1. Individualized Tx in NSCLC: How Do We Tackle Advanced Squamous Cell Ca of the Lung Corey J Langer MD, FACP Professor of Medicine Director of Thoracic Oncology Abramson Cancer Center University of Pennsylvania Philadelphia, PA 19104 Corey.langer@uphs.upenn.edu

2. Disclosures Grant/Research Support: Grant/Research Support: –Bristol Myers Squibb, Pfizer, Imclone, Lilly, Schering- Plough Research Institute, Sanofi-Aventis, Amgen, Cell Therapeutics Inc., OrthoBiotech, Celgene, Vertex, Genentech, OSI, AstraZeneca, Pfizer, Active Biothech, Medimmune Scientific Advisor: Scientific Advisor: –Bristol Myers Squibb, Imclone, Sanofi-Aventis, Pfizer- Pharmacia, Intrabiotics, GlaxoSmithKline, Pharmacyclics, Amgen, AstraZeneca, Novartis, Genentech, OSI, Savient, Bayer/Onyx, Abraxis, Clarient, Synta Speakers Bureau: curtailed as of 12/10 Speakers Bureau: curtailed as of 12/10 –Bristol Myers Squibb, Imclone, Sanofi- Aventis, Lilly, OrthoBiotech, Genentech, OSI

3. Lung Cancer In 2010, ~213,380 new cases and ~160,390 deaths are predicted in the United States In 2010, ~213,380 new cases and ~160,390 deaths are predicted in the United States Second most common cancer in men and women and leading cause of cancer deaths Second most common cancer in men and women and leading cause of cancer deaths Accounts for more deaths than breast, colon and prostate cancer combined Accounts for more deaths than breast, colon and prostate cancer combined Unfavorable stage distribution at the time of diagnosis Unfavorable stage distribution at the time of diagnosis Types of lung cancer Types of lung cancer –Non–small cell lung cancer (NSCLC): 87% 1/2 to 2/3 adenoca 1/2 to 2/3 adenoca 1/3+ squamous and other histologies 1/3+ squamous and other histologies –Small cell lung cancer (SCLC): 13% Cancer Facts and Figures 2007. Atlanta, GA: American Cancer Society; 2007.

4. Non-small Cell Lung cancer Adenocarcinoma Adenocarcinoma –Glandular pattern –Mucin positivity (50%) –CK7+/CK20- –TTF-1+ (75%) Squamous cell carcinoma Squamous cell carcinoma –Cellular keratinization –Intercellular bridges –Keratin “pearl” formation –CK7-/CK20- –TTF-1 neg –P63 or p40+ or CK5/6+ Common, but not 100% WHO Common, but not 100% WHO

5. Histologic Distinctions in NSCLC Squamous: Squamous: –More central presentation –Higher incidence of locoregional recurrence –Decreased incidence of metastatic spread –Relatively more common in men, Eastern Europe, smokers –Declining incidence overall Adenocarcinoma: Adenocarcinoma: –More often peripheral –Higher incidence of metastatic spread –Less profound link with tobacco use –Increasing incidence; relatively more common in women

6. Therapeutic Implications Histologic Prism Tendency until 2005 to “lump” NSCLC histologies Tendency until 2005 to “lump” NSCLC histologies –Little difference in Tx outcome Therapeutic Empiricism Therapeutic Empiricism –Increasing NOS designation Insufficient tissue Insufficient tissue Pathologic “laziness” Pathologic “laziness”

7. ECOG 1594: Overall Survival by Treatment Group 1207 patients, stage IIIB/IV :(15/85%), PS 0–2; Median age 63, M/F (64/36%) Schiller JH et al. NEJM. 2002;346(2):92-98.

8. Therapeutic Implications Histologic Prism Tendency until 2005 to “lump” NSCLC histologies Tendency until 2005 to “lump” NSCLC histologies –Little difference in Tx outcome Therapeutic Empiricism Therapeutic Empiricism –Increasing NOS designation Insufficient tissue Insufficient tissue Pathologic “laziness” Pathologic “laziness” Since 2004, histology and molecular fingerprints have become ascendant Since 2004, histology and molecular fingerprints have become ascendant –Tx restrictions and risk: bevacizumab –Histologic Variations in outcome Adenocarcinoma: better outcome with EGFr TKI, pemetrexed Adenocarcinoma: better outcome with EGFr TKI, pemetrexed –Province of Actionable molecular markers [EGFR; ALK; ROS-1, etc

9. Therapeutic Implications Histologic Prism Tendency until 2005 to “lump” NSCLC histologies Tendency until 2005 to “lump” NSCLC histologies –Little difference in Tx outcome Therapeutic Empiricism Therapeutic Empiricism –Increasing NOS designation Insufficient tissue Insufficient tissue Pathologic “laziness” Pathologic “laziness” Since 2004, histology and molecular fingerprints have become ascendant Since 2004, histology and molecular fingerprints have become ascendant –Tx restrictions and risk: bevacizumab –Histologic Variations in outcome Adenocarcinoma: better outcome with EGFr TKI, pemetrexed Adenocarcinoma: better outcome with EGFr TKI, pemetrexed –Province of Actionable molecular markers [EGFR; ALK; ROS-1, etc Squamous ca: tendency for better outcome Squamous ca: tendency for better outcome –gemcitabine vs pemetrexed –Nab-paclitaxel vs standard paclitaxel (RR%) –Immunologic Tx: Ipilimumab; PD1 –FGFR and PI3K as targets: still investigational

10. An Evolving View of Adenocarcinoma Emergence of “Actionable” Molecular Markers KRAS 2000 Pending EGFR BRAF PIK3CA EML4-ALK ROS1 HER2 2014

