Improved Survival With Nivolumab vs Docetaxel in Pts With Advanced Squamous Cell NSCLC After Platinum-Containing Chemotherapy: CheckMate 017 Slideset on: Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123-135. This activity is supported by educational grants from Genentech, Lilly, and Novartis.

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Background: Nivolumab in Metastatic NSCLC Few therapeutic options available for the ~ 30% of pts diagnosed with advanced squamous cell NSCLC[1] Nivolumab: fully human IgG4 anti–PD-1 monoclonal antibody May restore antitumor immune response[2] Showed antitumor activity in pts with previously treated advanced squamous-cell NSCLC in phase I, II studies[3,4] CheckMate 057 showed survival advantage with nivolumab over docetaxel in pts with previously treated nonsquamous NSCLC[5] Current study, CheckMate 017, compared nivolumab vs docetaxel in pts with advanced, previously treated squamous-cell NSCLC[1] NSCLC, non-small-cell lung cancer. 1. Brahmer J, et al. N Engl J Med. 2015;373:123-135. 2. Brahmer JR, et al. J Clin Oncol. 2010;28:3167-3175. 3. Gettinger SN, et al. J Clin Oncol. 2015;33:2004-2012. 4. Rizvi NA, et al. Lancet Oncol. 2015;16:257-265. 5. Borghaei H, et al. N Engl J Med. 2015;373:1627-1639. Slide credit: clinicaloptions.com

CheckMate 017: Phase III Study Schema Stratified by prior paclitaxel (yes vs no) and geographic region (US/Canada vs Europe vs rest of world) Treatment continued until PD or unacceptable AE; Pts receiving nivolumab could continue beyond progression based on investigator’s discretion Nivolumab 3 mg/kg IV q2w* (n = 135) Stage IIIB or IV or recurrent squamous-cell NSCLC after 1 prior platinum-containing chemotherapy regimen* (N = 272) Docetaxel 75 mg/m2 q3w* (n = 137) EGFR, epidermal growth factor receptor; IV, intravenous; NSCLC, non-small-cell lung cancer; OS, overall survival; q2w, every 2 weeks; q3w, every 3 weeks. *Prior maintenance therapy allowed, including EGFR tyrosine kinase inhibitor. Slide credit: clinicaloptions.com Brahmer J, et al. N Engl J Med. 2015;373:123-135.

Overall Survival (% of Patients) CheckMate 017: OS OS significantly longer with nivolumab vs docetaxel; benefit seen in most subgroups* 100 80 60 40 20 Median OS, mo (95% CI) 9.2 (7.3-13.3) 6.0 (5.1-7.3) 1-Yr OS, % of pts (95% CI) 42 (34-50) 24 (17-31) No. of Deaths 86 113 Nivolumab (N = 135) Docetaxel (N = 137) HR: 0.59 (95%CI: 0.44-0.79) P < .001 Overall Survival (% of Patients) CI, confidence interval; HR, hazard ratio; mOS, median OS; OS, overall survival. 3 6 9 12 15 18 21 24 Mos *Except for pts outside US, Europe and those aged ≥ 75 yrs Slide credit: clinicaloptions.com Brahmer J, et al. N Engl J Med. 2015;373:123-135.

CheckMate 017: PFS PFS significantly longer with nivolumab vs docetaxel 100 80 60 40 20 Median PFSS, mo (95% CI) 3.5 (2.1-4.9) 2.8 (2.1-3.5) 1-Yr PFS, % of pts (95% CI) 21 (14-28) 6 (3-12) No. of Events 105 122 Nivolumab (N = 135) Docetaxel (N = 137) HR: 0.62 (95% CI: 0.47-0.81) P < .001 PFS (% of Patients) CI, confidence interval; HR, hazard ratio; mPFS, median PFS; PFS, progression-free survival 3 6 9 12 15 18 21 24 Mos Slide credit: clinicaloptions.com Brahmer J, et al. N Engl J Med. 2015;373:123-135.

CheckMate 017: Other Efficacy Outcomes Secondary efficacy outcomes favored nivolumab vs docetaxel ORR (20% vs 9%; P = .008) Median duration of response (not reached vs 8.4 mos) Proportion of responders with ongoing response (63% vs 33%) PD-L1 expression not prognostic or predictive No difference in nivolumab benefit based on PD-L1 expression PD-L1 expression assessed with validated automated IHC assay using clone 28-8 (a rabbit monoclonal antihuman PD-L1 antibody) ORR, objective response rate; PD-L1, programmed death ligand-1. Slide credit: clinicaloptions.com Brahmer J, et al. N Engl J Med. 2015;373:123-135.

