Nivolumab combined with high dose multisite radiotherapy in previously untreated advanced melanoma (NIRVANA): A non-randomised, open-label, multicenter, phase 2 trial.

Abstract

e21505 Background: Outcome of advanced melanoma remains poor for the majority of patients (pts) and new treatment strategies are needed. Preclinical and clinical data suggest a potential increase of the immunotherapy efficacy when combined with hypofractionated multisite radiotherapy (HMR). Objective: To assess the impact of HMR combined with nivolumab in advanced melanoma. Methods: This is a non-randomised, open-label, multicentre phase 2 trial(NCT02799901). Pts must have locally advanced or metastatic melanoma (AJCC7), previously untreated. Pts with mucosal or uveal melanoma, those with brain metastasis and LDH ≥ 1.5 the upper limit were not included. Pts received (until progression or unacceptable toxicity) nivolumab (fixed dose 240 mg/15 days) plus radiotherapy (day 15) delivered 3 x 6 Gy every second day, at every metastatic organ, if feasible.At progression, second irradiation was authorized while pursuing nivolumab (rechallenging strategy).The primary endpoint was 1-year overall survival (OS) (hypothetic improvement of 1-year OS from 71%1). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Subgroups and multivariate analyses were performed. Results: A total of 64 pts were included, from 03/2017 to 07/2019. Median follow-up was 23.5 months [IQR 2.3-43.8]. Median age was 64 years [35-95], majority of pts were male (67%), had an ECOG-PS 0 (75%), a stage IV-M1C disease (47%) and were BRAF-wild-type (67%).] The 1-year OS and PFS rates were 79% and 56% respectively (p = 0.12 and p = 0.0.3 in comparison with the 1-year OS and PFS of 71% and 43% of Robert et al’study1). 39 pts were irradiated at 1 target, 25 at ≥2 targets (total of 92 tumor targets). The 2-years OS rates were 83% and 52% for pts who were irradiated on several sites and one site respectively (p = 0.03). The ORR in the whole cohort was 53% [95% CI, 40.23; 65.72], 33% [95% CI, 14.59; 56 .97] and 62% [95% CI, 45.64; 76.43] in BRAF mutated and BRAF-wild type respectively. Among BRAF status, gender, PS, stage, age, LDH level and number of irradiated sites (1 vs ≥ 1), the independent prognostic factors for OS in multivariate analysis were number of irradiated sites (HR = 0.26, p = 0.03) and ECOG-PS (HR = 6.2, p = 0.001). Rechallenging was performed in 11 pts, among them; 3 were progression-free at last follow-up, 10 were reirradiated once and 1 was reirradiated 3 times. ICI was stopped due to toxicities for 6 pts. Drug-related adverse events of grade 3-4 occurred in 8.3% of the patients (no grade 5). Conclusions: Combined nivolumab and HMR did not improve significantly OS compare to nivolumab alone but improve significantly PFS1. However, this strategy has an acceptable safety and could be a treatment option for some patients. Multisite irradation and rechallenging strategies deserve to be considered. 1 Robert et al, J Clin Oncol 2020. Clinical trial information: NCT02799901 .