Efficacy of ipilimumab plus nivolumab or ipilimumab plus fotemustine vs fotemustine in patients with melanoma metastatic to the brain: Primary analysis of the phase III NIBIT-M2 trial

Background Brain metastases (BM) represent a high-unmet medical need, in which the therapeutic potential of immune-checkpoint(s) (ICI) is being actively investigated. Temozolomide and fotemustine (FTM) have been the therapeutic mainstay of melanoma (MM) patients (pts) with BM for over two decades. The Italian Network for Tumor Biotherapy (NIBIT)-M1 trial firstly demostrated signs of activity of ipilimumab (Ipi) combined with FTM in a subset of 20 MM pts with active BM (Di Giacomo, Lancet Oncol, 2012), with a 3-year survival rate of 28% (Di Giacomo, Annals Oncol, 2015). Two subsequent phase II studies reported the efficacy of Ipi combined with nivolumab (Nivo) in MM pts with asymptomatic BM (Twabi, NEJM 2018; Long, Lancet Oncol 2018). We here report the results of the primary analysis of the NIBIT-M2 study, the first phase III trial that explored the efficacy of Ipi plus Nivo in MM pts with BM. Methods The NIBIT-M2 is a phase III, multicenter, open-label study in MM pts with active, untreated, and asymptomatic BM. BRAF wilde type or mutant pts were randomized to receive FTM (ARM A), the combination of Ipi and FTM (ARM B), or the combination of Ipi and Nivo (ARM C). Primary objective was overall survival (OS); among secondary were intracranial (i) objective response rate (iORR), i disease control rate (iDCR), and progression free survival (PFS). Results From January 2013 to September 2018, 96 MM pts were enrolled, 80 randomized, and 76 were treated: 23 in ARM A, 26 in ARM B, and 27 in ARM C. With a median follow-up of 39 months (mo), median OS was 8.5 mo (CI, 95%: 4.8-12.2) for ARM A, 8.2 mo (CI, 95%: 2.0-14.3) for ARM B, and 29.2 mo (CI, 95%: not yet evaluable) for ARM C. The iORR was 0%, 19.2% and 44.4% in ARM A, B, and C, respectively. The iDCR was 26.1%, 34.6% and 55.6% in ARM A, B, and C, respectively. Median PFS was 3.0 mo (CI, 95%: 2.3-3.6), 3.3 mo (CI, 95%: 1.2-5.4), and 8.4 mo (CI,95%: 4.2-12.7), in ARM A, B, and C, respectively. Conclusions Unlike Ipi plus FTM, Ipi plus Nivo significantly (p=0.009) improves the long-term survival of MM pts with BM, compared to FTM. Ipi plus Nivo should represent the treatment of choice in first line MM pts with BM.