11. An Evolving View of Squamous Cell Ca Emergence of “Actionable” Molecular Markers 2000 2014

12. An Evolving View of Squamous Cell Ca Emergence of “Actionable” Molecular Markers 2000 2014

13. Squamous Cell Ca: Wallflower at the Dance Safety Signals: Bevacizumab Safety Signals: Bevacizumab Lack of Efficacy: Pemetrexed Lack of Efficacy: Pemetrexed Lack of Actionable Molecular Markers: Lack of Actionable Molecular Markers:

14. Rand Phase II: Bevacizumab + Paclitaxel/Carboplatin in Advanced NSCLC Excluded: CNS metastasis On therapeutic anticoagulation Objectives = time to progression, response, survival, and safety * Crossover to 15 mg/kg q3w bevacizumab allowed Paclitaxel 200 mg/m 2 carboplatin AUC 6 (PC) q3w × 6 PC × 6 + bevacizumab 15 mg/kg q3w PC × 6 + bevacizumab 7.5 mg/kg q3w Previously untreated metastatic NSCLC (N=98) Bevacizumab 7.5 mg/kg q3w to PD or unacceptable toxicity Progression of disease* Bevacizumab 15 mg/kg q3w to PD or unacceptable toxicity 1. Johnson et al. J Clin Oncol. 2004;22:2184–2191.

15. Randomized Phase II Trial: Pulmonary Bleeding 6 cases of severe or fatal pulmonary hemorrhage 6 cases of severe or fatal pulmonary hemorrhage –4 (31%) of 13 bevacizumab-treated patients with squamous cell histology –2 (4%) of 53 bevacizumab-treated patients with histology other than squamous cell Patients receiving chemotherapy alone (N=32) had no pulmonary hemorrhages Patients receiving chemotherapy alone (N=32) had no pulmonary hemorrhages On the basis of this analysis, squamous cell histology and bevacizumab therapy were identified as risk factors for pulmonary hemorrhage On the basis of this analysis, squamous cell histology and bevacizumab therapy were identified as risk factors for pulmonary hemorrhage These phase II data were used to design the phase III trial exclusion criteria [squamous histology has been excluded ever since] These phase II data were used to design the phase III trial exclusion criteria [squamous histology has been excluded ever since] 1. Johnson et al. J Clin Oncol. 2004;22:2184–2191.

16. Study Design Gemcitabine 1250 mg/m 2 days 1 + 8 Cisplatin 75 mg/m 2 day 1;  Stage IIIB/IV NSCLC  PS 0 - 1  No prior chemo  Randomization: gender, PS, stage, histo vs cyto dx, brain mets RR Pemetrexed 500 mg/m 2 + Cisplatin 75 mg/m 2 day 1 Primary objective: Overall Survival 15% Non-inferiority margin (HR 1.17) N = 1700 Patients, Power 80% B12, folate, and dexamethasone given in both arms Scagliotti GV et al. JCO 2008; 26:3543

17. Ceppi, P et al. Cancer 107:1589, 2006 “May be useful in selecting patients with NSCLC who should receive treatment with TS-inhibiting agents” TS Expression Levels Are Higher in Squamous Versus Adenocarcinoma

18. Phase III Trial: Cisplatin/Pemetrexed vs Cisplatin/Gemcitabine - Overall Survival in Patients with Adenocarcinoma or Large Cell Ca -

19. Non-squamous groupSquamous group Pemetrexed (n=205) Docetaxel (n=194) Pemetrexed (n=78) Docetaxel (n=94) % ECOG PS 212.510.18.317.4 % TSPC <3 months51.0 48.741.9 % Stage IV81.578.957.766.0 % Male60.569.189.788.3 Median OS, months9.38.06.27.4 Adjusted OS HR (95% CI)0.778 (0.607, 0.997)1.563 (1.079, 2.264) Median PFS, months3.13.02.32.7 Adjusted PFS HR (95% CI)0.823 (0.664, 1.020)1.403 (1.006, 1.957) Second -Line Study of Pemetrexed vs. Docetaxel : Efficacy by Histology Treatment by Histology Interaction: Survival Adjusted for Cofactors (p=0.001) Peterson P. et al. 12 th World Conference on Lung Cancer 2007

20. Progression-free Survival by Histology JMEN Switch Maintenance Trial Pemetrexed 4.4 mos Pemetrexed 2.4 mos Placebo 1.8 mos Placebo 2.5 mosNon-squamous Squamous Time (months) Progression-free Probability HR=0.47 (95% CI: 0.37-0.6) P <0.00001 HR=1.03 (95% CI: 0.77-1.5) P =0.896

21. Overall Survival by Histology JMEN Switch Maintenance Trial Pemetrexed 15.5 mos Pemetrexed 9.9 mos Placebo 10.3 mos Placebo 10.8 mos Non-squamous (n=481) Squamous (n=182) HR=0.70 (95% CI: 0.56-0.88) P =0.002 HR=1.07 (95% CI: 0.49–0.73) P =0.678 Survival Probability Time (months)

22. Advanced NSCLC with Squamous Histology Disappointments to date have not prevented us from targeting this group of pts in ongoing, empiric trials

23. ECOG 4508: RP2 Non-Bev Eligible CTEP E4508 All histology NSCLC 1 st line CTEP E4508 All histology NSCLC 1 st line Carboplatin / Paclitaxel / Cetuximab Cetux Carboplatin / Paclitaxel / A12 Carboplatin / Paclitaxel / Cetuximab / A12 1 1 1 1 1 1 A12 Cetux / A12 PI: N. Hanna (ECOG) PFS N=225 PFS N=225

