Randomized Phase II trial of erlotinib (E) alone or in combination with carboplatin/paclitaxel (CP) in never or light former smokers with advanced lung adenocarcinoma: CALGB P.A. Jänne 1, X. Wang 2, M. A. Socinski 3, J. Crawford 4, M. Capelletti 1, M. Edelman 5, M.A. Villalona-Calero 6, R. Kratzke 7, E. Vokes 8 and V.A. Miller 9 1 Dana Farber Cancer Institute; 2 CALGB Statistical Center; 3 University of North Carolina; 4 Duke University; 5 University of Maryland; 6 Ohio State University; 7 University of Minnesota; 8 University of Chicago; 9 Memorial Sloan-Kettering Cancer Center

EGFR TKI Therapy in 2010 Efficacy (RR and PFS) greatest in EGFR mutant patients Single agent activity in EGFR mutants 1,2 –1 st line response rate: 60%-80% –1 st line progression free survival 10 – 14 months Gefitinib superior to 1 st line chemotherapy 1 –Higher RR and longer PFS –Better toxicity profile 1 Mok et al. NEJM 2009; 2 Rossell et al. NEJM 2009

Chemotherapy With Erlotinib or Placebo TRIBUTE Trial Intent-to-Treat Never Smokers Median survival 10.6 vs mos TTP 5.1 vs. 4.9 months RR: 22% vs. 19 % Herbst RS, et al. J Clin Oncol. 2005;23: (n = 539) Median survival 22.5 vs mos TTP 6.0 vs. 4.3 months RR: 30% vs. 11 % (n = 72) (n = 44)

CALGB Randomized Phase II Study: Trial Design Response evaluation every 2 cycles (6 weeks). Therapy could continue until disease progression or toxicity Chemotherapy-naive patients with stage IIIB/IV adenocarcinoma or BAC who are never or “light” former smokers* ECOG PS 0-1 Daily oral erlotinib Daily oral erlotinib + 6 cycles carboplatin/paclitaxel Daily oral erlotinib * never smoker:  100 cigarettes/lifetime; “light” former smoker: quit  1 year ago and  10 pack years

CALGB Study conduct –Written 2004; activated 8/05; closed 4/09 –Median follow-up: 30 months –Events: PFS: 82%; OS: 58% –26 pts (14%) still receiving study therapy Tissue submission part of eligibility –Routine genotyping not available in 2004 –Prospective evaluation of EGFR mutations Primary Endpoint –PFS in each arm Secondary Endpoints –RR, PFS and OS in EGFR WT and EGFR mutant pts.

CALGB 30406: Statistical Design Calculation based on PFS of chemotherapy alone arm in never smokers (TRIBUTE) Both arms: sample size driven by testing proportion of patients progression free at 18 weeks (4.1 mos) (p) with α=0.1 and β=0.1 Erlotinib alone arm: 80 pts. –H0: p 0.52; p=.37 ~ m PFS 2.9mos Erlotinib/carboplatin/paclitaxel: 100 pts. –H0: p 0.62; p=.49 ~ m PFS 4.0mos

Patient Characteristics CharacteristicE (n=81)ECP (n=100) Age58 (32-78)60 (34-81) Male/Female32 (40%) / 49 (60%)42 (42%) /58 (58%) ECOG PS (0/1)50 (62%) / 31 (38%) 47 (47%) / 52 (52%) Caucasian61 (75%)84 (84%) African American12 (15%)6 (6%) Asian/Other5 (6%) / 3 (4%)8 (8%) 2 (2%) Adenocarcinoma71 (87%)82 (82%) BAC2 (2%) Adeno with BAC8 (10%)14 (14%) Never-Smoker64 (79%)78 (78%) Former light smoker17 (21%)21 (21%)

Treatment Duration Erlotinib (n=81)Erlotinib/CP (n=100) Median68 Range1 – % of patients received > 18 cycles of therapy Chemotherapy MedianN/A3 RangeN/A1-6

Grade 3/4 Adverse Events Adverse EventE (n=81)ECP (n=100) Hematologic - any1/029/20 Anemia0/06/0 Neutropenia0/024/17 Febrile Neutropenia0/07/3 Thrombocytopenia0/01/4 Non-hematologic - any18/238/12 Rash6/010/0 Diarrhea4/06/0 Fatigue1/016/1 Nausea/Vomiting1/07/0 Dose reductions23%27% Death on Study3 (4%)2 (2%)

Response Rate Erlotinib: 35% Erlotinib/CP: 48% Progression Free and Overall Survivals Erlotinib : 6.7 ( ) Erlotinib/CP: 6.6 ( ) Progression Free Survival Erlotinib : 24.3 (18.4 –31.3) Erlotinib/CP: 19.6 (14.4 – 28.7) Overall Survival

181 patients 17 patients Insufficient material or no DNA 164 patients 91% EGFR mutant: 72 Exon 19: 39 Exon 21: 27 Exon 20: 6 HER2 mutant: 3 KRAS mutant: 17 Wild Type: 72 Tumor genotyping analyses Never Smokers EGFR mutant: 51/127 (40%) Former light smokers EGFR mutant: 15/36 (42%) P= 0.87 Erlotinib Total: 77/80 (96%) EGFR mutant: 33 EGFR WT: 44 Total: 87/100 (87%) EGFR mutant: 33 EGFR WT: 54 Erlotinib/CP Exon 19 deletion & L858R

Erlotinib – PFS and OS by EGFR mutation EGFR mutant : 15.7 (8.6 – 20.4) EGFR WT: 2.7 (1.4 – 4.4) Progression Free Survival P < Response Rate EGFR mutant: 67% EGFR WT: 9% P < EGFR mutant : 31.3 (23.8–42.8) EGFR WT: 18.1 ( ) Overall Survival P =

Erlotinib/CP – PFS and OS by EGFR mutation EGFR mutant : 17.2 (10.3 – NA) EGFR WT: 4.8 (3.1 – 5.6) Progression Free Survival P < Response Rate EGFR mutant: 73% EGFR WT: 33% P = EGFR mutant : 39.0 (38.1 –NA) EGFR WT: 13.7 ( ) Overall Survival P =

Conclusions Erlotinib and Erlotinib/CP yield similar outcomes in a predominately Caucasian never smoker population of NSCLC patients EGFR mutations identify patients most likely to benefit (RR, PFS & OS) from E or ECP E is better tolerated than ECP EGFR TKIs alone remain an acceptable first line therapy for advanced EGFR mutant NSCLC

Acknowledgements CALGB institutions University of North Carolina Duke University MSKCC Dana Farber Cancer Institute University of Maryland Ohio State University University of Chicago Massachusetts General Hospital University of California, San Diego University of Nebraska Washington University Christiana Care Health Services Rhode Island Hospital Greenville Hematology/Oncology Associates of Central New York Georgetown University Medical Center Mount Sinai Medical Center Northern Indiana Cancer Research Consortium Board of Regents of the University of Oklahoma Roswell Park Cancer Institute University of Iowa Long Island Jewish Medical Center University of Minnesota Funding: NCI CTEP TRI/SAIC-Frederick