According to results from a multi-center, phase 2 study presented at the 2023 ASCO Annual Meeting, adding navitoclax to standard combination dabrafenib-trametinib improved overall survival among patients with BRAF-mutant melanoma, when compared to standard dabrafenib and trametinib treatment alone.

These findings were presented by lead author Zeynep Eroglu, MD, Moffitt Cancer Center and Research Institute, Tampa, FL, at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting on Monday, June 5, 2023 in Chicago, Illinois.

There is evidence from preclinical trials which show that “targeting mediators of apoptosis improves response and survival with BRAF-targeted” treatment, as Dr Eroglu and coauthors wrote. Previously, the safety of daprafenib and trametinib combination therapy plus navitoclax was demonstrated among patients with BRAF-mutant solid tumors in a phase 1 trial. In this study, the triplet regimen is being evaluated in comparison to dabrafenib-trametinib alone (doublet therapy).

Between January 11, 2019 and March 25, 2022, 50 patients from 13 cancer centers were randomized on a 1-to-1 basis to receive either standard dose dabrafenib and trametinib (150 mg of dabrafenib twice daily/2 mg of trametinib once daily, doublet arm, n=25) or standard dose dabrafenib and trametinib, plus 225 mg of navitoclax once daily (triplet arm, n=25). Patients were stratified by maximal tumor burden. Primary end points in this study included complete response rate and maximal tumor shrinkage comparisons in each cohort. Secondary end points included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).

The trial met the primary end point of complete response rate, with 15% in the doublet arm and 20% in the triplet arm, at the time of data cutoff. No difference in maximal tumor shrinkage was observed between the 2 arms. The ORR of the doublet arm was 80% vs 84% in the triplet arm. At a median follow-up of 25.9 months, trends indicated that OS was improved with the addition of navitoclax. There was no difference in PFS between the 2 arms. Among those patients with smaller baseline tumor burden (n = 37, 74%) there was a statistically significant improvement in OS in the triplet arm (2-year OS estimate, 78%) vs the doublet arm (57%). Adverse events were similar between the 2 arms, with the most common events being nausea, diarrhea, fatigue, fever, and vomiting.

Dr Eroglu and coauthors concluded that the triplet therapy of navitoclax plus dabrafenib-trametinib was associated with a complete response rate of 20%, an objective response rate of 80%, and “there was a trend for improved OS in patients treated with [the triplet therapy] compared to [the doublet therapy]” and “the difference in OS was significant in [patients] with smaller tumor burden.” They added the triplet "regimen may be considered for further exploration in the post-[immune checkpoint inhibition] setting.”

Source:

Eroglu Z, Mehnert JM, Giobbie-Hurder A, et al. Randomized phase II trial of dabrafenib and trametinib with or without navitoclax in patients (pts) with BRAF-mutant (MT) metastatic melanoma (MM) (CTEP P9466). Presented at 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract 9511