24. ECOG 4508: RP2 Non-Bev Eligible CTEP E4508 All histology NSCLC 1 st line CTEP E4508 All histology NSCLC 1 st line Carboplatin / Paclitaxel / Cetuximab Cetux Carboplatin / Paclitaxel / A12 Carboplatin / Paclitaxel / Cetuximab / A12 1 1 1 1 1 1 A12 Cetux / A12 PI: N. Hanna (ECOG) PFS N=225 PFS N=225 Suspended because of untoward toxicity in both Cetuximab arms, including an increased rate of grade 5 toxicity

25. ESCAPE - Phase III Trial Comparing Carboplatin and Paclitaxel +/- Sorafenib in NSCLC Chemotherapy phase Maintenance phase n=900 Stratification:  Geographic region  ECOG PS 0 vs 1  Squamous vs non-squamous cell  Stage IIIb (with effusion) vs Stage IV RANDOMIZERANDOMIZE Carboplatin AUC 6 d1 + Paclitaxel 200 mg/m 2 d1 + Sorafenib 400 mg bid d2-19, q3w (CPS) Sorafenib 400 mg bid Carboplatin AUC 6 d1 + Paclitaxel 200 mg/m 2 d1 + Placebo d2-19, q3w (CPP) Placebo Scagliotti GV et al. Proc ESMO/IASLC 2008

26. CPS Median: 8.9 months 95% CI: 6.1, 13.9 CPP Median: 13.6 months 95% CI: 9.6, — Overall Survival by Histology 9741123CPP112280168222CPP350 732492CPS107281173385CPS357 Survival Probability 1.00 0.75 0.50 0.25 Survival Probability 1.00 0.75 0.50 0.25 Squamous CellNon-Squamous Cell CPS Median: 11.5 months 95% CI: 9.7, 14.8 CPP Median: 10.3 months 95% CI: 9.3, 11.5 Months 0 020 Patients at Risk 481216 Months 0 020 Patients at Risk 481216 HR = 1.81 95% CI: 1.19, 2.74 HR = 0.98 95% CI: 0.78, 1.24 Scagliotti GV et al. Proc ESMO/IASLC 2008

27. Study A1016: Phase III Study of Carboplatin + Paclitaxel +/- Figitumumab in 1 st Line NSCLC of non-adenocarcinoma histology Trial DesignEndpointsStratificationStudy Sites FSFV Multi-center, randomized, open-label Primary: OS Secondary: PFS, ORR, Safety, QoL, biomarkers, pharmacoeconomics Gender Histology (Sq vs non-Sq) Prior Adj Chemo (Y/N) Global2Q08 Key Entry Criteria ● Other than Adenoca ● Brain mets allowed ● Adjuvant > 12 month prior RANDOMIZERANDOMIZERANDOMIZERANDOMIZE RANDOMIZERANDOMIZERANDOMIZERANDOMIZE N=820 Figitumumab (20 mg/kg) Paclitaxel Carboplatin Paclitaxel Carboplatin N = 410

28. Overall Survival PC mOS = 10.3 mo PCF mOS = 8.5 mo Months % Probability of Survival HR (95%CI):1.23 (1.0,1.5), p=0.051 EventTotal1y OS2yr OS PCF18434234%17% PC16533939%20%

29. ECLIPSE Study Overview 29 RR Gemcitabine + Carboplatin + iniparib Gemcitabine + Carboplatin + iniparib Gemcitabine + Carboplatin Patient Population: Advanced squamous cell carcinoma Patient Population: Advanced squamous cell carcinoma N= 825 Endpoints: Primary: OS Secondary: PFS, TTP, ORR, safety/tolerability, QoL First Patient Enrolled: March 5, 2010 International, Open-label Doses: Gemcitabine 1000 mg/m 2 D 1 & 8 q3wk Carboplatin AUC 5 D1 q3wk; Iniparib 5.6 mg/kg IV D 1, 4, 8 & 11 q3wk Patients restaged by CT scans (per RECIST 1.1 version) q 2 cycles (6 wks) Patients may remain on study regimen after 6 cycles if there is no evidence of PD or the presence of DLTs 1:1

30. ECLIPSE Study Overview 30 RR Gemcitabine + Carboplatin + iniparib Gemcitabine + Carboplatin + iniparib Gemcitabine + Carboplatin Patient Population: Advanced squamous cell carcinoma Patient Population: Advanced squamous cell carcinoma N= 825 Endpoints: Primary: OS Secondary: PFS, TTP, ORR, safety/tolerability, QoL First Patient Enrolled: March 5, 2010 International, Open-label Doses: Gemcitabine 1000 mg/m 2 D 1 & 8 q3wk Carboplatin AUC 5 D1 q3wk; Iniparib 5.6 mg/kg IV D 1, 4, 8 & 11 q3wk Patients restaged by CT scans (per RECIST 1.1 version) q 2 cycles (6 wks) Patients may remain on study regimen after 6 cycles if there is no evidence of PD or the presence of DLTs 1:1 Negative

31. Is there any hope for patients with squamous cell histology?

32. Pemetrexed Plus Cisplatin in 1st-line: Survival with Gemcitabine/Cisplatin for Patients with Squamous Cell Carcinoma Survival probability 0 612182430 Survival time (months) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 32 Pemetrexed + cisplatinGemcitabine + cisplatin (N=244)(N=229) Median OS (95% CI) 9.4 mos (8.4-10.2) 10.8 mos (9.5-12.1) Adjusted HR a,b,c (95% CI) 1.23 (1.00-1.51) Scagliotti GV et al: J Clin Oncol. 26 (21), 2008: 3543-3551.

