1. Antiangiogenic Agents in Advanced NSCLC Jared Weiss, MD Assistant Professor of Medicine Division of Hematology and Oncology University of North Carolina School of Medicine Attending Physician UNC Lineberger Comprehensive Cancer Center Chapel Hill, North Carolina Corey Langer, MD Director of Thoracic Oncology Abramson Cancer Center and Professor of Internal Medicine Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Expanding Horizons

2. Program Goals Critically analyze clinical trial data for use of existing and emerging antiangiogenic agents in the treatment of advanced NSCLC Outline which patients with advanced NSCLC may potentially benefit from the use of an antiangiogenic agent

3. Rationale for Anti-VEGF Therapy Solid stresses and vascular leakiness result in decreased flow to some areas of tumor and increased pressure in tumors –Decrease access of drugs, immune cells –Result in hypoxia, which induces tumor progression and decreases efficacy of drugs that require oxygen, and low pH Antiangiogenic therapy targeting VEGF or VEGFR may restore a more normal vasculature, generating an environment less favorable to cancer cell growth Weinmann M, et al. Onkologie. 2004;27:83-90 [2] ; Goel S, et al. Physiol Rev. 2011;91:1071-1121. [26]

4. Targeted Approaches to Anti-VEGF Therapy Anti-receptor- blocking antibodies Anti-ligand-blocking antibodies Tyrosine kinase inhibitors Bevacizumab Nintedanib Ramucirumab VEGF VEGFR Image courtesy of C. Langer, MD.

5. Bevacizumab Recombinant humanized IgG1 monoclonal antibody Binds VEGF and prevents interaction of VEGF to its receptors Half-life is approximately 20 days (range, 11-50 days) Avastin (bevacizumab) [package insert]; 2014. [3]

6. Bevacizumab + Paclitaxel/Carboplatin in Advanced NSCLC Phase 2 Study Design Excluded: –CNS metastasis –Therapeutic anticoagulation Primary efficacy end points = TTP and tumor response rate. *Patients received up to 6 cycles. † Crossover to single agent bevacizumab (15 mg/kg) was allowed at disease progression. Johnson DH, et al. J Clin Oncol. 2004;22:2184-2191. [4] Paclitaxel 200 mg/m 2 carboplatin AUC 6 3 times weekly*; N = 32 PC* + Bevacizumab 15 mg/kg every 3 wk; N = 35 PC* + Bevacizumab 7.5 mg/kg every 3 wk; N = 32 Bevacizumab 7.5 mg/kg every 3 wk to PD or unacceptable toxicity Progression of disease † Bevacizumab 15 mg/kg every 3 wk to PD or unacceptable toxicity Patients with previously untreated advanced NSCLC ECOG PS≤2 (N = 98) Randomized

7. 6 cases of severe (n = 2) or fatal (n = 4) 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 Based on this analysis, squamous cell histology was identified as a risk factor for pulmonary hemorrhage for treatment with bevacizumab These phase 2 data were used to design the phase 3 trial exclusion criteria Bevacizumab + PC in Advanced NSCLC Pulmonary Bleeding in Phase 2 Study Johnson DH, et al. J Clin Oncol. 2004;22:2184-2191. [4]

8. Bevacizumab + PC in Advanced NSCLC Phase 2 Study Efficacy Results: Nonsquamous Patients Only Control (n = 25) Bev (7.5 mg/kg) (n = 22) Bev (15 mg/kg) (n = 32) ORR, %2031.850 Median TTP, mo4.06.37.1 Median survival time, mo 12.214.017.8 Johnson DH, et al. J Clin Oncol. 2004;22:2184-2191. [4]

9. ECOG 4599: PC ± Bevacizumab in Nonsquamous Advanced NSCLC Phase 3 Study Design Sandler A, et al. N Engl J Med. 2006;355:2542-2550. [5] *No crossover to bevacizumab permitted. Excluded: –CNS metastasis –History of hemoptysis Primary end point: OS Paclitaxel 200 mg/m 2 carboplatin AUC 6 every 3 wk up to 6 cycles* N = 444 PC + bevacizumab (15 mg/kg every 3 wk) up to 6 cycles N = 434 Single- agent bev every 3 wk until PD or unaccept- able toxicity Randomized Patients with previously untreated nonsquamous advanced NSCLC ECOG PS=0/1 N = 878

10. E4599 Efficacy Results PCPCB P Value RR16%35%<.001 PFS4.5 mo6.2 mo<.001 Median OS10.3 mo12.3 mo.003 1-y survival44%51% 2-y survival15%23% Sandler A, et al. N Engl J Med. 2006;355:2542-2550. [5]

11. Patients Event (Grade 3-5) PC (n = 440) PCB (n = 427) Clinically significant bleeding event a 0.7% 4.4% (P <.001) Hypertension (grade 3/4) b 0.7% 7% (P <.001) Neutropenia16.8% 25.5% (P =.002) Treatment-related deaths (actual numbers) a,b 215 E4599 Selected Safety Issues a. Sandler A, et al. N Engl J Med. 2006;355:2542-2550. [5] b. Avastin (bevacizumab) [package insert]; 2014. [3] *Pulmonary hemorrhagic events are included with the clinically significant bleeding events.

