Ipilimumab plus nivolumab versus nivolumab alone in patients with melanoma brain metastases (ABC): 7-year follow-up of a multicentre, open-label, randomised, phase 2 study

Abstract

Background

Patients with melanoma brain metastases respond well to immunotherapy, but long-term comparative survival data are scarce. We aimed to assess the efficacy of ipilimumab plus nivolumab versus nivolumab alone in patients with melanoma brain metastases at 7 years.

Methods

This open-label, randomised, phase 2 study was conducted at four sites (two research institute cancer centres and two university teaching hospitals) in Australia. Patients aged 18 years or older with active, immunotherapy-naive melanoma brain metastases and Eastern Cooperative Oncology Group performance status of 0–2 were eligible. Asymptomatic patients with no previous brain-directed therapy were randomly assigned (5:4) using the biased-coin minimisation method (after a safety run-in of six patients) to cohort A (intravenous ipilimumab 3 mg/kg plus nivolumab 1 mg/kg every 3 weeks for four doses, then nivolumab 3 mg/kg every 2 weeks) or cohort B (intravenous nivolumab 3 mg/kg every 2 weeks). Patients with previous brain-directed therapy, neurological symptoms, or leptomeningeal disease were assigned to cohort C (non-randomised; intravenous nivolumab 3 mg/kg every 2 weeks). The primary endpoint was best intracranial response (complete or partial response) from week 12. Secondary survival endpoints included intracranial progression-free survival and overall survival. Safety was assessed from the first dose of treatment to at least 100 days after treatment discontinuation. Analyses were performed in patients who received at least one dose of study drug. The main analysis has been reported, and this is a long-term follow up of the ABC trial. This trial is registered with ClinicalTrials.gov, NCT02374242, and is ongoing.

Findings

Between Nov 4, 2014, and April 21, 2017, 89 patients were assessed for eligibility, 79 of whom were enrolled and assigned to cohort A (n=36), cohort B (n=27), or cohort C (n=16). Three patients (one in cohort A and two in cohort B) were excluded due to ineligibility. 17 (22%) of 76 patients were female and 59 (78%) were male. At data cutoff (March 26, 2024), the median follow-up was 7·6 years (IQR 6·9–8·2). Overall intracranial responses occurred in 18 (51% [95% CI 34–69]) patients from cohort A, five (20% [7–41]) from cohort B, and one (6% [0–30]) from cohort C. 7-year intracranial progression-free survival was 42% (95% CI 29–63) in cohort A, 15% (6–39) in cohort B, and 6% (1–42) in cohort C. 7-year overall survival was 48% (34–68) in cohort A, 26% (13–51) in cohort B, and 13% (3–46) in cohort C. Safety results were consistent with the primary analysis. 50 patients died, including 18 (51%) from cohort A, 18 (72%) from cohort B, and 14 (88%) from cohort C.

Interpretation

Our findings suggest that ipilimumab plus nivolumab maintains efficacy to at least 7 years in patients with active asymptomatic brain metastasis. Upfront ipilimumab plus nivolumab should be the standard of care for patients with melanoma brain metastasis; a trial investigating the role of stereotactic surgery in this new paradigm is ongoing.

Funding

Melanoma Institute Australia and Bristol Myers Squibb.