33. Non-squamous groupSquamous group Pemetrexed (n=205) Docetaxel (n=194) Pemetrexed (n=78) Docetaxel (n=94) % ECOG PS 212.510.18.317.4 % TSPC <3 months51.0 48.741.9 % Stage IV81.578.957.766.0 % Male60.569.189.788.3 Median OS, months9.38.06.27.4 Adjusted OS HR (95% CI)0.778 (0.607, 0.997)1.563 (1.079, 2.264) Median PFS, months3.13.02.32.7 Adjusted PFS HR (95% CI)0.823 (0.664, 1.020)1.403 (1.006, 1.957) Second -Line Study of Pemetrexed vs. Docetaxel : Efficacy by Histology Treatment by Histology Interaction: Survival Adjusted for Cofactors (p=0.001) Peterson P. et al. 12 th World Conference on Lung Cancer 2007

34. Phase III nab-P/C vs P/C Study Design Chemo-naive PS 0-1 Stage IIIb/IV NSCLC N = 1,050 Stratification factors:  Stage (IIIb vs IV)  Age ( 70)  Sex  Histology (squamous vs nonsquamous)  Geographic region nab-Paclitaxel 100 mg/m 2 d1, 8 15 Carboplatin AUC 6 d1 No Premedication n = 525 1:1 Paclitaxel 200 mg/m 2 d1 Carboplatin AUC 6 d1 With Premedication of Dexamethasone + Antihistamines n = 525 Socinski et al 2010, ASCO

35. Response Rate (%) Objective Responses by Histology* P < 0.001 RR =1.680 P = 0.808 RR=1.034 n = 228n = 221n = 292n = 310 * Not a pre-specified subgroup analysis 41% 26% 24% 25% 0% 10% 20% 30% 40% 50% Ab-P/C P/C Interaction p- Value for Histology: 0.036 Squamous Histology Non-Squamous Histology

36. PFS – ITT Population Proportion Not Progressed Months Pt at risk Ab-P P 521 531 330 321 167 162 86 75 38 48 23 19 10 4444 0202 0101 0000 Ab-P/carboplatin (N=521) paclitaxel/carboplatin (N=531) 0 3 6912151821 24 2730 33 0.00 0.25 0.50 0.75 1.00 Nab-P/ Carbo Paclitaxel/ Carbo HRP-Value N/Events521/297531/312 Median PFS (mo)* 6.35.80.9020.214 95% CI5.6-7.05.6-6.70.767-1.060 * PFS based on Independent assessment

37. Overall Survival – ITT Population Probability of Survival Months Pt at risk Ab-P Pac 521 531 469 470 381 389 313 308 246 243 200 191 163 148 98 89 23 24 0505 0101 Ab-P/carboplatin (N=521) Paclitaxel/carboplatin (N=531) 0 3 6912151821 24 2730 33 0.00 0.25 0.50 0.75 1.00 0000 Nab- P/Carbo Paclitaxel/ Carbo HRP-Value N/Events521/360531/384 Median OS (mos) 12.111.20.9220.271 95% CI10.8-12.910.3-12.60.797-1.066

38. Secondary Endpoint: OS Median PFS (mo) Events / NHRab-P/CP/C 744 / 1052 86 / 149 521 / 724 127 / 165 589 / 789 155 / 263 639 / 896 105 / 156 343 / 450 401 / 602 142 / 218 602 / 834 0.922 0.950 1.019 0.622 0.894 0.995 0.999 0.583 0.890 0.950 0.896 0.917 12.1 16.7 11.0 12.7 11.4 16.8 11.4 19.9 10.7 13.1 12.4 12.0 11.2 17.2 11.1 9.8 10.0 16.0 11.3 10.4 9.5 13.0 13.6 11.0 Favors ab-P/C

39. Secondary Endpoint: OS Median PFS (mo) Events / NHRab-P/CP/C 744 / 1052 86 / 149 521 / 724 127 / 165 589 / 789 155 / 263 639 / 896 105 / 156 343 / 450 401 / 602 142 / 218 602 / 834 0.922 0.950 1.019 0.622 0.894 0.995 0.999 0.583 0.890 0.950 0.896 0.917 12.1 16.7 11.0 12.7 11.4 16.8 11.4 19.9 10.7 13.1 12.4 12.0 11.2 17.2 11.1 9.8 10.0 16.0 11.3 10.4 9.5 13.0 13.6 11.0 Favors ab-P/C

40. Chinese Trial: RP2 NCI CTG 01236716; PI: Wu Yilong RANDOMIZERANDOMIZE Gemcitabine Carboplatin Nab-Paclitaxel Carboplatin Restricted to Tx-naïve advanced NSCLC with squamous histology N= 120; started 11/10

41. Efficacy in Total NSCLC Population 41 Response Control Pbo+ Chemo (n=66) Concurrent IPI+ Chemo (n=70) Phased IPI+ Chemo (n=68) irPFS, median mo4.65.55.7 - - HR = 0.81 P = 0.13 HR = 0.72 P = 0.05* mWHO-PFS, median mo 4.24.15.1 - - HR = 0.88 P = 0.25 HR = 0.69 P = 0.02* OS, median mo8.39.712.2 - - HR = 0.99 P = 0.48 HR = 0.87 P = 0.23 irBORR18%21%32% mWHO-BORR14%21%32% *Statistically significant per protocol-stipulated one-sided  = 0.1; P values not adjusted for multiple comparisons irPFS, PFS by immune-related response criteria (irRC); irBORR, best overall response rate by irRC; mWHO- PFS, PFS by modified WHO criteria (mWHO); mWHO-BORR, best overall response rate by mWHO Ipilimumab and NSCLC histology, WCLC 2011, Abstr 701

