1. 2015.08.21 R4 박재훈 / F 황인경

2. Introduction Squamous-cell carcinoma about 30% of NSCLC Treatment for advanced squamous-cell NSCLC docetaxel for secondline treatment in 1999 remains an unmet need no single-agent therapy has resulted in better survival than that seen with docetaxel

3. Introduction Programmed death 1 (PD-1) receptor expressed on activated T cells, engaged by ligands PD-L1, PD-L2, which are expressed by tumor cells and infiltrating immune cells Tumor PD-L1 expression is prevalent in NSCLC interaction of PD-1 with PD-L1,L2 ligands inhibits T-cell activation and promotes tumor immune escape Nivolumab fully human IgG4 PD-1 immune-checkpoint–inhibitor antibody disrupts PD-1–mediated signaling and restores antitumor immunity 15% RR, 8.2~9.2 months median overall survival, 41%(1 year) & 19%(3 years) survival rate among previously treated with advanced squamous-cell NSCLC (in phase 1 and 2 trials) Randomized, openlabel, international, phase 3 study compared nivolumab monotherapy with docetaxel monotherapy in patients with advanced squamous-cell NSCLC in progressed disease during or after one prior platinum-containing chemotherapy regimen

5. Patients Stage IIIB or IV squamous-cell NSCLC Disease recurrence after one prior platinum-containing regimen Inclusion criteria ≥ 18 years 0, 1 ECOG score(no symptoms, and 1 mild symptoms) Treated, stable brain metastases prior maintenance therapy, including an EGFR tyrosine kinase inhibitor Exclusion criteria autoimmune disease, symptomatic ILD, systemic immunosuppression, prior therapy with T-cell costimulation or checkpoint-targeted agents, prior docetaxel therapy more than one prior systemic therapy for metastatic disease

6. Study Design and Treatments 2012.10~2013.12 352 patients  272 underwent randomization 135 patients : nivolumab(3 mg/kg iv q 2 weeks) – Dose reductions not permitted 137 patients : docetaxel(75 mg/m 2 BSA iv q 3 weeks) Patients were treated until disease progression or discontinuation of treatment owing to toxic effects or for other reasons Randomization prior use of paclitaxel therapy (yes vs. no) geographic region (USA or Canada vs Europe vs rest of the world [Argentina, Australia, Chile, Mexico, and Peru])

7. End Points and Assessments Primary end point overall survival followed for survival continuously while receiving drugs and then every 3 months after discontinuation of treatment Secondary end point rate of investigator-assessed confirmed objective response at week 9, every 6 weeks thereafter progression-free survival patient-reported outcomes disease-related symptoms, health status efficacy according to tumor PD-L1 expression safety incidence of adverse events

8. PD-L1 Biomarker Analysis & Study Oversight PD-L1 protein expression evaluated retrospectively in pretreatment tumor-biopsy specimens used a rabbit monoclonal antihuman PD-L1 antibody positive : tumor-cell membrane staining was observed at expression levels of 1%, 5%, 10% of cells in a section that included > 100 tumor cells that could be evaluated On 2015.1.10, the committee recommended early termination of the study overall survival among patients receiving nivolumab was superior to that among those receiving docetaxel database lock : 2014.12.15

9. Statistical Analysis Overall survival, progression-free survival analysis two-sided log-rank test stratified according to prior or no prior paclitaxel use and geographic region Hazard ratios, corresponding confidence intervals stratified Cox proportional-hazards model Survival curves for each treatment group Kaplan–Meier method Survival rates derived from the Kaplan–Meier estimates

10. Statistical Analysis Objective response rates two-sided, stratified Cochran–Mantel–Haenszel test Demographic, efficacy analyses included all the patients who underwent randomization (intention-to-treat population) Safety analyses included all the treated patients

12. Patients and Treatment 96% of randomized patients(260/272 patients) received treatment with a study drug 131 with nivolumab 129 with docetaxel Minimum follow-up : approximately 11 months Median age : 63 years Most patients : Men, ECOG 1, stage IV, current or former smokers All the patients had received platinum-based therapy previously 34% paclitaxel Slight between-group imbalances % of female patients, patients ≥ 75 years, ECOG score 1

15. Patients and Treatment Nivolumab group Median 8 doses(1~48) 85% patients received > 90% of planned dose intensity At least one dose delay : 37% Docetaxel group Median 3 doses(1~29) 69% patients received > 90% of planned dose intensity 27% dose reductions At least one dose delay : 31% Dose delay 4~7 days in duration nivolumab group : personal or administrative reasons, disease progression, or the administration of radiotherapy docetaxel group : adverse events

16. Patients and Treatment At the time of the database lock(2014.12.15), 16%(nivolumab group), 2%(docetaxel group) were continuing treatment After discontinuation of treatment, 36%(nivolumab group), 30%(docetaxel group) received subsequent systemic cancer therapy In the nivolumab group 24% received subsequent docetaxel In the docetaxel group 2% received subsequent immunotherapy

17. Efficacy

18. Hazard ratios for death in the analysis of overall survival favored nivolumab across all prespecified subgroups Exceptation subgroups of patients in the rest of-world geographic region (Argentina, Australia, Chile, Mexico, and Peru) and those who were ≥ 75 years of age

