COMBI-i Regimen Shows Promise for Patients With BRAF V600–Mutant Melanoma

An ongoing trial of an experimental anti–PD-1 antibody, spartalizumab, in combination with the BRAF inhibitor dabrafenib and MEK inhibitor trametinib appears to have a tolerable safety profile and durable objective response rate in previously untreated patients with advanced BRAF V600–mutant melanoma, according to the updated results of COMBI-i (abstract 9531) presented during a poster session at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago.

While targeted therapies and immune checkpoint inhibitors have improved outcomes in patients with BRAF V600–positive advanced melanoma, many patients experience disease progression and are in need of new treatments.

“This study is trying to take patients who have the BRAF mutation and offer them both targeted agents and immune therapy at the same time,” said Mario Sznol, MD, of Yale Cancer Center in New Haven, Connecticut, in an interview with Cancer Network.

COMBI-i is investigating first-line spartalizumab (400 mg every 4 weeks) in combination with dabrafenib (150 mg twice daily) and trametinib (2 mg daily) in patients with unresectable or metastatic BRAF V600–mutant melanoma. At ASCO, the authors reported pooled efficacy and safety data from two parts of the study: a run-in cohort and a biomarker cohort.

For the run-in cohort, the primary objective was to determine the recommended phase III dosing of spartalizumab in combination therapy as indicated by the incidence of dose-limiting toxicities. For the biomarker cohort, the primary objective was to evaluate changes in PD-L1 levels and CD8+ cells following the combination treatment. The secondary endpoints for both cohorts included safety, progression-free survival (PFS), overall survival (OS), objective response rate (ORR), duration of response (DOR), disease control rate, and pharmacokinetics.

In total, 36 patients were enrolled in the study (run-in cohort, n = 9; biomarker cohort, n = 27). Notable patient characteristics included stage IV M1c disease (50% of patients) and elevated lactate dehydrogenase (LDH) levels (42% of patients). At data cutoff, the median follow-up duration was 15.2 months, and treatment was still ongoing in 47% of patients.

The ORR was 78%, and 42% of patients had complete responses. Of the patients with complete responses, 20% had elevated baseline LDH levels, and 40% had stage IV M1c disease. The median DOR was 20.7 months (95% CI, 16.8 months–not estimable [NE]); 29% of responding patients had subsequent disease progression.

The median PFS was 23.7 months (95% CI, 12.0 months–NE). However, patients with elevated baseline LDH levels had a much lower median PFS (10.7 months; 95% CI, 4.6 months–NE). The OS was not yet reached; however, at data cutoff, 22% of patients had died.

All patients had at least one adverse event, and 64% of patients had adverse events grade ≥ 3. At data cutoff, 17% of patients had discontinued all study drugs due to adverse events. Adverse events of any grade that occurred in at least 40% of patients were pyrexia, chills, fatigue, cough, and arthralgia. The most common adverse event was pyrexia (89%). Other common adverse events were pancreatitis (grade ≥ 3), cellulitis, pneumonia, and decrease in ejection fraction. No treatment-related deaths occurred.

The third part of COMBI-i is a placebo-controlled, randomized, double-blind, phase III clinical trial that is currently in progress.

“What we don’t know yet is whether doing it in this way [combination therapy] is going to be better than giving these therapies in sequence,” said Sznol, “and we’ll only know for sure from conducting a randomized trial.”