3556 - Long-term efficacy of combination nivolumab and ipilimumab for first-line treatment of advanced melanoma: a network meta-analysis

Background

Targeted and checkpoint inhibitor therapies for advanced melanoma have led to major improvements in overall survival (OS). Using long-term evidence, the objective was to estimate the relative efficacy of nivolumab plus ipilimumab (NIVO+IPI) vs. relevant comparators among treatment-naïve patients with advanced, unresectable stage III/IV melanoma.

Methods

A systematic literature review of randomized controlled trials (RCTs) of first-line advanced melanoma therapies was conducted in November 2018. Key comparators were immunotherapies (NIVO+IPI; NIVO; pembrolizumab [PEM]), and BRAF+MEK inhibitors (dabrafenib + trametinib [DAB+TRAM]; encorafenib + binimetinib [ENC+BIN]; vemurafenib + cobimetinib [VEM+COB]). Bayesian network meta-analysis (NMA) models were used to estimate comparative OS. The NMAs used models of constant (overall) hazard ratio (HR) over time, and fractional polynomials to estimate time-varying HR, along with 95% credible intervals (CrI). Subgroup analyses and alternate models were explored to evaluate effect modification of immunotherapies by BRAF-mutation status.

Results

In total, 12 RCTs formed the network of evidence for OS (maximum follow-up: 30 to 60 months). For NIVO+IPI vs. each BRAF+MEK inhibitor, the HR decreased steadily over time. The hazard of death was similar by 6 months and lower at 12 months; thereafter, NIVO+IPI was associated with a significantly reduced hazard of death. At 18 months, HRs for NIVO+IPI vs. each BRAF+MEK inhibitor ranged from 0.45 to 0.52; by 42 months (longest duration of observed data for BRAF+MEK inhibitors), HRs were 0.24 to 0.29 (all CrIs < 1). The HR of NIVO+IPI relative to other immunotherapies was less varied over time, yet showed similar or significantly improved OS from 6 months onward. Over the follow-up period, overall HRs (95% CrI) for NIVO+IPI were: 0.73 (0.49, 1.10) vs. DAB+TRAM, 0.81 (0.52, 1.26) vs. ENC+BIN, 0.70 (0.45, 1.09) vs. VEM+COB, 0.83 (0.60, 1.13) vs. PEM, and 0.86 (0.70, 1.05) vs. NIVO. Subgroup analyses and alternate model estimates were broadly consistent with the main findings.

Conclusions

NIVO+IPI confers similar or sustained improvements in long-term OS compared with immunotherapies and BRAF+MEK inhibitors.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Bristol-Myers Squibb.

Disclosure

P. Mohr: Honoraria (self), To manually add email to ESMO: To manually add email to ESMO. K. Toor: Full / Part-time employment, KT is an employee of Precision Xtract. Precision Xtract received funding for this project from Bristol-Myers Squibb: Precision Xtract. S. Goring: Advisory / Consultancy, SG acted as a consultant to Precision Xtract. Precision Xtract received funding for this project from Bristol-Myers Squibb: Precision Xtract. K. Chan: Full / Part-time employment, KC is an employee of Precision Xtract. Precision Xtract received funding for this project from Bristol-Myers Squibb: Precision Xtract. M. Besada: Full / Part-time employment, MB is an employee of Precision Xtract. Precision Xtract received funding for this project from Bristol-Myers Squibb: Precision Xtract. H.M. Johnson: Advisory / Consultancy: Bristol-Myers Squibb. A. Moshyk: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. S. Kotapati: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb.