Treatment with nivolumab plus ipilimumab resulted in clinically meaningful efficacy for melanoma patients with asymptomatic, previously untreated brain metastases, results of an open-label, multicenter, phase 2 study have shown.
The combination of these two immune checkpoint inhibitors produced intracranial responses in more than half of the patients treated, and perhaps more importantly, according to the study investigators, the combination treatment prevented intracranial progression for more than 6 months in 64% of the study population.
“These results are relevant in a population in whom progression can quickly result in substantial neurologic symptoms, functional impairment, and the need for glucocorticoid therapy,” the study investigators wrote in the New England Journal of Medicine.
The investigators, led by Hussein A. Tawbi, MD, PhD, of the University of Texas MD Anderson Cancer, Houston, initially enrolled 101 patients with histologically confirmed melanoma and metastases to the brain that were asymptomatic. All patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had not received systemic glucocorticoid therapy within 10 days of study treatment.
The primary endpoint of the study was the rate of intracranial benefit, defined as the percentage of patients with complete response, partial response, or stable disease for at least 6 months after starting treatment.
For 94 patients with at least 6 months of follow-up at the time of analysis (median follow-up, 14 months), the rate of intracranial benefit was 57%, including complete responses in 26%, partial responses in 30%, and stable disease in 2%, the investigators reported. The rate of extracranial benefit was similar, at 56%.
The 6-month rate of progression-free survival was 64.2% for intracranial assessments, while the 6-month overall survival rate was 92.3%, according to results of an initial assessment.
Grade 3 or 4 adverse events thought to be related to treatment occurred in 55% of patients and led to treatment discontinuation in 20%; the most common were increased levels of ALT and AST.
Dr. Tawbi and his colleagues said that, while cross-trial comparisons have inherent limitations, the rate of intracranial response seen in this trial is similar to what was seen in the COMBI-MB study of dabrafenib plus trametinib in patients with BRAF-mutant melanoma and brain metastases. However, in that study, published in 2017 in the Lancet, the combination of a BRAF inhibitor and MEK inhibitor had rates of intracranial response and progression-free survival that were “substantially shorter” than the rates of extracranial response and progression-free survival.
“In our study, the use of immunotherapy seemed capable of inducing intracranial responses that were very similar to extracranial responses in character, depth, and duration,” they wrote.
Dr. Tawbi and his coinvestigators enrolled an additional 20 symptomatic patients with brain metastases following a study protocol amendment; however, results from that cohort are not being reported yet because of inadequate follow-up length, they said.
The study was supported by Bristol-Myers Squibb and a grant from the National Cancer Institute. Dr. Tawbi reported disclosures related to Bristol-Myers Squibb, Merck, Genentech, and Novartis. His coauthors reported additional disclosures related to MedImmune, AstraZeneca, Dynavax Technologies, Genoptix, Exelixis, Acceleron Pharma, and Eisai, among others.
SOURCE: Tawbi HA et al. N Engl J Med. 2018 Aug 23. doi: 10.1056/NEJMoa1805453.