Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain

Abstract

Background: Brain metastases are a common cause of disabling neurologic complications and death in patients with metastatic melanoma. Previous studies of nivolumab combined with ipilimumab in metastatic melanoma have excluded patients with untreated brain metastases. We evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with melanoma who had untreated brain metastases.

Methods: In this open-label, multicenter, phase 2 study, patients with metastatic melanoma and at least one measurable, nonirradiated brain metastasis (tumor diameter, 0.5 to 3 cm) and no neurologic symptoms received nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for up to four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks until progression or unacceptable toxic effects. The primary end point was the rate of intracranial clinical benefit, defined as the percentage of patients who had stable disease for at least 6 months, complete response, or partial response.

Results: Among 94 patients with a median follow-up of 14.0 months, the rate of intracranial clinical benefit was 57% (95% confidence interval [CI], 47 to 68); the rate of complete response was 26%, the rate of partial response was 30%, and the rate of stable disease for at least 6 months was 2%. The rate of extracranial clinical benefit was 56% (95% CI, 46 to 67). Treatment-related grade 3 or 4 adverse events were reported in 55% of patients, including events involving the central nervous system in 7%. One patient died from immune-related myocarditis. The safety profile of the regimen was similar to that reported in patients with melanoma who do not have brain metastases.

Conclusions: Nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases. (Funded by Bristol-Myers Squibb and the National Cancer Institute; CheckMate 204 ClinicalTrials.gov number, NCT02320058 .).

Figure 1.. Time to and Duration of Intracranial Response.

The plot shows the onset and durability of intracranial objective responses to the combination of nivolumab and ipilimumab, according to modified Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, criteria. Open circles indicate the first evidence of objective response (complete or partial response), and arrows indicate an ongoing response; 47 of 52 responses (90%) were ongoing at the time of the analysis. The dashed line indicates 1 year after treatment initiation. The median time to response was 2.3 months (range, 1.1 to 10.8). The median duration of intracranial response has not been reached.

Figure 2.. Kaplan–Meier Estimates of Survival.

Panel A shows the Kaplan–Meier estimates of progression-free survival as assessed by the investigators. Patients were followed for a minimum of 6 months. The median progression-free survival has not been reached for intracranial, extracranial, or global disease. For intracranial, extracranial, and global disease, respectively, the rates of progression-free survival were 64.2% (95% CI, 53.0 to 73.4), 75.9% (95% CI, 65.0 to 83.9), and 61.1% (95% CI, 50.0 to 70.5) at 6 months and 59.5% (95% CI, 47.9 to 69.3), 70.4% (95% CI, 58.4 to 79.6), and 56.6% (95% CI, 45.2 to 66.5) at 9 months. The corresponding estimated rates of progression-free survival at 12 months were 59.5% (95% CI, 47.9 to 69.3), 70.4% (95% CI, 58.4 to 79.6), and 56.6% (95% CI, 45.2 to 66.5). Panel B shows the Kaplan–Meier estimates of overall survival. The median overall survival has not been reached. The overall survival rates were 92.3% (95% CI, 84.5 to 96.3) at 6 months and 82.8% (95% CI, 73.1 to 89.3) at 9 months. The estimated rate of overall survival at 12 months was 81.5% (95% CI, 71.5 to 88.2). Symbols indicate censored data.

Figure 2.. Kaplan–Meier Estimates of Survival.

Panel A shows the Kaplan–Meier estimates of progression-free survival as assessed by the investigators. Patients were followed for a minimum of 6 months. The median progression-free survival has not been reached for intracranial, extracranial, or global disease. For intracranial, extracranial, and global disease, respectively, the rates of progression-free survival were 64.2% (95% CI, 53.0 to 73.4), 75.9% (95% CI, 65.0 to 83.9), and 61.1% (95% CI, 50.0 to 70.5) at 6 months and 59.5% (95% CI, 47.9 to 69.3), 70.4% (95% CI, 58.4 to 79.6), and 56.6% (95% CI, 45.2 to 66.5) at 9 months. The corresponding estimated rates of progression-free survival at 12 months were 59.5% (95% CI, 47.9 to 69.3), 70.4% (95% CI, 58.4 to 79.6), and 56.6% (95% CI, 45.2 to 66.5). Panel B shows the Kaplan–Meier estimates of overall survival. The median overall survival has not been reached. The overall survival rates were 92.3% (95% CI, 84.5 to 96.3) at 6 months and 82.8% (95% CI, 73.1 to 89.3) at 9 months. The estimated rate of overall survival at 12 months was 81.5% (95% CI, 71.5 to 88.2). Symbols indicate censored data.