Modelling Survival of Patients Treated with Adjuvant Nivolumab Who Have Melanoma with Lymph Node Involvement or Metastatic Disease After Complete Resection

Abstract

Introduction Nivolumab demonstrated significant recurrence-free survival (RFS) gains versus ipilimumab in the Check-Mate-238 trial, whereas the CA184-029 trial showed superior RFS gains for ipilimumab versus placebo. No head-to-head trial data were available to compare the efficacy of nivolumab to that of observation, so indirect treatment comparisons were required. Additionally, overall survival (OS) data were not available from CheckMate-238, and the clinical pathway for melanoma has changed significantly over the last decade. Four modelling options were developed using different methods and evidence sources to estimate OS and the impact of nivolumab on predicted life-years in the adjuvant setting; however, this article focuses on two primary methods. Methods RFS for nivolumab and observation were informed by a patient-level data meta-regression. The first model was a partitioned survival model, where the parametric OS curve for observation was derived from CA184-029 and nivolumab OS was based on a surrogacy relationship between RFS and OS specific to adjuvant melanoma. The other option used a state-transition model to estimate post-recurrence survival using different data sources. Results The modelling options estimated different OS for both nivolumab and observation but demonstrated at least a 32% increase in life-years gained for nivolumab versus observation. Conclusion This analysis demonstrated the difficulties in modelling within the adjuvant setting. Each model produced different survival projections, showing the need to explore different techniques to address the extent of uncertainty. This also highlighted the importance of understanding the impact of RFS in the long term in a setting where the aim of treatment is to remain disease free.

Predicting Survival for Chimeric Antigen Receptor T-Cell Therapy: A Validation of Survival Models Using Follow-Up Data From ZUMA-1

“…Nevertheless, other approaches may also be helpful to consider within the context of informing HTA. For example, Batteson et al 27 considered a range of approaches to both directly and indirectly estimate OS for patients with melanoma treated with adjuvant nivolumab. Repeating the analyses described in our study and those conducted by others for different patient populations would further increase the understanding of the most appropriate methods to produce suitable survival estimates for HTA.…”

Adjuvant treatment of high-risk melanoma – cost-effectiveness analysis of treatment options for BRAF 600 mutated tumors

“…For nivolumab, due to immature data, no survival curves for overall survival were not available until late 2020. Different approaches to construct surrogates for the missing survival curve were presented [71,72], which usually project results from study CA184-029 (ipilimumab vs. placebo) [21] to the relationship ipilimumab vs. nivolumab, which was investigated in study Checkmate-238 [33]. Batteson et.al [71].…”

“…Different approaches to construct surrogates for the missing survival curve were presented [71,72], which usually project results from study CA184-029 (ipilimumab vs. placebo) [21] to the relationship ipilimumab vs. nivolumab, which was investigated in study Checkmate-238 [33]. Batteson et.al [71]. presented an alternative surrogate based on systematic research of available literature.…”

“…The model presented here consists of a mixture of a Partitioned SA approach, which takes into account the survival curves obtained in the Combi-AD trial, with a Markov state transition model reflecting the proportions of patients in the progression stages. Advantages and disadvantages of the two methods are discussed in the literature [71,78]. The use of Partitioned SA as an outer model has the advantage that the empirically determined survival curves of the first 60 months are not distorted by further model assumptions.…”

Clinical Significance of Distant Metastasis-Free Survival (DMFS) in Melanoma: A Narrative Review from Adjuvant Clinical Trials

“…CheckMate 238 obtained lower HR (0.73; 95% CI 0.55–0.95); however, it was developed with two treatment arms (nivolumab and ipilimumab) without an observation arm as in the previous study. A recent paper analyzed the potential values of HR in CheckMate 238, considering whether this study would have been conducted with a comparator observation: it showed that nivolumab would have a significant RFS benefit over observation, with an HR value of 0.54 (95% CI 0.41–0.69), similar to those of COMBI-AD and KEYNOTE-054 [ 57 ].…”