2. Faculty Mark A. Socinski, MD Professor of Medicine and Thoracic Surgery Director, Lung Cancer Section, Division of Hematology/Oncology Co-Director, UPMC Lung Cancer Center of Excellence Co-Director, Lung and Thoracic Malignancies Program University of Pittsburgh Pittsburgh, PA

3. Activity Planners Shari J. Dermer, PhD Manager, Educational Strategy and Content Med-IQ Baltimore, MD Lisa R. Rinehart, MS, ELS Director, Editorial Services Med-IQ Baltimore, MD

4. Lung Cancer Facts and Figures Most common cause of cancer-related mortality in US Accounts for more deaths than breast, prostate, and colorectal cancers combined Histologically and molecularly a very heterogeneous disease Unfavorable stage distribution at the time of diagnosis (screening not routinely practiced) 25,000 to 30,000 never-smoking Americans will develop lung cancer this year (more common than esophageal, gastric, ovarian, testicular, Hodgkin, myeloma, CML) Historically shrouded by therapeutic nihilism American Cancer Society. Facts & Figures. 2010.

5. First-Line Considerations How well established is the histologic diagnosis? Is tissue available for “special” studies? – EGFR mutation, EML4-ALK, others Optimal chemotherapy Role of targeted therapies –Antiangiogenic –Anti-EGFR Genotypically driven therapy Treatment-related side effects and toxicities M. Socinski, MD.

6. Molecular Profiling and Therapeutic Decision Making for Advanced NSCLC NCCN 1 –Test for EGFR mutations and ALK in lung adenocarcinoma, large-cell lung cancer, NSCLC NOS as determinants for treatment selection ASCO 2 –Test for EGFR mutations in patients with advanced NSCLC who are being considered for first-line treatment with an EGFR TKI CAP/IASLC/AMP 3 –Test for EGFR mutation and ALK fusion (+ others?) in NSCLC adenocarcinoma patients at the time of diagnosis and after a targeted therapy intervention (to assess for tumor evolution in the molecular profile) 1. NCCN. Clinical Practice Guidelines in Oncology. NSCLC V1.2014; 2. Keedy VL, et al. J Clin Oncol. 2011;29:2121-7; 3. Lindeman NI, et al. J Thorac Oncol. 2013;8:823-59.

7. Mutations in NSCLC Association between EGFR mutations and sensitivity to TKIs –Exon 19 deletion –Exon 21 (L858R) –Exon 18 (G719X) Exon 20 insertion may predict resistance to TKIs EGFR and KRAS mutations are mutually exclusive in NSCLC 10% of Western and 50% of Asian NSCLC patients have mutation of EGFR KRAS mutation associated with primary resistance to TKIs Presented by: Bruce E. Johnson, MD. NCCN. Clinical Practice Guidelines in Oncology. NSCLC V1.2014. Distribution of Mutations in 733 Genotyped

8. ALK Translocations in NSCLC ALK: anaplastic lymphoma kinase Gene rearrangements: –Chromosome 2 inversion –Fusion with EML4 gene Abnormal expression and activation Rearrangement occurs in 2% to 5% of NSCLC Occurs independently of EGFR or KRAS mutations Predominantly in: –Young patients (50 years or younger) –Never- or former-smokers with adenocarcinoma Gridelli C, et al. Cancer Treat Rev.2013;39:466-72

9. ORR a by Independent Radiologic Review ORR ratio: 3.4 (95% CI: 2.5-4.7); P < 0.0001 Shaw AT, et al. N Engl J Med. 2013;368:2385-94. Treatment 80 60- 40 20 0 ORR, % Crizotinib (n = 173 b ) Chemotherapy (n = 174 b ) 19.5 _ | _ _ Treatment 80 60- 40 20 0 ORR, % Crizotinib (n = 172 C ) Pemetrexed (n = 99 C ) Docetaxel (n = 72 C ) 65.3 _ | _ 6.9 _ | _ 29.3 _ | _ 65.7 _ | _ a RECIST v1.1 b ITT population c as-treated population Treatment-related AEs (≥ grade 3): elevated liver aminotransferase (16%) and neutropenia (13%); there was 1 patient with febrile neutropenia. Other common treatment-related AEs were visual impairment and GI disturbances.

10. Cisplatin/Pemetrexed vs. Cisplatin/ Gemcitabine in Advanced NSCLC: Results 1.23;1.00, 1.51 9.4;8.4, 10.2 10.8;9.5, 12.1 Survival Time (months) in Patients With Squamous-Cell Carcinoma Survival Probability 9.4 mos Median Survival 10.8 mos Adjusted HR CP vs. CG 1.23 SquamousNonsquamous Median Survival 0.81;0.70, 0.94 Survival Time (months) in Patients With Nonsquamous Histology Survival Probability 10.4 mos 0.81 11.8 mos Adjusted HR CP vs. CG Reprinted with permission from Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26(21):3543-3551.

11. Efficacy Outcomes in Trials of Sequential vs. Delayed Second-Line Therapy Fidias 1 JMEN 2 SATURN 3 ATLAS 4 No. of patients (entered/ randomized after 4 cycles) 562/307 (55%) ?/663 (?) 1,949/889 (46%) 1,145/743 (66%) RR (%) Rx vs. control 11 vs. 11*3 vs. 112 vs. 5NR DCR (%) Rx vs. control 67 vs. 56*49 vs. 2961 vs. 51NR PFS HR (P value) NR (< 0.0001) 0.60 (< 0.00001) 0.71 (< 0.0001) 0.71 (0.001) ∆ in Med PFS3.7 months2 months1 week1.1 months OS HR (P value) NR (0.085) 0.79 (0.012) 0.81 (0.008) NS ∆ in MST2.6 months2.8 months1 month1.1 months 1.Fidias PM, et al. J Clin Oncol. 2009;27:591-8; 2. Belani CP, et al. Lancet Oncol. 2012;13:292-9; 3. Cappuzzo F, et al. Lancet Oncol. 2010;11:521-9; 4. Johnson B, et al. J Clin Oncol. 2013;31:3926-34. * Compares patients treated on the immediate vs. delayed docetaxel arms

12. Maintenance Therapy: Strategies Continuation –Continuing one of the same agents from the original combination –Continuing a targeted agent Switch –Initiating a new agent NCCN. Clinical Practice Guidelines in Oncology. NSCLC V1.2014.

