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.

2. 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

4. Clinical Challenges and Opportunities in Squamous Cell Carcinoma Clinical Challenges and Opportunities in Squamous Cell Carcinoma Mark A. Socinski, MD Professor of Medicine and Thoracic Surgery Director, Lung Cancer Section, Division of Hematology/Oncology University of Pittsburgh

5. Overview of NSCLC Histologies Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARCPress. 2004:26-30. NSCLC squamous cell carcinoma Squamous cell carcinoma is a malignant epithelial tumor showing keratinization and/or intercellular bridges that arise from bronchial epithelium. These features vary with degree of differentiation, being prominent in well- differentiated tumors and focal in poorly differentiated tumors. NSCLC adenocarcinoma Adenocarcinoma is a malignant epithelial tumor with glandular differentiation or mucin production, showing acinar, papillary, bronchoalveolar, or solid with mucin growth patterns or a mixture of these patterns. NSCLC large cell carcinoma Large cell carcinoma is an undifferentiated non-small cell carcinoma that lacks the cytologic and architectural features of small cell carcinoma and glandular or squamous differentiation.

6. Retrospective Analysis of ECOG 1594 by Histology Histological subtypes did not influence overall survival and progression free survival in chemo-naïve patients treated with platinum-based doublets involving paclitaxel, docetaxel or gemcitabine Tien H et al. J Thorac Oncol 4:S493, 2009 Squamous (n=224) Adenocarcinoma (n=647) Large Cell (n=74) Other (n=194) RegimenMedian95% C1Median95% C1Median95% C1Median95% C1 p - value OS (mo) CP6.9(5.3, 9.4)9.1(7.9, 10.9)6.1(2.9, inf)6(3.9, 9.1)0.09 CG9.4(5.7, 15.5)8.1(6.8, 9.8)9.7(4.5, 17.1)7.9(6.3, 11.3)0.63 CD8.1(5.5, 11.2)7.7(6.5, 9.4)6.854.9, 11.78.2(5.6, 12.4)0.01 CbP9.3(7.3, 12.1)7.6(6.6, 9.8)8.3(3.6, 16.7)6.9(4.9, 11.6)0.37 p -value0.180.390.370.82 PFS (mo) CP2.6(1.7, 4.2)3.7(3.1, 4.3)3.5(1.4, inf)2.8(1.8, 4.0)0.43 CG4.1(3.3, 6.6)4.4(3.8, 5.4)4.5(2.0, 11.5)3.4(2.8, 5.1)0.43 CD3.1(2.4, 5.0)3.7(2.6, 4.6)4.2(2.0, 6.6)3.6(2.7, 5.6)0.54 CbP3.7(3.0, 5.0)3.5(2.9, 4.2)3.91.9, 7.8)2.21.7, 3.9)0.25 p -value0.20.190.560.68

7. Why did we start caring about Squamous cell carcinoma? Bleeding in a Randomized Phase II Trial Johnson. J Clin Oncol. 2004;22:2184; Sandler. New Engl J Med 355:2542-50, 2006. 6 life-threatening PHs; 4 fatal Overall incidence: 9% (6/66) 5 occurred with bevacizumab 7.5 mg/kg Apparent risk factors Baseline hemoptysis Histology - Squamous histology: 31% (4/13) - Non-squamous histology: 4% (2/53) Squamous histology patients subsequently excluded from the pivotal phase III trial (ECOG 4599)

8. Pemetrexed in Squamous Carcinoma Scagliotti, G. V. et al. J Clin Oncol; 26:3543-3551 2008 Ciuleanu T et al. Lancet 374:1432-1440, 2009 First line: Median survival CP: 9.4 months; 95% CI 8.4, 10.2 CG: 10.8 months; 95% CI 9.5, 12.1 –Adjusted HR; 95% CI: 1.23; 1.00, 1.51 Maintenance Pemetrexed, 9.9 months Placebo, 10.8 months –HR = 1.07 (95% CI: 0.49-1.73) –p = 0.678

