A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC).

Abstract

9508 Background: Nivolumab (nivo) and the combination of nivo + ipilimumab (ipi) improve response rates (RR) and progression-free survival (PFS) compared with ipi alone in clinical trials of metastatic melanoma pts, but pts with untreated brain mets were excluded. Brain mets are a major cause of morbidity and mortality in melanoma and their management is critical. We sought to determine the antitumour activity and safety of nivo and nivo+ipi in pts with active melanoma brain mets (NCT02374242). Methods: This open-label, ph II trial enrolled 3 cohorts of pts naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014 - Feb 2017. Pts with asymptomatic melanoma brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3W x4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets 1) that failed local therapy (new +/- progressed in previously treated met), 2) were neurologically symptomatic and/or 3) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥ wk12. Secondary endpoints were best extracranial response (ECR), best overall response (OR), IC PFS, EC PFS, overall PFS, OS, and safety. Results: A total of 66 pts (med f/u 14 mo) were included in this analysis of total 76 planned; median age 60y, 77% male. For cohorts A, B and C: elevated LDH 48%, 58% and 19%; V600BRAF 44%, 56% and 81%; prior BRAFi 24%, 24%, 75%. Table shows RR, PFS and OS. ICR in cohort A treatment naïve vs prior BRAFi was 53% vs 16%. Treatment-related gd 3/4 toxicity in cohorts A, B and C were 68%, 40% and 56%, respectively. There were no treatment-related deaths. Conclusions:Nivo monotherapy and ipi+nivo and are active in melanoma brain mets. Ipi+nivo had reduced activity in pts who progressed on BRAFi. Pts with symptomatic brain mets, leptomeningeal mets or previous local therapy responded poorly to nivo alone. Clinical trial information: NCT02374242. [Table: see text]

Anti–PD-1/anti–CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+T cell trafficking

“…1C). Thus, the outcome of anti-PD-1/anti-CTLA-4 combination therapy was superior to the two monotherapies, which is in line with the reported intracranial response rate for anti-PD-1 monotherapy (21-25%) (12)(13)(14)(15) and anti-PD-1/anti-CTLA-4 combination therapy (50-55%) (15,16), as well as the 6 month progression-free survival rate of 28% and 46%, respectively (15). Due to these promising data, we focused on the anti-PD-1/anti-CTLA-4 combination therapy.…”

“…A handful of retrospective and prospective clinical studies indicated activity of ipilimumab in melanoma BrM with 16-25% intracranial response rate, but also suggested that only a subgroup of patients is likely to benefit (4,5,11). Pembrolizumab and nivolumab also showed efficacy in melanoma BrM with an ~21% response rate in the brain (12)(13)(14)(15). A very recent interim analyses from two clinical trials in drug-treatment naïve patients with melanoma BrM (ABC trial (15) and CheckMate 204 trial (16)) reported a 50% and 55%…”

“…Pembrolizumab and nivolumab also showed efficacy in melanoma BrM with an ~21% response rate in the brain (12)(13)(14)(15). A very recent interim analyses from two clinical trials in drug-treatment naïve patients with melanoma BrM (ABC trial (15) and CheckMate 204 trial (16)) reported a 50% and 55%…”

Focal radiation necrosis of the brain in patients with melanoma brain metastases treated with pembrolizumab

“…Another nonrandomized clinical trial showed similar results with the combination of nivolumab and ipilimumab in patients with asymptomatic previously treated MBM, that is, an intracranial response of 55% (PFS not reached). These results show that the combination treatment has high activity in asymptomatic patients with MBM …”

Leptomeningeal melanoma—A case series in the era of modern systemic therapy

“…Landmark trials of BRAF inhibitors (BRAFi) and anti-PD-1 checkpoint inhibitor immunotherapy have shown high response rates and prolonged survival in patients with melanoma, but have tended to exclude patients with central nervous system metastasis, particularly those with leptomeningeal metastases (Larkin, Hodi, & Wolchok, 2015;Long et al, 2014;Robert et al, 2015). Subsequent trials in those with parenchymal brain metastases have shown these agents have similar and often concordant responses to extracranial metastasis, but the activity in those with leptomeningeal metastases has not been adequately addressed in any prospective trial (Goldberg et al, 2016;Long et al, 2012Long et al, , 2017Tawbi et al, 2017).…”