42. Activity of Phased-Ipilimumab by Baseline Histology 42 In the Phased-Ipilimumab arm, improvements in irPFS, mWHO-PFS and OS vs. Control appeared greater for squamous histology than for non-squamous Small sample size warrants caution in interpretation ResponsePatient groupEvents/PatientsHR (95% CI) Phased vs. Control Non-Squamous Squamous 13/21 vs 14/150.48 (0.22-1.03) 38/47 vs 37/511.17 (0.74-1.86) OS All 51/68 vs 51/660.87 (0.59-1.28) Squamous 19/21 vs 15/150.40 (0.18-0.87) Non-Squamous 37/47 vs 46/510.81 (0.53-1.26) mWHO-PFS All 56/68 vs 61/660.69 (0.48-1.00) Squamous 18/21 vs 15/150.55 (0.27-1.12) Non-Squamous 36/47 vs 41/510.82 (0.52-1.28) irPFS All 54/68 vs 56/66 0.72 (0.50-1.06) Favors Phased-IpiControl HR and 95% CI 0.5 11.5 Ipilimumab and NSCLC histology, WCLC 2011, Abstr 701

43. Activity of Phased-Ipilimumab by Baseline Histology 43 In the Phased-Ipilimumab arm, improvements in irPFS, mWHO-PFS and OS vs. Control appeared greater for squamous histology than for non-squamous Small sample size warrants caution in interpretation ResponsePatient groupEvents/PatientsHR (95% CI) Phased vs. Control Non-Squamous Squamous 13/21 vs 14/150.48 (0.22-1.03) 38/47 vs 37/511.17 (0.74-1.86) OS All 51/68 vs 51/660.87 (0.59-1.28) Squamous 19/21 vs 15/150.40 (0.18-0.87) Non-Squamous 37/47 vs 46/510.81 (0.53-1.26) mWHO-PFS All 56/68 vs 61/660.69 (0.48-1.00) Squamous 18/21 vs 15/150.55 (0.27-1.12) Non-Squamous 36/47 vs 41/510.82 (0.52-1.28) irPFS All 54/68 vs 56/66 0.72 (0.50-1.06) Favors Phased-IpiControl HR and 95% CI 0.5 11.5 Ipilimumab and NSCLC histology, WCLC 2011, Abstr 701

44. OS: Squamous NSCLC Subset 44 Proportion Alive Regimen Events/ PatientsMedian moHR Control Concurrent Phased 14/15 17/21 13/21 7.9 6.2 10.9 -- 1.02 0.48 Months Patients at risk Concurrent Phased Control Ipilimumab and NSCLC histology, WCLC 2011, Abstr 701

45. Phase 3 Trial Comparing Ipilimumab Plus Paclitaxel and Carboplatin Versus Placebo Plus Paclitaxel and Carboplatin in Squamous NSCLC (CA184- 104/NCT01285609) Start Date: August 2011 Estimated Study Completion Date: June 2016 Estimated Primary Completion Date: September 2014 Status: Recruiting Study Director: BMS Primary Endpoint OS Secondary Endpoints OS in pts that receive one dose of blinded therapy PFS BORR Key Eligibility Criteria ≥ 18 years of age Squamous cell NSCLC Stage IV or recurrent NSCLC ECOG PS ≤ 1 No brain metastases or autoimmune disease Phase 3 Trial Squamous cell NSCLC or Stage IV or recurrent NSCLC N=920 IPI 10 mg/kg IV Q3W x 4 doses Q12W from W24 PAC 175 mg/m² IV Q3W x 6 doses CARB AUC 6 IV Q3W x 6 doses PBO IV Q3W x 4 doses Q12W from W24 PAC 175 mg/m² IV Q3 W x 6 doses CARB AUC 6 IV Q3W x 6 doses Treat until progression or unacceptable toxicity Overall Survival (OS) BORR, Best overall response rate; CARB, Carboplatin; ECOG PS, Eastern Cooperative Oncology Group Performance Status; IPI, ipilimumab; OS, Overall survival; PAC, Paclitaxel; PFS, Progression-free survival; PBO, Placebo; W, Week

46. Actionable Targets in Lung Adenocarcinomas Unknown 75% 1999 2005-2014 EGFR 2004 Unknown 60% Kris M et al. IASLC 2012 Targeted Therapies Conference

47. Actionable Targets ? in Squamous Cell Lung Cancers Unknown 100% 1999 20142004-2010 Unknown 100% FGFR1 amplification PIK3CA mutation PTEN mutation DDR2 mutation PTEN loss Okudela et al. Cancer Res 2008 Yamamoto et al. Pathol Int 2007 Weiss et al. Sci Transl Med 2010 Hammerman et al. Cancer Discovery 2011 TCGA Nature 2012

48. 2002-2012 – Changes in the therapeutic landscape of stage IV lung cancer TargetNFrequency95% CI FGFR1 amplification 13/5225%15–38% PTEN mutation 3/1817% 5 – 37% PTEN loss, complete 3/2711% 3 – 26% PIK3CA mutation 4/528% 2 – 17% KRAS mutation 1/522% 1 – 9% DDR2 mutation 0/180% 0 – 15% Paik et al. J Clin Oncol 30: 2012 (suppl; abstr 7505)

49. Novel Therapeutic Targets FGFR1 amplification FGFR1 amplification NFE2L2 oxidative stress pathway NFE2L2 oxidative stress pathway DDR2 mutations DDR2 mutations PI3K pathway PI3K pathway EGFR EGFR