9. Heterogeneity of mRNA Expression Levels in NSCLC: AC versus SCCA Heterogeneity of mRNA Expression Levels in NSCLC: AC versus SCCA (Reference <2.33 for pemetrexed) % Below Reference Level NSCLC-Total41.3% NSCLC-Adenoca45.7% NSCLC-SCCA25.9% Gandara D et al. ASCO 2010 NSCLC Total NSCLC Squamous NSCLC Adenocarcinoma SCCA vs AC Biomarker N = 1,802 (SCCA) N = 392 (AC) N = 920 p-value TSN1,014264500<0.001* Median2.924.312.5 Range0.14-60.580.14-59.160.39-30.33 * Mann-Whitney test

10. New Cytotoxics in Squamous Cell Carcinoma

11. Phase III nab-P/C vs P/C Study Design Socinski MA et al. ASCO 2010, LBA# 7511 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

12. Results: Baseline Demographics nab-P/C (n = 521) P/C (n = 531) All Patients (N = 1052) Age, median (range) years60 (28, 81)60 (24, 84) <70 years, n (%) ≥70 years, n (%) 448 (86) 73 (14) 449 (85) 82 (15) 897 (85) 155 (15) Female, n (%)129 (25)134 (25)263 (25) ECOG, n (%) 0133 (26)113 (21)246 (23) 1385 (74)416 (78)801 (76) Histology of Primary Diagnosis, n (%)* Adenocarcinoma254 (49)264 (50)518 (49) Squamous Cell Carcinoma228 (44)221 (42)449 (43) Large Cell Carcinoma9 (2)13 (2)22 (2) Other29 (6)33 (6)62 (6) Stage at Current Diagnosis, n (%)* Stage III99 (19)107 (20)206 (20) Stage IV421 (81)424 (80)845 (80) Prior Chemotherapy, n (%)12 (2)8 (2)20 (2) Smoking Status, n (%)5135211034 Never Smoked138 (27)144 (28)282 (27) Smoked and Quit165 (32)146 (28)311 (30) Smoked and Still Smokes210 (41)231 (44)441 (43) *Data was missing for 1 pt at the time of this analysis

13. Response Ratio = 1.31 (1.082 – 1.593) P = 0.005 Response Ratio = 1.26 (1.060 – 1.496) P = 0.008 Percent Responses Primary Endpoint Results (ITT Population) Objective Response Rates – All Histologies

14. Percent Responses Objective Responses by Histology SquamousNonsquamous P < 0.001P = 0.060P = 0.808P = 0.069 n = 228n = 221n = 292n = 310 Socinski MA et al. ASCO 2010 #7511

15. Secondary Endpoints: PFS and OS Carboplatin/ paclitaxel Carboplatin/ nab paclitaxel Hazard ratio p-value Median PFS — all patients (n = 531, 521) 5.8 months 6.3 months 0.9020.214 Median OS — all patients (n = 531, 521) 11.2 months 12.1 months 0.9220.271

16. Exploratory Overall Survival Analysis in Selected Strata Carboplatin/ paclitaxel Carboplatin/ nab paclitaxel Hazard ratio p-value Squamous (n = 221, 229) 9.5 months 10.7 months 0.8900.284* Age ≥70 years (n = 82, 74) 10.4 months 19.9 months 0.5830.009* * Subgroup analyses exploratory in nature

17. Nab Paclitaxel Phase II Trial In Advanced Squamous Carcinoma of the Lung Nab-paclitaxel Carboplatin Gemcitabine Carboplatin Primary Endpoints: ORR R N=120 NCT01236716 Chinese Society of Lung Cancer

18. Trial Outcome with Targeted Agents in Squamous Cell CA AgentTrialResults Bevacizumab Phase II Associated with increased risk of severe pulmonary hemorrhage (4/13 pts) Sorafenib Phase III ESCAPE Increased risk of death Motesanib Phase III MONET Increased risk of hemoptysis Cediranib Phase II BR24 No increased toxicity or efficacy Figitumumab Phase III ADVIGO (2) No histology specific findings but increased toxicity and no benefit Cetuximab Phase III FLEX No histology specific findings

19. FLEX Overall Survival Time: ITT CT + Cetuximab (n = 557) CT (n = 568) No. of events421447 Median OS, months [95% CI] 11.3 [9.4–12.4] 10.1 [9.1–10.9] HR [95% CI] 0.871 [0.762–0.996] p-value0.044 1-year survival, %4742