20. Efficacy of Nivolumab versus Docetaxel in Patients with Advanced Squamous-Cell Non–Small-Cell Lung Cancer 2.2 months 2.1 months 8.4 months

21. Efficacy of Nivolumab versus Docetaxel in Patients with Advanced Squamous-Cell Non–Small-Cell Lung Cancer

22. Efficacy 83% of the patients who underwent randomization (225/272 patients) had quantifiable PD-L1 expression Rates of PD-L1 positivity were balanced between the two groups PD-L1 expression was neither prognostic nor predictive of any of the efficacy end points Rates of overall survival, progression-free survival, objective response in the PDL1 subgroups favored nivolumab

23. Efficacy of Nivolumab versus Docetaxel in Patients with Advanced Squamous-Cell Non–Small-Cell Lung Cancer

24. 2% of grade 5 Safety none of grade 5

25. Safety Treatment-related serious adverse events occurred less frequently with nivolumab than with docetaxel Nivolumab group 7% had serious events of any grade 2% had serious events of grade 3 or 4 none had grade 5 serious events Docetaxel group  hematologic toxic events and infections 24% had serious events of any grade 19% had serious events of grade 3 or 4 2% had serious events of grade 5

26. Safety The most frequently reported (in ≥3% of patients) treatment-related select adverse events of any grade hypothyroidism (4% with nivolumab vs. 0% with docetaxel) diarrhea (8% vs. 20%) pneumonitis (5% vs. 0%) increased sCr level (3% vs. 2%) rash (4% vs. 6%) 3 treatment-related select adverse events of grade 3 were reported in the nivolumab group tubulointerstitial nephritis, colitis, pneumonitis

27. Safety Management of treatment-related adverse events Immune-modulating medications(m/c systemic glucocorticoids) Topical preparations for skin-related events Median resolution times : 0.3~5.0 weeks in the nivolumab group Treatment-related pulmonary events Median time to onset : 15.1 weeks all but one patient received glucocorticoids all cases resolved, median resolution time of 5.0 weeks

28. Safety Treatment discontinuation due to adverse events 3%(nivolumab group) vs 10%(docetaxel group) pneumonitis in the nivolumab group (in 2%) peripheral neuropathy and fatigue in the docetaxel group (in 3% and 2%) No deaths were attributed to nivolumab 3 deaths were attributed to docetaxel (ILD, pulmonary hemorrhage, sepsis)

29. Discussion Previously treated squamous-cell NSCLC little progress since the approval of docetaxel in 1999 Poor survival receiving second-line treatment 6.4 months median overall survival 22%(1 year), 5%(2 years) survival rates International, prospective, randomized, phase 3 trial that showed superior survival and an improved safety profile with nivolumab vs docetaxel in patients with advanced, previously treated squamous-cell NSCLC

30. Discussion docetaxel + ramucirumab > docetaxel Significant, modest improvement in overall survival (hazard ratio for death, 0.86), but added toxicity In this trial, nivolumab monotherapy was 41 % lower risk of death 3.2-month longer median survival (9.2 vs 6.0 months) nearly twice the 1-year survival rate (42 vs 24 %)

31. Discussion Nivolumab significant improvement across secondary efficacy end points rate of confirmed objective response was more than double most patients had a response by the time the first scan was obtained significantly longer progression-free survival(38% lower risk of progression) The observed efficacy of nivolumab was similar to that observed in a phase 2, single-group trial (CheckMate 063) of nivolumab in the context of third-line therapy and beyond for squamous-cell NSCLC 15% response rate, 8.2 months median overall survival, 41% 1-year survival rate formed the basis for the March 2015 approval of nivolumab by the FDA for the treatment of patients with metastatic squamous-cell NSCLC who had disease progression during or after platinum based chemotherapy

32. Discussion Treatment effect favoring nivolumab was observed in prespecified subgroups, except in the group of patients ≥ 75 years of age & in the rest-of-the- world geographic region due to small sample sizes, a lack of adjustment of type I error for multiple comparisons, and imbalance in ECOG performance-status score In this study, the efficacy of nivolumab was observed regardless of tumor PD-L1 expression levels PD-L1 expression was neither prognostic nor predictive of efficacy in the population of patients with squamous-cell NSCLC Limitations PD-L1 expression was assessed in archival tumor tissue may not have reflected tumor PD-L1 status at the time of treatment only 83% of the patients had quantifiable PD-L1 expression

33. Discussion Safety of nivolumab was more favorable than that of docetaxel infrequently reported toxic effects that are expected with cytotoxic chemotherapies used as secondline therapies  leading to treatment discontinuation No new safety concerns were identified, and no deaths were attributed to nivolumab Immune-mediated adverse events with nivolumab differ from those seen with traditional cytotoxic therapies adverse events, including pneumonitis, were infrequent and of low severity in this study and were managed with the use of established guidelines

34. Conclusion Nivolumab in patients with advanced, previously treated squamous-cell NSCLC PD-1 checkpoint inhibitor clinically meaningful survival benefit improved safety profile regardless of PD-L1 expression level Further research is needed to identify relevant biomarkers that have sufficient sensitivity and specificity to predict which patients are most likely to benefit