13. AVAPERL: Trial Design Barlesi F, et al. ESMO 2011.[Abstract 34LBA]. Slide courtesy of F Barlesi. Previously untreated stage IIIB-IV nsNSCLC Arm A: Bevacizumab N = 125 Arm B: Bevacizumab + pemetrexed* N = 128 Bevacizumab b + pemetrexed b + cisplatin b N = 376 N = 253 67% Follow-Up R First-line induction 4 cycles, q3w Continuation maintenance q3w until PD CR/PR/SD Per RECIST C PD Stratification factors: Gender Smoking status Response at randomization Primary objective: PFS Secondary objectives: OS, response rate, DCR, duration of response, duration disease control, safety, QOL a Randomized open-label phase 3 study b Dose of bevacizumab = 7.5 mg/kg; dose of pemetrexed = 500 mg/m 2 ; dose of cisplatin = 75 mg/m 2. RECIST-related end points measured from the preinduction phase *Investigational

14. 100 – 75 – 50 – 25 – 0 – Barlesi F, et al. ESMO 2011.[Abstract 34LBA]. Slide courtesy of F Barlesi. AVAPERL: PFS Bev+pem7.4 months (81 events) Bev3.7 months (104 events) HR, 0.48 (0.35-0.66); P < 0.001 Cont. maintenance bev+pem (n = 128) Cont. maintenance bev (n = 125) Patients at risk Bev+pem128104672540 Bev12573361320 Time, months |0|0 |3|3 |6|6 |9|9 | 15 | 12 PFS From Date of Randomization, % Median follow-up time in ITT population (excluding induction): 8.28 months (bev+pem arm), 7.95 months (bev arm)

15. PointBreak: Pemetrexed/Carboplatin/Bevacizumab* vs. Paclitaxel/Carboplatin/Bevacizumab Inclusion Criteria: Stage IIIB/IV NSCLC ECOG PS 0-1 No prior systemic Rx for lung cancer Exclusion Criteria: Peripheral neuropathy ≥ grade 1 Uncontrolled pleural effusions Reprinted with permission from Patel JD, Bonomi P, Socinski MA, et al. Treatment rationale and study design for the pointbreak study: a randomized, open-label phase III study of pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed/bevacizumab versus paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. Clin Lung Cancer. 2009;10(4):252-256. Pemetrexed 500 mg/m 2 IV q21d Carboplatin AUC of 6 IV q21d Bevacizumab ‡ 15 mg/kg IV q21d Arm A 450 patients Pemetrexed* 500 mg/m 2 IV q21d Bevacizumab ‡ 15 mg/kg IV q21d Paclitaxel 200 mg/m 2 IV q21d Carboplatin AUC of 6 IV q21d Bevacizumab ‡ 15 mg/kg IV q21d Arm B 450 patients Bevacizumab ‡ 15 mg/kg IV q21d Induction Therapy: Up to four 21-day cycles Patients with CR, PR, or SD after 4 cycles of induction therapy continue on to maintenance therapy Maintenance Therapy: Until PD or treatment discontinuation RANDOMIZERANDOMIZE *Investigational

16. | 33 PointBreak: OS and PFS for the Maintenance Population Reprinted with permission from Patel JD, Socinski MA, Garon EB, et al. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013;31(34):4349-4357. |3|3 | 30 1.0 — 0.9 — 0.8 — 0.7 — 0.6 — 0.5 — 0.4 — 0.3 — 0.2 — 0.1 — 0.0 — Survival Probability Time From Induction, months |6|6 | 12 |9|9 |0|0 | 15 | 18 | 21 | 24 | 27 | 33 | 36 Pem+Cb+BevPac+Cb+Bev (n = 292)(n = 298) OS median (mos)17.715.7 Censoring (%) 36.030.2 | 39 Pem-Bev Bev |3|3 | 30 1.0 — 0.9 — 0.8 — 0.7 — 0.6 — 0.5 — 0.4 — 0.3 — 0.2 — 0.1 — 0.0 — Survival Probability Time From Induction, months |6|6 | 12 |9|9 |0|0 | 15 | 18 | 21 | 24 | 27 Pem+Cb+BevPac+Cb+Bev (n = 292)(n = 298) PFS median (mos)8.66.9 Censoring (%) 24.714.1 | 36 Pem-Bev Bev Prespecified exploratory non-comparative subgroup analyses OS PFS

17. Supportive Care Issues in NSCLC Smoking cessation Pain/discomfort management Nutrition Psychosocial issues Palliative care Patient preferences –Treatment –Palliative care

18. Acknowledgement of Commercial Support This activity is supported by educational grants from Bayer HealthCare Pharmaceuticals, Onyx Pharmaceuticals, Celgene Corporation, Daiichi Sankyo, Inc., and Lilly. For further information concerning Lilly grant funding visit www.lillygrantoffice.com www.lillygrantoffice.com Copyright © 2014 Med-IQ®. All rights reserved.