50. FGFR1 AMPLIFICATION

51. Chromosomal gain is common Amplification (FGFR1:CEP8 ≥ 2) Amplification (FGFR1:CEP8 ≥ 2) –16-25% Correlation with protein expression unknown Correlation with protein expression unknown FGFR1 amplification TCGA Nature 2012 Paik ASCO 2012 Heist J Thorac Oncol 2012

52. FGFR1 amplification in squamous cell lung carcinoma Abstract No of cases Histology subtype Disease stage(s ) Technique Definition of amplification % amplified % polysomy (if available) 7041101SquamousI–IVFISHMedian of 6 or more gene copies 6.943/94 7061447SquamousI–IVFISHMean of 6 or more gene copies 8.3- 7063119SquamousI–IVQuantitative PCR Predicted CNV of ≥2 in ≥1 exon 24.4- 7545177SquamousI–IVFISHCopy number >2 and 9 (high) 25.2- Martinez Marti et al. J Clin Oncol 30, 2012 (suppl; abstr 7041) Toschi et al. J Clin Oncol 30, 2012 (suppl; abstr 7061) Cote et al. J Clin Oncol 30, 2012 (suppl; abstr 7063) Wei et al. J Clin Oncol 30, 2012 (suppl; abstr 7545) CNV, copy number variation

53. Therapeutic targets in squamous cell lung carcinoma GeneEvent typeFrequency CDKN2ADeletion/mutation/methylation72 PI3KCAMutation16 PTENMutation/Detection15 FGFR1Amplification15 EGFRAmplification9 PDGFRAAmplification/Mutation9 CCND1Amplification8 DDR2Mutation4 BRAFMutation4 ERBB2Amplification4 FGFR2Mutation3 Govindan et al. J Clin Oncol 30, 2012 (suppl; abstr 7006)

54. FGFR1 signaling: PI3K, Ras/MAPK, and PKC activation PI3K Ras/Raf/ MAPK PKC Fibroblast growth factors Receptor dimerization Growth, division, angiogenesis

55. Amplification predicts sensitivity to drug in vitro and in vivo Weiss et. al. Sci Transl Med 2010

56. FGFR1 and PI3K: not mutually exclusive Significant overlap in putative oncogenes may complicate target validation in trials Significant overlap in putative oncogenes may complicate target validation in trials cBio GDAC Lung Squamous TCGA data

57. FGFR1-directed trials are myriad Radiographic PRs reported in response to BGJ398 Radiographic PRs reported in response to BGJ398 All trials are ongoing All trials are ongoing DrugTarget(s)Clinicaltrials.gov # AZD4547Pan-FGFR NCT01824901 (phase 2) NCT00979134 (phase 1 expansion) BGJ398Pan-FGFRNCT01004224 (phase 1) GSK305220FGF ligandsNCT01868022 (phase 1) Debio 1347FGFR1-3 JNJ42756493Pan-FGFRNCT01703481 (phase 1)

58. NFE2L2/KEAP1 MUTATIONS

59. NFE2L2 and KEAP1 overview Members of an oxidative stress pathway Members of an oxidative stress pathway NFE2L2 codes for Nrf2, a transcription factor that binds Antioxidant Response Elements (AREs) in promoters NFE2L2 codes for Nrf2, a transcription factor that binds Antioxidant Response Elements (AREs) in promoters –Target genes include glutathione synthesis, drug transport pumps, ROS eliminators Keap1 binds to Nrf2 and degrades it Keap1 binds to Nrf2 and degrades it

60. NFE2L2 and KEAP1 homeostasis: Keap1 targets Nrf2 for degradation

61. Oxidative stress activates Nrf2 pathway

62. NFE2L2 and KEAP1: nature of alterations in SQCLC Hotspot mutations (activating) Sporadic mutations (inactivating)

63. Changes in NFE2L2 and KEAP1 are common in SQCLC TCGA Nature 2012

64. Mutant Nrf2 is oncogenic Isogenic HEK293 clones overexpressing T80R (TR1/2) and L30F (LF1/2) mutations form colonies

65. Mutant Nrf2 is druggable through mTOR inhibition

66. DDR2

67. Discoidin domain receptor 2 (DDR2): ECM/collagen signaling Stimulated by collagen as a ligand Downstream signaling in cancer cells is poorly understand May be via SRC and STAT signaling pathways. Similar to integrin receptors, DDR2 may play a role in modulating cellular interactions with the extracellular matrix

68. DDR2 mutations are sporadic and uncommon Hammerman et. al. Cancer Discovery 2012 Sanger sequencing of 290 SQCLC resections uncovered 11 mutations in DDR2 (3.8%) No hotspots DDR2 mutations

69. Purified kinase activity (TR-FRET) Collagen-dependent autophosphorylation Eur J Pharmacol [2008] 599:44–53 IC50 = 55nM IC50 = 5.2nM DDR2 is druggable with dasatinib in vitro data

70. DDR2 is druggable with dasatinib: in vivo data DDR2 I638F mutant

71. DDR2 clinical trials DrugTarget(s)Clinicaltrials.gov # dasatinibDDR2 mutationsNCT01514864 (phase 2)

72. Clinical response to dasatinib (DDR2 S768I): Phase 1 dasatinib + erlotinib trial

73. PI3K PATHWAY

74. PI3K is a canonical downstream RTK partner in cancer Weitgelt Frontiers Oncol 2009

75. PI3K is a canonical downstream RTK partner in cancer Weitgelt Frontiers Oncol 2009

76. PI3K is a canonical downstream RTK partner in cancer Weitgelt Frontiers Oncol 2009

77. Oncogenic PI3K pathway changes are common in SQCLC PIK3CA mutation PTEN mutation PTEN loss PI3K alterations (PIK3CA mutations, PTEN mutations, PTEN loss) occur in ~30-50% of SQCLCs PIK3CA amplification occurs in another 20-30% TCGA Nature 2012