12. AVAiL Cisplatin + Gemcitabine ± Bevacizumab in Nonsquamous Disease Phase 3 trial 1043 patients in a 1:1:1 ratio to chemotherapy + placebo; chemotherapy + bevacizumab (7.5 mg/kg); chemotherapy + bevacizumab (15 mg/kg) End points included: ̶ PFS – primary ̶ OS – secondary Efficacy results: ̶ PFS Bev (7.5 mg/kg) arm vs placebo: HR = 0.75 (0.64-.0.87); P =.0003 Bev (15 mg/kg) arm vs placebo: HR = 0.85 (0.73-1.00); P =.0456 ̶ OS Bev (7.5 mg/kg) arm vs placebo: HR = 0.93 (0.78-1.11); P =.420 Bev (15 mg/kg) arm vs placebo: HR = 1.03 (0.86-1.23); P =.761 Reck, M, et al. Ann Oncol. 2010;21:1804-1809. [6]

13. POINTBREAK: Pemetrexed/Carboplatin + Bevacizumab vs PCB Phase 3 Study Design Patel J, et al. J Clin Oncol. 2013;34:4349-4357. [10] Primary end point: OS *Stable treated brain metastases allowed; patients were excluded if they had a coagulopathy or were taking full-dose anticoagulation at the time of randomization. Pemetrexed (500 mg/m 2 )/carboplatin (AUC 6)/bevacizumb (15 mg/m 2 ) every 3 wk up to 4 cycles; N = 472 Paclitaxel (200 mg/m 2 )/carboplatin (AUC 6)/bevacizumab (15 mg/m 2 ) every 3 wk up to 4 cycles; N = 467 Patients with advanced nonsquamous NSCLC* No prior systemic treatment for lung cancer ECOG PS = 0/1 N = 939 Single-agent Bev every 3 wk until PD or treatment d/c Bev + pemetrexed every 3 wk until PD or treatment d/c Randomized

14. Patel J, et al. J Clin Oncol. 2013;34:4349-4357. [10] POINTBREAK Efficacy and Safety Results Efficacy for pemetrexed/carboplatin/bevacizumab vs PCB −OS: HR = 1.00; median OS = 12.6 vs 13.4 mo; P =.949 −PFS: HR = 0.83; median PFS = 6.0 vs 5.6 mo; P =.012 −ORR: 34.1% vs 33.0% −DCR: 65.9% vs 69.8% Safety −Significantly more grade 3/4 neutropenia, febrile neutropenia, sensory neuropathy, and alopecia with PCB −Significantly more grade 3/4 anemia, thrombocytopenia, and fatigue with pemetrexed/carboplatin/bevacizumab

15. ECOG 5508 Phase 3 Study Design Excluded : –Untreated CNS metastases Primary end point: OS ClinicalTrials.gov NCT01107626. [15] PC + bevacizumab every 3 wk x 4 cycles Patients with advanced nonsquamous NSCLC No prior systemic treatment for advanced lung cancer ECOG PS=0/1 Single-agent Bev every 3 wk Bev + pemetrexed every 3 wk Single- agent pemetrexed every 3 wk Randomized

16. E4599 Subgroup Analyses of Median Survival Time According to Sex and Age < 45 y< 60 y≥ 60 y P Value (< 60 y vs ≥ 60 y) Women (PC)5.8 mo11.0 mo13.8 mo.11 Women (PCB) 16.8 mo (P =.07 ± Bev) 15.5 mo (P =.12 ± Bev) 12.8 mo (P =.2 ± Bev).18 Men (PC)9.3 mo8.5 mo.85 Men (PCB) 12.4 mo11.0 mo.59 P Value: sex/treatment.0006<.0001 Wakelee H, et al. Lung Cancer. 2012;76:410-415. [18]

17. E4599 Landmark Analyses of Effect of Maintenance Bevacizumab Analyses conducted in patients in both the PC and PCB groups alive and progression free through the completion of 6 cycles + 21 d 217 patients in PCB group; 134 patients in PC group Postinduction PFS, 4.4 vs 2.8 mo (HR = 0.64; P <.001) for PCB and PC groups, respectively Median OS (PCB vs PC), 12.8 vs 11.4 mo (HR = 0.75; P =.03) In the maintenance setting, Bev was associated with < 1% grade 3 or 4 hematologic toxicities; no grade 3 or 4 nausea, vomiting or diarrhea; no grade 5 toxicities Lopez-Chavez J, et al. J Thorac Oncol. 2012;7:1707-1712. [19]

18. CompoundMechanism of ActionN trialsNEnd Point ThalidomideAntiangiogenic21267OS CediranibVEGFR TKI1296OS VandetanibMultikinase TKI32698PFS/OS AE-941Antiangiogenic1379OS SorafenibMultikinase TKI21830OS SunitinibMultikinase TKI1960OS AfliberceptVEGF/PlGF1913OS Total118343 Clinically Negative Phase 3 Trials in NSCLC With Antiangiogenic Agents (2000-2011) Image courtesy of C. Langer, MD.

