Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study

Summary

Background

Nivolumab monotherapy and combination nivolumab plus ipilimumab increase proportions of patients achieving a response and survival versus ipilimumab in patients with metastatic melanoma; however, efficacy in active brain metastases is unknown. We aimed to establish the efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with active melanoma brain metastases.

Methods

This multicentre open-label randomised phase 2 trial was done at four sites in Australia, in three cohorts of immunotherapy-naive patients aged 18 years or older with melanoma brain metastases. Patients with asymptomatic brain metastases with no previous local brain therapy were randomly assigned using the biased coin minimisation method, stratified by site, in a 30:24 ratio (after a safety run-in of six patients) to cohort A (nivolumab plus ipilimumab) or cohort B (nivolumab). Patients with brain metastases in whom local therapy had failed, or who had neurological symptoms, or leptomeningeal disease were enrolled in non-randomised cohort C (nivolumab). Patients in cohort A received intravenous nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg every 3 weeks for four doses, then nivolumab 3 mg/kg every 2 weeks; patients in cohort B or cohort C received intravenous nivolumab 3 mg/kg every 2 weeks. The primary endpoint was intracranial response from week 12. Primary and safety analyses were done on an intention-to-treat basis in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02374242, and is ongoing for the final survival analysis.

Findings

Between Nov 4, 2014, and April 21, 2017, 79 patients were enrolled; 36 in cohort A, 27 in cohort B, and 16 in cohort C. One patient in cohort A and two in cohort B were found to be ineligible and excluded from the study before receiving the study drug. At the data cutoff (Aug 28, 2017), with a median follow up of 17 months (IQR 8–25), intracranial responses were achieved by 16 (46%; 95% CI 29–63) of 35 patients in cohort A, five (20%; 7–41) of 25 in cohort B, and one (6%; 0–30) of 16 in cohort C. Intracranial complete responses occurred in six (17%) patients in cohort A, three (12%) in cohort B, and none in cohort C. Treatment-related adverse events occurred in 34 (97%) of 35 patients in cohort A, 17 (68%) of 25 in cohort B, and eight (50%) of 16 in cohort C. Grade 3 or 4 treatment-related adverse events occurred in 19 (54%) patients in cohort A, four (16%) in cohort B, and two (13%) in cohort C. No treatment-related deaths occurred.

Interpretation

Nivolumab combined with ipilimumab and nivolumab monotherapy are active in melanoma brain metastases. A high proportion of patients achieved an intracranial response with the combination. Thus, nivolumab combined with ipilimumab should be considered as a first-line therapy for patients with asymptomatic untreated brain metastases.

Funding

Melanoma Institute Australia and Bristol-Myers Squibb.

Introduction

Brain metastasis affects 25% of patients at diagnosis of advanced melanoma and has a poor prognosis, with a median survival time of about 4 months.1, 2 Immunotherapy with PD-1 or anti-CTLA4 checkpoint inhibitors, or both, and BRAF-directed targeted therapy have significantly improved the overall survival of patients with advanced melanoma compared with standard therapy.3, 4, 5, 6, 7 However, patients with active brain metastases are largely excluded from clinical trials of these drug therapies because of their poor prognosis, and the activity of immunotherapy in this population is unknown.

Large phase 2 clinical trials of BRAF-directed targeted therapies have shown significant activity in untreated (no previous local brain therapy or drug therapy) melanoma brain metastases with 39% of patients achieving a response with BRAF inhibitors alone and 58% with combined BRAF and MEK inhibitors; however, the responses are short lived.8, 9, 10 A small study of 18 patients with active brain metastases treated with pembrolizumab showed a response in 22% of patients.¹¹ Stereotactic radiosurgery and surgery are highly effective for treated metastases, but have no proven effect on the risk of developing further melanoma brain metastases, and thus have little effect on survival, except in patients with isolated monometastatic or oligometastatic brain disease.

Research in context

Evidence before this study

We searched PubMed up to Dec 8, 2017, for clinical trials using the search terms “brain metastases” and “melanoma” and “drug therapy”, and excluding “radiotherapy” and “radiation”, and identified 103 published articles. Only six were reports of phase 1 or 2 clinical trials of drug therapies (excluding chemotherapies) in patients with active brain metastases, and no phase 3 trials in this population were identified. Four trials tested BRAF inhibitor-based therapies in patients with active brain metastases, and the highest proportion of patients achieving a response and longest progression-free survival was observed for the combination of dabrafenib and trametinib, with 58% of patients achieving an intracranial response and 6-month landmark progression-free survival of 44% in asymptomatic, previously untreated (no local brain-directed therapy) patients with BRAF^V600E (ie, Val600Glu) mutation-positive melanoma. Two studies tested ipilimumab or pembrolizumab monotherapy in patients with active brain metastases, showing an intracranial response in eight (16%) of 51 and four (22%) of 18 people, respectively. A single-arm trial of ipilimumab combined with nivolumab in patients with active melanoma brain metastases has been reported at the 2017 American Society for Clinical Oncology Annual Meeting (Chicago, USA), showing an intracranial response in 55% of patients and 6-month progression-free survival in 67% of patients.

Added value of this study

Our study randomly assigned patients with untreated (no local brain-directed therapy) brain metastases to nivolumab monotherapy or combination nivolumab and ipilimumab, and had the largest single cohort of patients ever treated with anti-PD-1 monotherapy (nivolumab). Furthermore, the study included patients previously treated with BRAF and MEK inhibitors.

Implications of all the available evidence

Our results suggest that patients with asymptomatic, untreated (no local brain-directed therapy) brain metastases have a high chance of long-term durable intracranial response when treated with the combination of ipilimumab and nivolumab upfront—higher than reported with BRAF and MEK inhibitors. Additionally, fewer patients have durable responses when treated with first-line anti-PD-1 monotherapy or when previously treated with combined BRAF and MEK inhibitor therapy. Our results suggest that combination therapy with ipilimumab and nivolumab should be considered as first-line therapy in patients with asymptomatic melanoma brain metastases, and induces durable responses in at least 50% of patients. Patients with brain metastases should be included in ongoing clinical trials of novel drug therapies.

We sought to establish the antitumour activity and safety of nivolumab monotherapy and nivolumab combined with ipilimumab in patients with active melanoma brain metastases. We did a phase 2 randomised trial, which included two randomised cohorts of asymptomatic untreated (no previous local brain-directed therapy) patients, as well as a single non-randomised cohort of patients with poor prognostic features, including leptomeningeal disease, neurological symptoms, or disease progression after local brain-directed therapy.