78. PI3K pathway clinical trials Overlap with FGFR1 amplification, NFE2L2/KEAP1 mutations complicates clinical validation Overlap with FGFR1 amplification, NFE2L2/KEAP1 mutations complicates clinical validation DrugTarget(s)Clinicaltrials.gov # BKM120PIK3CANCT01297491 (phase 2) carboplatin + paclitaxel + BKM120 PIK3CANCT01723800 (phase 1) GDC0032PIK3CApending

79. Doc or Gem FGFRi + Doc or Gem FGFR Amplification, Mutation, Fusion CDK 4/6i Doc or Gem Cyclin D1 Amplification or CDKN2 loss + RB WT PI3Ki Doc or Gem PI3KCA Mutation Biomarker Profiling (NGS/CLIA) HGFi + Erlotinib MET Expression (IHC score) PD-L1i Biomarker Non-Match Biomarker Non-Match Multiple Phase II- III Arms with “Rolling” Opening & Closure MASTER LUNG-1 (S1400): Biomarker s and 2nd Line Therapy for Squamous Cell NSCLC

80. EGFR EGFR

81. EGFR alterations in SQCLC Canonical exon 19 deletions and exon 21 L858R mutations are extraordinarily rare in SQCLCs Canonical exon 19 deletions and exon 21 L858R mutations are extraordinarily rare in SQCLCs Rare EGFR L861Q mutations have been reported Rare EGFR L861Q mutations have been reported EGFR amplification occurs in 7-10% of SQCLCs EGFR amplification occurs in 7-10% of SQCLCs As with adenocarcinomas, increased EGFR expression by IHC is common As with adenocarcinomas, increased EGFR expression by IHC is common –Role of H-score awaits prospective validation Rekhtman Modern Pathology 2012 TCGA Nature 2012

82. Chemotherapy- naïve advanced NSCLC Vinorelbine 25 mg/m 2 d1,8 + cisplatin 80 mg/m 2 d1 q3w Primary endpoint: OS Secondary endpoints: PFS, ORR, DCR, QoL, safety Phase III FLEX: Vinorelbine/Cisplatin ± Cetuximab in 1 st -Line Advanced NSCLC n=557 n=568 Cetuximab 400 mg/m 2 d1 wk1, then 250 mg/m 2 qw + vinorelbine 25 mg/m 2 d1,8 + cisplatin 80 mg/m 2 d1 q3w RANDOMIZERANDOMIZERANDOMIZERANDOMIZE Up to 6 cycles of chemotherapy; patients not progressing continue on cetuximab maintenance Pirker R, et al. ASCO 2008. Oral presentation and abstract 3. Stratified by  IIIB or IV  ECOG PS 0,1 or 2

83. FLEX Overall survival Months Patients at risk CT + Cetuximab557383251155533 CT568383225134480 Overall Survival (%) p-value = stratified log-rank test (2-sided) Median OS 1-year survival ▬CT + Cetuximab (n=557) 11.3 months47 % ▬CT ( n=568) 10.1 months42 % HR=0.871 (95% CI 0.762–0.996), p=0.044

84. FLEX: OS in Caucasian Subgroup (Pre-specified Analysis) Pirker R, et al. ASCO 2008. Oral presentation and abstract 3. 9.1 10.5 Months 1-year OS 45% vs 37% HR = 0.803, 0.694–0.928 Log-rank P =.003 Cet + vin/cis, n=466 Vin/cis, n=480 Patients surviving, % 100 80 60 40 20 0 0612182430

85. FLEX trial subgroup analysis TCGA Nature 2012

86. High and low EGFR expression Low EGFR expression IHC score <200 High EGFR expression IHC score ≥200 IHC score=270 IHC score=30 IHC score=0* IHC, immunohistochemistry; *IHC score=7 for tumor overall O’Byrne K et al. JTO 2010, 12 (suppl), S558 (LBOA1)

87. Retrospective FLEX H-score analysis Pirker Lancet Oncol 2012

88. FLEX H Score Elevated Cohort (> 200) ArmC225Control Number178176 OR %44 *28 PFS (mos)5.04.4 Med Surv (mos)12^9.6 1 yr OS %5037 2 yr OS %2415 * p = 0.002 ^ HR = 0.73, p = 0.011

89. Elevated Cohort (> 200) Breakdown by Histology ArmC225Control Adenocarcinoma * MS (mos)20.213.3 1 yr OS %6552 Squamous Cell ca^ MS (mos)11.28.9 1 yr OS %4525 * HR = 0.72 ^ HR = 0.62

90. Completed and ongoing trials TitleTreatmentClinicaltrials.gov # SWOG 0819 Randomized carbo/paclitaxel or carbo/pac/bev +/- cetuximab NCT00946712 (accruing) SQUIRE Cisplatin + gemcitabine +/- necitumumab NCT00981058 (completed)

91. SQUIRE Trial*: RP3 RANDOMIZERANDOMIZE Gemcitabine Cisplatin X 6 Necitumumab^ *Restricted to Tx-naïve advanced NSCLC with squamous histology ^ Maintenance Tx included Planned sample size to show med OS inc from 11 to 13.75 mos N= 1093; Gemcitabine Cisplatin X 6

92. SQUIRE Trial*: RP3 RANDOMIZERANDOMIZE Gemcitabine Cisplatin X 6 Necitumumab^ *Restricted to Tx-naïve advanced NSCLC with squamous histology ^ Maintenance Tx included Planned sample size to show med OS inc from 11 to 13.75 mos N= 1093; Gemcitabine Cisplatin X 6 Reported (+) mid August 2013

