1. Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.

4. First-line therapy for metastatic EGFR mutation- positive NSCLC John Heymach, MD, PhD Associate Professor Thoracic/Head and Neck Medical Oncology and Cancer Biology 9th Annual Winter Lung Cancer Conference Hollywood, FL

5. Evolving world of NSCLC into molecularly defined subsets squamous Non- squamous EML4-ALK fusion EGFR mutant KRAS, other drivers EGFR wild-type Platinum doublet (Pem) Bevacizumab EGFR TKI ALK inhibitor Other

6. First-line treatment of EGFR-mutant NSCLC EGFR mutant EGFR TKI 1.Is EGFR TKI monotherapy better than chemo? 2.What about combinations of TKI and chemo? 3.Are all the mutants the same? 4.Why are responses to EGFR TKIs heterogenous? 5.What pathways are driving (relative) resistance?

7. IPASS trial design Gefitinib (250 mg daily) Carboplatin (AUC 5 or 6)/ paclitaxel (200 mg/m 2 ) 3 weekly # 1:1 randomization * Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped  15 years ago and smoked  10 pack years; # limited to a maximum of 6 cycles Carboplatin/paclitaxel was offered to IRESSA patients at progression PS, performance status; EGFR, epidermal growth factor receptor Patients Chemonaïve Age ≥18 years Adenocarcinoma histology Never or light ex-smokers* Life expectancy ≥12 weeks PS 0-2 Measurable stage IIIB / IV disease Primary Progression-free survival (non-inferiority) Secondary Objective response rate Overall survival Quality of life Disease-related symptoms Safety and tolerability Exploratory Biomarkers EGFR mutation EGFR gene copy number EGFR protein expression Endpoints Mok et al 2009, Fukuoka 2009

8. Mok et al, NEJM 2009 IPASS study: PFS by EGFR mutational status Mok et al, NEJM 2009 Mutation positiveMutation negative Gefitinib Carboplatin/ paclitaxel Gefitinib Carboplatin/ paclitaxel PFS Events, n (%)97 (73.5%)111 (86.0%)88 (96.7%) 70 (82.4%) p-valuep < 0.001 HR0.48 (95% CI, 0.36-0.64)2.85 (95% CI, 2.05-3.98)

9. Randomized Phase III studies established improved PFS and RR for EGFR TKIs vs chemo in patients with EGFR mutations StudyPatient groupEGFR mut+ (n) RR (TKI vs chemo) PFS months HR (95%CI) OS months HR (95%CI) IPASS † (Gefitinib vs Carb/Pac) East Asian, light non-smoker, adenocarcinoma 26171.2% vs 47.3%9.8 vs 6.4 0.48 (0.36, 0.64) 21.6 vs 21.9 1.00 (0.76, 1.33) p=0.990 First-SIGNAL † (Gefitinib vs Gem/Cis) Korean, non-smoker, adenocarcinoma 4284.6% vs 37.5%8.4 vs 6.7 0.61 (0.31, 1.22) 30.6 vs 26.5 0.82 (0.35, 1.92) WJTOG3405 (Gefitinib vs Cis/Doc) Japanese, EGFR mutation 17262.1% vs 32.2%9.2 vs 6.3 0.49 (0.34, 0.71) Not available yet NEJGSG002 (Gefitinib vs Carb/Pac) Japanese, EGFR mutation 22473.7% vs 30.7%10.8 vs 5.4 0.30 (0.22, 0.41) 30.5 vs 23.6 OPTIMAL (Erlotinib vs Gem/Carb) China, EGFR mutation 15083% vs 36%13.1 vs 4.6 0.16 (0.10, 0.26) Not available yet EURTAC (Erlotinib vs platinum doublet) Europe, EGFR mutation 15054.5% vs 10.5%5.2 vs 9.4 0.42 (0.27, 0.64) Not available yet LUX Lung 3 (Afatinib* vs Cis/Pem) Global, Adenocarcinoma, EGFR mutation 330Not available yet *This is an investigational agent. Its efficacy and safety have not been established. † Patients selected according to clinical background. All other trials selected patients according to EGFR mutation status. Mok TS, et al. N Engl J Med 2009;361:947–957; Lee JS, et al. WCLC 2009;Abs PRS.4; Mitsudomi T, et al. Lancet Oncology 2010;12:121– 128; Maemondo M, et al. N Engl J Med 2010;362:2380–2388

10. OPTIMAL study design Primary endpoint PFS Secondary endpoints OS, ORR, QoL and safety Erlotinib 150 mg/day until PD Chemo-naїve advanced NSCLC (N~150) EGFR mutation positive (exon 19 or 21) ECOG PS 0–2 Gemcitabine + carboplatin (1,000 mg/m 2 d1, 8; AUC5 d1) q3w, up to 4 cycles R 1:1 Phase III study initiated by Tongji University, Shanghai, China Recruitment ongoing in China