Nivolumab in Squamous NSCLC: OS by PD-L1 Expression Level mOS, Mos Nivo Doc PD-L1 ≥ 1% 9.3 7.2 PD-L1 < 1% 8.7 5.9 mOS, Mos Nivo Doc PD-L1 ≥ 5% 10 6.4 PD-L1 < 5% 8.5 6.1 mOS, Mos Nivo Doc PD-L1 ≥ 10% 11 7.1 PD-L1 < 10% 8.2 6.1 100 90 80 70 60 OS (%) 50 40 30 NSCLC, non-small-cell lung cancer. 20 10 3 6 9 12 15 18 21 24 3 6 9 12 15 18 21 24 3 6 9 12 15 18 21 24 Mos Mos Mos Nivolumab PD-L1+ Nivolumab PD-L1- Docetaxel PD-L1+ Docetaxel PD-L1- Slide credit: clinicaloptions.com Brahmer J, et al. N Engl J Med. 2015;373:123-135.

CheckMate 017: Most Common AEs Most common treatment-related AEs*, n (%) Nivolumab (n = 131) Docetaxel (n = 129) Any Grade Grade 3/4 Grade 3/4† Any 76 (58) 9 (7) 111 (86) 71 (55) Fatigue 21 (16) 1 (1) 42 (33) 10 (8) Decreased appetite 14 (11) 25 (19) Asthenia 13 (10) 18 (14) 5 (4) Nausea 12 (9) 30 (23) 2 (2) Diarrhea 26 (20) 3 (2) Arthralgia 7 (5) Pyrexia 6 (5) Pneumonitis AE, adverse event. *In ≥ 5% of pts in nivolumab arm. †Treatment with docetaxel also resulted in 3 grade 5 AEs, including interstitial lung disease, pulmonary hemorrhage, and sepsis (n = 1 each). Slide credit: clinicaloptions.com Brahmer J, et al. N Engl J Med. 2015;373:123-135.

CheckMate 017: Select Tx-Related AEs Select treatment-related AEs, n (%) Nivolumab (n = 131) Docetaxel (n = 129) Any Grade Grade 3/4 Skin 12 (9) 11 (9) 2 (2) Gastrointestinal Diarrhea Colitis 11 (8) 10 (8) 1 (1) 26 (20) 3 (2) Pulmonary Pneumonitis Lung infiltration Interstitial lung disease 7 (5) 6 (5) 1 (1)* Endocrine 5 (4) Renal 4 (3) Hepatic Hypersensitivity/infusion rxn AE, adverse event. *Grade 5 event. Slide credit: clinicaloptions.com Brahmer J, et al. N Engl J Med. 2015;373:123-135.

Conclusions and Faculty Assessment Nivolumab conferred significant survival benefit over docetaxel for pts with previously treated squamous-cell NSCLC Median OS, 9.2 vs 6.0 mos (P < .001) Median PFS, 3.5 vs 2.8 mos (P < .001) ORR higher with nivolumab vs docetaxel (20% vs 9%; P = .008) Treatment-related grade 3/4 AEs less common with nivolumab vs docetaxel (7% vs 55%) Nivolumab represents a new standard of care for treatment of patients with squamous-cell NSCLC after therapy with a platinum-based chemotherapy regimen AE, adverse event; NSCLC, non-small-cell lung cancer; ORR, overall response rate; OS, overall survival; PD-L1, programmed death ligand-1; PFS, progression-free survival. Slide credit: clinicaloptions.com Brahmer J, et al. N Engl J Med. 2015;373:123-135.

Conclusions and Faculty Assessment No association between PD-L1 expression and nivolumab benefit Weaknesses of this study: Interpretation of subgroup analyses limited by small patient numbers, statistical factors, imbalance in ECOG PS favoring docetaxel in older patients Assessment of PD-L1 is not a perfect biomarker for predicting efficacy of nivolumab in this setting, and additional research is needed Future directions: Explore role of nivolumab as first-line therapy for squamous NSCLC Using combination approaches: immunotherapy combinations, immunotherapy plus targeted agents Explore optimal use of PD-L1, and other biomarkers, to select pts mostly likely to benefit from nivolumab ECOG PS, Eastern Cooperative Oncology Group performance status; NSCLC, non-small-cell lung cancer; OS, overall survival; PD-1, programmed death ligand-1. Slide credit: clinicaloptions.com Brahmer J, et al. N Engl J Med. 2015;373:123-135.

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