Immunotherapy Combination in Melanoma Brain Metastases
In the phase II CheckMate 204 study reported in The New England Journal of Medicine, Tawbi et al found that combined nivolumab (Opdivo) and ipilimumab (Yervoy) produced a high rate of intracranial clinical benefit in patients with melanoma brain metastases.
Study Details
The study included 94 patients from 28 U.S. sites with metastatic melanoma and at least one measurable, nonirradiated brain metastasis with tumor diameter of 0.5 cm–3 cm and no neurologic symptoms. Patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for up to four doses, followed by nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity.
The primary endpoint was the rate of intracranial clinical benefit, defined as stable disease for ≥ 6 months, complete response, or partial response as assessed by modified RECIST criteria.
Intracranial Responses
Median follow-up was 14.0 months. The rate of intracranial clinical benefit was 57%, including complete response in 26% of patients, partial response in 30%, and stable disease for ≥ 6 months in 2%. The rate of extracranial clinical benefit was 56%, with complete response in 7% of patients, partial response in 43%, and stable disease for ≥ 6 months in 6%. The rate of intracranial clinical benefit was higher among patients with lactate dehydrogenase levels above the upper limit of normal (ULN) vs patients with levels ≤ ULN (67% vs 51%) and higher in patients with tumor programmed cell death ligand 1 (PD-L1) expression ≥ 5% vs < 5% (76% vs 48%). At time of analysis, response was ongoing in 47 (90%) of 52 patients with intracranial objective response, with median duration of response not being reached. Median time to response was 2.3 months.
With minimum follow-up of 6 months, progression-free survival among all patients was 64.2% at 6 months and 59.5% at 9 months for intracranial assessment and 75.9% and 70.4% for extracranial assessment. Overall survival was 92.3% and 82.8% at 6 and 9 months, and estimated at 81.5% at 12 months.
Adverse Events
The most common treatment-related adverse events of any grade were fatigue (48%), increased ALT (37%), maculopapular rash (36%), and diarrhea (35%). Treatment-related grade 3 or 4 adverse events were reported in 55% of patients, with the most common being increased ALT (16%) and increased AST (15%). Treatment-related grade 3 or 4 adverse events involving the central nervous system occurred in 7%, including headache (3%), brain edema (2%), intracranial hemorrhage (1%), peripheral motor neuropathy (1%), and syncope (1%). Grade 3 or 4 adverse events led to treatment discontinuation in 20% of patients. One patient died from immune-related myocarditis.
The investigators concluded, “Nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases.”
The study was funded by Bristol-Myers Squibb and the National Cancer Institute.
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