20. OS by Subgroups: Ethnic Origin and Histology (ITT) Median OS (months) CT + CetuximabCTHR [95% CI]p-value All (n=1125)11.310.1 0.871 [0.762–0.996] 0.044 Caucasian (n=946) Adenoca. (n=413) SCC (n=347) 10.59.1 0.803 [0.694–0.928] 0.003 12.010.3 0.815 [0.649–1.023] 0.077 10.28.9 0.794 [0.626–1.007] 0.057 Asian (n=121)17.620.4 1.179 [0.730–1.905] 0.499

21. High and low EGFR expression O’Byrne et al. J Thorac Oncol 2010 High EGFR expression IHC score ≥200 Low EGFR expression IHC score <200

22. FLEX survival: High EGFR expression Squamous cell carcinoma (N = 144) Survival Median1-year CT + cetuximab 11.2 mo44% CT8.9 mo25% HR = 0.62 [95% CI 0.43–0.88]

23. Ongoing Trials in Squamous NSCLC

24. Iniparib in Untreated Stage IV Squamous NSCLC Homologous Recombination Repair (HR) Target Cancers = defective in HR BRCA1/2 mutant (breast, ovarian), ERCC1 abnormalities (colon, NSCLC), p53 mutant tumors. Chemo DNA replication DNA SSB Base excision repair PARP wt p53/ mt p53 DNA DSB ATM/ATR γ-H2AX Rad50 MRE11NBS1 BRCA2 Adapted from N.J. Curtin, 2006 Iniparib BRCA1 RAD51 RPARad52/4 ERCC1

25. ECLIPSE Study Overview 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

26. Necitumumab Fully human IgG1 monoclonal antibody to EGFR Fully human IgG1 monoclonal antibody to EGFR Increases antitumor activity when combined with Increases antitumor activity when combined with gemcitabine/cisplatin or pemetrexed/cisplatin in gemcitabine/cisplatin or pemetrexed/cisplatin in NSCLC xenografts NSCLC xenografts First in human study: DLT grade 3 headache First in human study: DLT grade 3 headache associated with nausea, vomiting, and fever (2 pts) associated with nausea, vomiting, and fever (2 pts) RP2D 800 mg weekly or every 2 weeks RP2D 800 mg weekly or every 2 weeks PR-2 pts; SD-16 pts PR-2 pts; SD-16 pts Kuenen B et al. Clin Cancer Res 15:1915-1923, 2010

27. RANDOMIZERANDOMIZE IMC-11F8 Arm B: CIS + GEM Cisplatin 75 mg/m 2 (30-60 min IV), D1 Gemcitabine 1250 mg/m 2 (30 min IV), D1, 8 Arm A: IMC-11F8 + CIS + GEM IMC-11F8 800 mg (50-min IV), D1, 8 Cisplatin 75 mg/m 2 (30-60 min IV), D1 Gemcitabine 1250 mg m 2 (30 min IV), D1, 8 SQUIRE: Phase III, 1 st line NSCLC, squamous 947 patients Stage 4 NSCLC Squamous ECOG PS 0-2 PR CR SD PD 1 1

28. Squamous Cell Lung Cancer: An Unmet Need Platinum Doublets remain the standard of carePlatinum Doublets remain the standard of care – Gemcitabine- or Taxane-Based Regimens Commonly Used (? Role of ) – Gemcitabine- or Taxane-Based Regimens Commonly Used (? Role of Nab- paclitaxel) Antiangiogenic strategies are felt to be too toxicAntiangiogenic strategies are felt to be too toxic Pemetrexed no longer approved for use in this subsetPemetrexed no longer approved for use in this subset Cetuximab + cisplatin-vinorelbine (FLEX study): improved median OS (10.2 vs 8.9 months) in SQLC – Not FDA-ApprovedCetuximab + cisplatin-vinorelbine (FLEX study): improved median OS (10.2 vs 8.9 months) in SQLC – Not FDA-Approved New strategies are needed for this large group of patients New strategies are needed for this large group of patients

29. 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