A Comparison of Alternative Network Meta-Analysis Methods in the Presence of Nonproportional Hazards: A Case Study in First-Line Advanced or Metastatic Renal Cell Carcinoma.

OBJECTIVES: Network meta-analysis (NMA) of time-to-event outcomes based on constant hazard ratios can result in biased findings when the proportional hazards (PHs) assumption does not hold in a subset of trials. We aimed to summarize the published non-PH NMA methods for time-to-event outcomes, demonstrate their application, and compare their results. METHODS: The following non-PH NMA methods were compared through an illustrative case study in oncology of 4 randomized controlled trials in terms of progression-free survival and overall survival: (1) 1-step or (2) 2-step multivariate NMAs based on traditional survival distributions or fractional polynomials, (3) NMAs with restricted cubic splines for baseline hazard, and (4) restricted mean survival NMA. RESULTS: For progression-free survival, the PH assumption did not hold across trials and non-PH NMA methods better reflected the relative treatment effects over time. The most flexible models (fractional polynomials and restricted cubic splines) fit better to the data than the other approaches. Estimated hazard ratios obtained with different non-PH NMA methods were similar at 5 years of follow-up but differed thereafter in the extrapolations. Although there was no strong evidence of PH violation for overall survival, non-PH NMA methods captured this uncertainty in the relative treatment effects over time. CONCLUSIONS: When the PH assumption is questionable in a subset of the randomized controlled trials, we recommend assessing alternative non-PH NMA methods to estimate relative treatment effects for time-to-event outcomes. We propose a transparent and explicit stepwise model selection process considering model fit, external constraints, and clinical validity. Given inherent uncertainty, sensitivity analyses are suggested.

Indirect treatment comparison of nivolumab versus placebo as adjuvant treatment for resected melanoma.

BACKGROUND: Nivolumab (an anti-programmed death-1 antibody) is an adjuvant standard of care for patients with high-risk resected melanoma, although a watch-and-wait strategy remains an option. In the absence of head-to-head evidence, an indirect treatment comparison (ITC) of adjuvant nivolumab versus placebo, the proxy for a watch-and-wait strategy, was conducted in patients with high-risk resected melanoma. METHODS: An ITC using the Bucher method compared nivolumab with placebo using intention-to-treat population data from the phase III CheckMate 238 (nivolumab vs ipilimumab; minimum follow-up, 4 years; NCT02388906) and European Organisation for Research and Treatment of Cancer (EORTC) 18071 (ipilimumab vs placebo; minimum follow-up, ≈4.5 years; NCT00636168) trials. The end-points were recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and overall survival (OS). To account for cross-trial differences in staging and subsequent therapy, additional analyses examined patients with stage IIIB/IIIC disease and adjusted post-recurrence survival in EORTC 18071, respectively. RESULTS: Nivolumab versus placebo was associated with clinically meaningful improvements in RFS (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.42-0.68) and OS (HR, 0.63; 95% CI, 0.45-0.89). Nivolumab versus placebo was also associated with clinically meaningful improvements in RFS (HR, 0.53; 95% CI, 0.40-0.69), DMFS (HR, 0.62; 95% CI, 0.46-0.83) and OS (HR, 0.67; 95% CI, 0.47-0.97) in patients with stage IIIB/IIIC disease and in OS (HR, 0.65; 95% CI, 0.46-0.92) in the overall population after adjusting post-recurrence survival in EORTC 18071. CONCLUSION: This ITC shows that adjuvant nivolumab provides clinically meaningful improvements in RFS, DMFS and OS versus a watch-and-wait strategy in high-risk resected melanoma.

Indirect treatment comparison of nivolumab versus placebo for the adjuvant treatment of melanoma.

INTRODUCTION: Until recently, adjuvant treatment options for stage III and IV resectable melanoma have been limited. Patients were often managed through routine surveillance. The phase III randomised controlled trial (RCT) CheckMate 238 (238) demonstrated the safety and efficacy of nivolumab as an adjuvant treatment for melanoma in patients with stage IIIB/C or IV disease (American Joint Committee on Cancer [AJCC], 7th edition) versus ipilimumab. The study objective was to estimate the relative efficacy, safety and health-related quality of life (HRQoL) between nivolumab and routine surveillance. METHODS: Indirect treatment comparisons (ITCs) of nivolumab versus placebo were constructed using data from 238 and EORTC 18071. EORTC 18071 is a phase III RCT comparing ipilimumab with placebo in patients with resected stage IIIA-IIIC melanoma (AJCC, 6th edition). ITCs were performed using the Bucher comparison method and patient-level data for efficacy, safety and HRQoL. RESULTS: For the efficacy outcomes, nivolumab performed significantly better than placebo for recurrence-free survival (hazard ratio [HR]: 0.53 [95% confidence interval {CI}: 0.41, 0.68]) and distant metastases-free survival (HR: 0.59 [95% CI: 0.44, 0.78]). Safety ITCs indicated that patients receiving nivolumab had a greater hazard of experiencing an adverse event (AE) and AEs leading to treatment discontinuation, whereas there was a non-significant increased hazard of experiencing a serious AE. HRQoL ITCs showed comparable time to deterioration in 14 of the 15 QLQ-C30 domains; only the dyspnoea domain significantly favoured placebo. CONCLUSION: Nivolumab was associated with significantly improved efficacy outcomes versus placebo, whereas maintaining patient's overall HRQoL. Across the different analysis and populations, there was a high level of consistency in the effect size.