinib & Cetuximab Dose escalation schema 3– 6 patients per cohort Pathology confirmed NSCLC with EGFR mutation 1 OR SD 6 months on erlotinib/gefitinib OR Partial or complete response to erlotinib/gefitinib ECOG PS 0 2 Age ≥ 18 years 1 EGFR Disease progression 2 Stop erlotinib/ gefitinib for ≥ 72 hours 3 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 MTD cohort expanded up to 80 EGFR mutation-positive patients 4: 40 T 790 M+ and 40 T 790 M– G 719 X, exon 19 deletion, L 858 R, L 861 Q; 2 Progression of disease (Response Evaluation Criteria in Solid Tumors v 1. 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.

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 O 19. 07.

Randomized Phase 2 Study of Dacomitinib (PF 299804) vs. Erlotinib Key Eligibility: Advanced NSCLC 1 2 prior chemotherapies ECOG PS 0‒ 2 Available tumor tissue No prior EGFR TKI Stratification: Non smokers vs smokers Adeno vs Non adeno East Asian vs non East Asian Boyer et al. WCLC 2011 R A N D O M I Z E D PF 299804 45 mg QD N=94 Recruited 11/08 – 10/09 47 Centres, 12 countries Treated till PD, death or unacceptable toxicity Erlotinib 150 mg QD N=94 Primary endpoint: PFS Secondary endpoints: OS, response, safety, patient reported outcomes 128 PFS events to show 45% improvement, with 80% power, a=0. 1 (1 sided)

Progression-Free Survival (PFS) PF 299804 vs Erlotinib: All and KRAS WT (both 12% Censored) 2 -sided p-value PF 299804 Erlotinib Stratified HR PFS, all patients (n=94) 12. 4 weeks 8. 3 weeks 0. 66 (95% CI: 7. 9 -11. 7) 0. 012 PFS, KRAS WT (n=57) 16. 1 weeks 8. 3 weeks 0. 50 (95% CI: 0. 33 -0. 78) 0. 002 Boyer et al. WCLC 2011

First Line Phase II Trial of PF 299804 Patients clinically selected: Endpoints: Never-* or former lightsmoker †; Asian or KRAS WT non-Asian Primary • PFS rate at 4 months OR Known EGFR mutation PF 299804 45 mg QD (amended to 30 mg) Additional inclusion criteria: • Adenocarcinoma histology • Chemotherapy naϊve • ECOG PS 0/1 Secondary: • PFS • ORR • Safety Exploratory: • Serial tissue- and blood-based biomarkers (T 790 M) Data cut-off: July 28, 2010 *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 Mok et al. ESMO 2010

Best Tumor Change in Target Lesions: Overall Population Treated with PF 299804 40 Best change from baseline (%) 20 0 – 20 – 40 – 60 – 80 – 100 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 (PF 299804) – – High RR (~60% in EGFR mutants) – PFS – ASCO 2012 • Afatinib 1 – RR 64%; PFS 14. 7 months • Afatinib vs. chemotherapy – ASCO 2012 1 Yang et al. ASCO 2010

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