93. Press Release Aug 13, 2013 Necitumumab Improves Overall Survival in Lung Cancer Necitumumab Improves Overall Survival in Lung Cancer SQUIRE, a Phase 3 study met its primary endpoint, finding that patients with stage IV metastatic squamous non-small cell lung cancer (NSCLC) experienced increased overall survival (OS) when necitumumab (IMC-11F8) in combination with gemcitabine and cisplatin was administered as first-line treatment compared to chemotherapy alone. Necitumumab is a fully human IgG1 monoclonal antibody designed to block the ligand binding site of the human epidermal growth factor receptor (EGFR). SQUIRE, a Phase 3 study met its primary endpoint, finding that patients with stage IV metastatic squamous non-small cell lung cancer (NSCLC) experienced increased overall survival (OS) when necitumumab (IMC-11F8) in combination with gemcitabine and cisplatin was administered as first-line treatment compared to chemotherapy alone. Necitumumab is a fully human IgG1 monoclonal antibody designed to block the ligand binding site of the human epidermal growth factor receptor (EGFR).non-small cell lung cancernon-small cell lung cancer SQUIRE enrolled 1093 patients with histologically- or cytologically-confirmed, stage IV squamous NSCLC, who had received no prior therapy for metastatic disease. Patients were randomized to receive first-line necitumumab plus chemotherapy consisting of gemcitabine and cisplatin in study Arm A, or gemcitabine-cisplatin chemotherapy alone in study Arm B. Patients underwent radiographic assessment of disease status (computed tomography or magnetic resonance imaging) every six weeks (+/- 3 days), until radiographic documentation of progressive disease (PD). Chemotherapy continued for a maximum of six cycles in each arm or until there was radiographic documentation of PD, toxicity requiring cessation, or withdrawal of consent. Patients in Arm A continued to receive necitumumab (IMC-11F8) until there was radiographic documentation of PD, toxicity requiring cessation, or withdrawal of consent. SQUIRE enrolled 1093 patients with histologically- or cytologically-confirmed, stage IV squamous NSCLC, who had received no prior therapy for metastatic disease. Patients were randomized to receive first-line necitumumab plus chemotherapy consisting of gemcitabine and cisplatin in study Arm A, or gemcitabine-cisplatin chemotherapy alone in study Arm B. Patients underwent radiographic assessment of disease status (computed tomography or magnetic resonance imaging) every six weeks (+/- 3 days), until radiographic documentation of progressive disease (PD). Chemotherapy continued for a maximum of six cycles in each arm or until there was radiographic documentation of PD, toxicity requiring cessation, or withdrawal of consent. Patients in Arm A continued to receive necitumumab (IMC-11F8) until there was radiographic documentation of PD, toxicity requiring cessation, or withdrawal of consent. For more information call (800) 545-5979 or visit www.lillyoncology.com For more information call (800) 545-5979 or visit www.lillyoncology.comwww.lillyoncology.com

94. CONCLUSIONS

95. Perspectives on First-line Tx wrt Histology Based on E4599 and Scagliotti trials, use of Pemetrexed and Bevacizumab is limited to NON-squamous histology Based on E4599 and Scagliotti trials, use of Pemetrexed and Bevacizumab is limited to NON-squamous histology Standard cytotoxic platform for Adenoca: Standard cytotoxic platform for Adenoca: –platinum plus either pemetrexed or taxane Standard platform for Squamous cell ca: Standard platform for Squamous cell ca: –platinum plus either gemcitabine or taxane

96. Histologic Distinctions in the Tx of NSCLC: Conclusions II Prognosis is generally inferior in squamous vs non-sq NSCLC Prognosis is generally inferior in squamous vs non-sq NSCLC Gemcitabine appears superior to pemetrexed in the 1 st line setting in squamous NSCLC [in combination with cisplatin], while pemetrexed appears superior in non-squamous cell ca Gemcitabine appears superior to pemetrexed in the 1 st line setting in squamous NSCLC [in combination with cisplatin], while pemetrexed appears superior in non-squamous cell ca Docetaxel appears superior to pemetrexed in the 2 nd line setting in squamous cell ca, whereas pemetrexed appears superior in adenoca Docetaxel appears superior to pemetrexed in the 2 nd line setting in squamous cell ca, whereas pemetrexed appears superior in adenoca C225’s survival advantage is independent of histology C225’s survival advantage is independent of histology Though squamous ca pts fared worse overall, EGFR TKIs still conferred a survival advantage In both squamous and adenocarcinoma in the 2 nd /3 rd line setting Though squamous ca pts fared worse overall, EGFR TKIs still conferred a survival advantage In both squamous and adenocarcinoma in the 2 nd /3 rd line setting Necitumumab in combination with gem/plat is “superior” to chemo alone Necitumumab in combination with gem/plat is “superior” to chemo alone The role of PARP inhibitors, Iplilumumab, and PD1 in squamous NSCLC is uncertain The role of PARP inhibitors, Iplilumumab, and PD1 in squamous NSCLC is uncertain Actionable molecular markers may be emerging, but it remains to be seen whether FGFR inhibitors or agents targeting PTEN mutation or deletion, Death receptors or PI3K will prove efficacious Actionable molecular markers may be emerging, but it remains to be seen whether FGFR inhibitors or agents targeting PTEN mutation or deletion, Death receptors or PI3K will prove efficacious

97. I think we need to place more patients on clinical trials, don’t you agree? Corey Langer preaching to the choir at the weekly Wednesday thoracic tumor board