TOPLINE

Greater overall survival (OS) was seen with spartalizumab added to dabrafenib and trametinib (sparta-DabTram) than with dabrafenib and trametinib alone in patients with BRAF V600-mutant metastatic melanoma in a trial. But the new phase 3 study failed to meet its primary endpoint of progression-free survival (PFS).

METHODOLOGY

• The combination of targeted therapies and immunotherapies for BRAF-mutant melanoma has been hypothesized to merge the benefit of the rapid responses to BRAF and MEK inhibitors with the long-term benefit of anti-PD-1 immunotherapy.
• Researchers conducted a phase 3, randomized, double-blind, placebo-controlled trial (COMBI-I; ClinicalTrials.gov identifier: NCT02967692) involving 532 adult patients with histologically confirmed unresectable or metastatic BRAF V600-mutant cutaneous melanoma.
• Participants were randomly assigned to receive either the immunotherapy spartalizumab, 400 mg intravenously once every 4 weeks, plus the oral BRAF kinase inhibitor dabrafenib, 150 mg twice daily, and the MEK kinase inhibitor trametinib, 2 mg once daily (sparta-DabTram; n = 267), or intravenous placebo plus oral dabrafenib, 150 mg twice daily, and trametinib, 2 mg once daily (placebo-DabTram; n = 265). 
• The median duration of follow-up from randomization to data cutoff was 76.9 months (range, 73.7-83.3 months), with the final analysis conducted on August 21, 2024. 
• OS was not formally tested, as the study failed to meet its primary endpoint of PFS; the reported P value is exploratory and descriptive. 

TAKEAWAY

• Death was reported in 127 patients (47.6%) in the sparta-DabTram arm and 151 patients (57.0%) in the placebo-DabTram arm, with a median OS of 61.5 months vs 41.6 months, respectively (hazard ratio, 0.760).
• The estimated OS rate at 60 months was 50.1% for the sparta-DabTram arm compared with 42.8% for the placebo-DabTram arm.
• Treatment-related adverse events (TRAEs) were reported in 98.5% of patients in the sparta-DabTram arm and 88.6% in the placebo-DabTram arm, with grade ≥ 3 TRAEs occurring in 57.3% and 36.7% of patients, respectively.
• The most common TRAE was pyrexia, occurring in 65.9% of patients in the sparta-DabTram arm vs 46.2% in the placebo-DabTram arm, with a median duration of 13.0 days (interquartile range, 6.0-32.0 days) vs 9.0 days (interquartile range, 4.0-19.0 days), respectively.

IN PRACTICE

“The combination of sparta-DabTram appears to improve OS compared with dabrafenib and trametinib alone in patients with BRAF V600-mutant metastatic melanoma,” wrote the authors of the study.

SOURCE

This study was led by Antoni Ribas, MD, of the University of California, Los Angeles. It was published online on August 12 in the Journal of Clinical Oncology.

LIMITATIONS

According to the authors, the key limitation of this study is the high number of patients with interrupted survival data collection because of study termination, resulting in censoring for OS. Other limitations include the imbalanced use of immune checkpoint inhibitors post-progression, with PD-1 inhibitors used in only approximately two thirds of patients (n = 102) in the placebo arm. Treatment discontinuation due to grade ≥ 3 adverse events and nonadherence to protocol-specified dosing also posed limitations. The onset of pyrexia, the most common adverse event, could have influenced the dosing schedule.

DISCLOSURES

Novartis Pharmaceuticals Corporation provided support for this study. Ribas disclosed leadership roles with Lutris and Arcus Biosciences and stock ownership in multiple companies, including Compugen, CytomX Therapeutics, Arcus Biosciences, Tango Therapeutics, Lutris, Highlight Therapeutics, Kite/Gilead, Synthekine, Sastra, and Lyell Immunopharma. Ribas also disclosed receiving honoraria from Merck Sharp & Dohme and Amgen, consulting or advisory roles with Merck and Amgen, and research funding from Agilent and Bristol Myers Squibb. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.