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Supplemental material, sj-docx-1-mpp-10.1177_23814683221089659 for Heterogeneity in Survival with Immune Checkpoint Inhibitors and Its Implications for Survival Extrapolations: A Case Study in Advanced Melanoma by Victoria Federico Paly, Murat Kurt, Lirong Zhang, Marcus O. Butler, Olivier Michielin, Adenike Amadi, Emma Hernlund, Helen M. Johnson, Srividya Kotapati, Andriy Moshyk and John Borrill in MDM Policy & Practice

Additional file 3: Appendix C. Results of the stage III/IV subgroup analyses. Table C.1. Stage III/IV population – constant hazard ratios estimated from fixed-effects network meta-analysis for recurrence-free/disease-free survival. Table C.2. Stage III/IV population – constant hazard ratios estimated from fixed-effects network meta-analysis for distant metastasis-free survival

Additional file 1: Appendix A. Systematic literature review details and results. Figure A.1. Study selection flow diagram of updated SLR (May 2019). Table A.1. Study selection criteria to identify trials for the systematic literature review. Table A.2. Search strategy for EMBASE (EMBASE 1974 to October 11, 2017; Search executed: October 12, 2017). Table A.3. Search strategy for MEDLINE (Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present; Search executed: October 12, 2017). Table A.4. Search strategy for Cochrane Register of Controlled Trials (Cochrane Register of Controlled Trials September 2017; Search executed: October 12, 2017). Table A.5. Search strategy for EMBASE (EMBASE 1974 to 2018 May 07; Search executed: May 8, 2018). Table A.6. Search strategy for MEDLINE (Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present; Search executed: May 8, 2018). Table A.7. Search strategy for Cochrane Register of Controlled Trials (Cochrane Register of Controlled Trials March 2018; Search executed: May 8, 2018). Table A.8. Search strategy for EMBASE (EMBASE 1974 to 2019 April 30; Search executed: May 1, 2019). Table A.9. Search strategy for MEDLINE (Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present; Search executed: May 1, 2019). Table A.10. Search strategy for Cochrane Register of Controlled Trials (Cochrane Register of Controlled Trials April 2019; Search executed: May 1, 2019). Table A.11. Patient characteristics in randomized controlled trials included in network meta-analyses. Table A.12. Cochrane risk of bias assessment of randomized controlled trials included in the feasibility assessment. Table A.13. Safety data from randomized controlled trials included in the feasibility assessment

Additional file 4: Appendix D. Safety analyses. Figure D.1. Network diagrams of randomized controlled trials for subgroup. Table D.1. Stage II/III/IV population – odds ratios estimated from fixed-effects network meta-analysis for grade 3/4 adverse events analysis of safety outcomes. Table D.2. Stage II/III/IV population – odds ratios estimated from fixed-effects network meta-analysis for discontinuations due to adverse events. Table D.3. Stage II/III/IV population – odds ratios estimated from fixed-effects network meta-analysis for discontinuations

Background We have previously performed indirect treatment comparisons (ITCs) to demonstrate improvements in recurrence-free survival (RFS) and distant metastasis-free survival with nivolumab versus placebo as adjuvant treatment for resected melanoma; however, overall survival (OS) data were not available at the time. Recently, results of the phase 3 CheckMate 238 trial in patients with resected stage IIIB–IIIC/IV melanoma (American Joint Committee on Cancer [AJCC], 7th edition) showed no statistically significant difference in OS between nivolumab and ipilimumab; however, OS events were fewer than expected. In the phase 3 EORTC 18071 trial in patients with resected stage IIIA–IIIC melanoma (AJCC, 6th edition), OS was improved with ipilimumab versus placebo. Here, we provide an update on RFS and an analysis of OS in ITCs of nivolumab and placebo using data from these 2 trials with a common comparator arm: ipilimumab 10 mg/kg. Methods ITCs of nivolumab versus placebo were conducted using 4-year minimum follow-up data from CheckMate 238 (NCT02388906) and 5.3-year median follow-up data from EORTC 18071 (NCT00636168). Bucher ITCs were performed to estimate RFS and OS in the intention-to-treat populations. A sensitivity analysis of OS adjusting for subsequent therapy options was conducted in 2 steps: (1) after controlling for possible confounders and assuming that the only difference was the effect of different subsequent therapies, postrecurrence survival was compared between the 2 ipilimumab arms in each study, and (2) after adjusting for differences in postrecurrence survival, ITCs of nivolumab versus adjusted placebo were performed. Results In these ITC analyses, RFS and OS results with nivolumab suggested an improvement compared with placebo. In the intention-to-treat population, nivolumab was associated with a lower risk of recurrence or death (RFS HR, 0.55; 95% CI, 0.43–0.70) and a lower risk of death (OS HR, 0.62; 95% CI, 0.44–0.88) than placebo. In the sensitivity analysis, a 63% average increase in postrecurrence survival benefit was estimated with ipilimumab in CheckMate 238 compared with ipilimumab in EORTC 18071. After adjusting for this increase in both the ipilimumab and placebo arms in EORTC 18071, nivolumab was associated with a lower risk of death than placebo (OS HR, 0.65; 95% CI, 0.45–0.91), similar to the unadjusted analysis. Conclusions Despite the changing treatment landscape and the increased number of therapeutic options for metastatic melanoma, these ITCs suggested clinically meaningful improvement in RFS and OS with adjuvant nivolumab compared with a wait-and-watch strategy in high-risk patients with resected melanoma. Acknowledgements Writing and editorial assistance were provided by Kakoli Parai, PhD, and Andrea Lockett of Ashfield Healthcare Communications, funded by Bristol-Myers Squibb Company. kein CA

Additional file 1. Basis for inclusion of drug and non-drug resources in the cost comparison analysis.