11. OPTIMAL: 1 st -line erlotinib is associated with longer PFS vs GC in EGFR-mutant NSCLC Zhou, You, Lancet Oncology 2011 Median PFS Erlotinib (N = 82), 13.1 months Gemcitabine plus carboplatin (N = 72), 4.6 months –Hazard ratio 0.16 (95% CI 0.10-0.26) –Log-rank p < 0.0001

12. EURTAC study design Primary endpoint PFS Secondary endpoints ORR, 1-year survival, OS, safety, QoL, localization of PD Erlotinib 150 mg/day until PD Chemo-naїve advanced NSCLC EGFR mutation positive (exon 19 or L858R) ECOG PS 0–2 (n~150) Platinum-based doublet chemotherapy R 1:1 Phase III study initiated by the Spanish Lung Cancer Group (GECP) Recruitment ongoing in Spain, Italy and France

13. Primary endpoint: PFS in ITT population (interim analysis 2 Aug 2010) PFS Erlotinib (n = 77), 9.4 months Chemotherapy (n = 76), 5.2 months –HR = 0.42 (0.27-0.64) –Log-rank p < 0.0001 Rosell et al. Proc ASCO 2011.

14. First-line treatment of EGFR mutant NSCLC: Is more better? Rationale for chemotherapy plus EGFR TKI –EGFR-mutant tumors are more sensitive to chemotherapy than EGFR wt –Chemotherapy and EGFR TKI may target different populations –Greater reduction in tumor bulk  delay in the emergence of resistant clones –BUT: EGFR TKIs with chemotherapy did not improve outcomes in unselected patients (TRIBUTE, TALENT, INTACT studies)

15. Herbst R S et al. JCO 2005;23:5892-5899 ©2005 by American Society of Clinical Oncology TRIBUTE: ECP not better than CP in unselected NSCLC pts ErlotinibPlaceboHazard ratiop-value Median survival, ITT population 10.6 mo10.5 mo0.995.95 Median TTP, ITT population 5.1 mo4.9 mo0.937.36 Median survival, never smokers 22.5 mo10.1 mo0.49.01 TTP, never smokers6.0 mo 4.3 mo0.50.002

16. Eberhard D A et al. JCO 2005;23:5900-5909 ©2005 by American Society of Clinical Oncology Prognostic and predictive value of EGFR mutation from TRIBUTE ECP in mut+: 53% ORR, 12.5m TTP CP in mut+: 21% ORR, 6.6m TTP

17. CALGB 30406: Randomized phase II trial of E vs ECP for first-line NSCLC in never or light former smokers Janne et al, J Clin Oncol 2010;28:15s (suppl);abstr 7503 Erlotinib (n = 33)ECP (n = 33)p-value PFS14.1 (7.0-19.6) mo17.2 (8.2-27.8) mo0.3490 OS31.3 (23.8-NA) mo38.1 (19.6-NA) mo0.9227

18. Different outcomes for L858R and exon19 mutations Janne et al, Proc IASLC World Lung 2011 Exon 19 (n = 39)L858R (n = 27)p-value PFS17.7 (9.4-27.5) mo12.1 (7.0-20.1) mo0.1777 OS37.5 (24.6-NA) mo35.5 (17.4-NA) mo0.5556

19. Secondary mutations in EGFR (T790M) lead to acquired resistance to EGFR TKIs Kobayashi et al, NEJM 2005 T790M known as a major mechanism of acquired resistance Data suggests that it often is present at a low frequency at baseline and selected for after treatment with EGFR TKI –EGFR TKIs may kill non-T790M containing clones preferentially, enriching for T790M+ population

20. Baseline T790M associated with worse outcome in EGFR-mutant NSCLC after treatment with TKI Rosell et al, CCR 2011;17(5):1160-8 T790M+ (n = 45) T790M- (n = 84)95% CIp-value Median PFS12 mo18 mo7.6-16.40.05* Median survival27 mo29 mo24.8-33.20.47 * Tarone-Ware p = 0.02

21. Pretreatment EGFR T790M mutation predicts shorter EGFR TKI response duration in NSCLC Su et al, JCO 2012: 30:433-440 Cox Regression Model VariableHazard ratio95% CIp-value L858R or Del19 without T790M1.000 L858R or Del19 with T790M1.8541.044–3.2920.35 Without L858R, Del19 and T790M4.9652.524–9.765<.001

22. High IGF-1R is associated with shorter PFS in EGFR-mutant NSCLC High expression ≤165 (n = 41), median OS = 22.6 mo Low expression >165 (n = 14), median OS = 16.3 mo –p =.1445 Low expression ≤165, median PFS = 12.0 mo High expression >165, median PFS = 7.3 mo –p =.0435 Kato et al, Proc IASLC World Lung, 2011

23. Summary: First-line treatment of EGFR- mutant NSCLC EGFR mutant 1.EGFR monotherapy is a standard. PFS for TKI is better than chemo. Addition of chemo not beneficial thus far. 2. All mutants are not the same. 3. We may be missing baseline T790M  should we be using combinations for these patients at onset? Or different TKIs? 4. In the future, other markers (e.g. IGF-1R) may predict worse outcome  combination Rx? Which mutant? T790M? Other markers?

24. 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