19. Predicting Response to Bevacizumab Patient selection for antiangiogenic therapy is now primarily based on exclusion for toxicity Circulating VEGF-A seems prognostic, but not predictive a Retrospective analysis suggests improved outcomes associated with bevacizumab in patients developing hypertension on therapy b ̶ Available evidence does not suggest hypertension as a surrogate for the efficacy of antiangiogenic therapy in advanced NSCLC a. Hegde PS, et al. Clin Cancer Res. 2013;19:929-937. [21] b. Koyama N. Cancer Biomark. 2014;14:259-265. [22]

20. LUME-Lung 1: Second-line Docetaxel + Nintedinib vs Docetaxel + Placebo Phase 3 Study Design Primary end point: PFS Secondary end points: OS, ORR, safety *555 patients had advanced squamous NSCLC. Reck M, et al. Lancet Oncol. 2014;15:143-155. [23] Patients with advanced NSCLC (all histologies)* and disease progression on first-line chemotherapy ECOG PS=0/1 Docetaxel (75 mg/m 2 ; d1) every 3 wk + nintedanib (200 mg twice daily) (d2-21) N =655 Docetaxel (75 mg/m 2; d1) every 3 wk + placebo (twice daily) (d2-21) N = 659 Randomized

21. LUME-Lung 1 Efficacy and Safety Outcomes Reck M, et al. Lancet Oncol. 2014;15:143-155. [23] ArmNo mPFS (all) mOS (all) mOS (ad) 1 yr OS (ad) 2 yr OS (ad) NTB6553.4 mo 10.1 mo 12.6 mo 52.7%25.7% PBO6592.7 mo 9.1 mo 10.3 mo 44.7%19.1% HR0.790.940.83 P Value0.00190.2720.0359 Arm Diarrhea (all) Diarrhea Grade 3-5ALT Grade 3- 4 ALT NTB, %42.36.728.57.8 PBO, %21.82.68.40.9

22. REVEL: Second-line Docetaxel + Ramucirumab vs Docetaxel + Placebo Phase 3 Study Design Primary end point: OS Secondary end points: PFS, ORR *25% in the ramucirumab arm and 27% in the placebo arm had advanced squamous NSCLC.; † Patients who discontinued combination therapy due to toxicity of ramucirumab or docetaxel were allowed to continue with monotherapy. Garon EB, et al. Lancet. 2014;665-673. [25] Patients* with squamous or nonsquamous advanced NSCLC and disease progression on first-line platinum-based chemotherapy ECOG PS=0/1 N= 1253 Docetaxel (75 mg/m 2 ) + ramucirumab (10 mg/kg) d1 every 21 d † N = 628 Docetaxel (75 mg/m 2 ) + placebo d1 every 21 d N = 625 Randomized

23. Efficacy (Arm)NORRmPFSmOS* RAM23%4.5 mo10.5 mo PBO14%3.0 mo9.1 mo HR0.760.86 P Value<.0001.0001.023 Safety: ≥ Grade 3 AEsRAM (N =627), %PBO (N =618), % Neutropenia4939 Febrile neutropenia1610 Hypertension62 Pulmonary hemorrhage † 11 Any Gr pulmonary hemorrhage 87 Garon EB, et al. Lancet. 2014;665-673. [25] REVEL Efficacy and Safety Outcomes *Median OS was longer for RAM + DOC for most patient subgroups, including patients with disease characterized by squamous or nonsquamous histology. † Rates of pulmonary hemorrhage did not differ by histologic group.

24. Summary Antiangiogenic Agents in Advanced NSCLC Bevacizumab, the first targeted agent to receive FDA approval for first-line use in advanced NSCLC, is approved: ̶ In combination with PC ̶ For patients with nonsquamous histology ̶ Not approved in those with antecedent hemoptysis or untreated brain metastases Ramucirumab is the first monoclonal antibody to show a survival benefit in the second-line setting (in combination with docetaxel) and the first to benefit patients with disease characterized by squamous histology Nintedanib is the only TKI to show a potential OS benefit in the second-line setting

25. You may now revisit those questions presented at the beginning of the activity to see what you’ve learned by clicking on the Earn CME Credit link. The CME posttest will follow. Please also take a moment to complete the program evaluation at the end. Thank you for participating in this activity.