NEW YORK — Extended treatment with dabrafenib plus trametinib demonstrated consistent tolerability profiles in patients with BRAF V600–mutant melanoma, according to a pooled analysis presented at HemOnc Today Melanoma and Cutaneous Malignancies.
The phase 3 COMBI-d and COMBI-v studies — designed to evaluate dabrafenib (Tafinlar, Novartis), a BRAF kinase inhibitor, plus trametinib (Mekinist, Novartis), a MEK inhibitor — showed tolerability and efficacy with the combination with a median follow-up of 20.2 months.
Jean-Jacques Grob, MD, PhD, from Aix-Marseille University in Marseille, France, and colleagues conducted a retrospective analysis of pooled data from both studies to understand the safety profile of dabrafenib plus trametinib after extended follow-up.
“Considering the long-term benefits achievable with dabrafenib plus trametinib, understanding the safety profile of these agents with extended follow-up (ie, based on a 3-year analysis) is critical for optimizing patient management,” the researchers wrote.
The studies included 563 patients (COMBI-d, n = 211; COMBI-v, n = 352) with BRAF V600–mutated melanoma randomly assigned to receive the combination of 150 mg dabrafenib twice daily plus 2 mg trametinib once daily for a median duration of 12.4 months (range, 0.1-47.3). Most of the patients (n = 559) were included in the pooled safety population.
Ninety-eight percent of patients experienced any adverse event. The most common adverse events included pyrexia (58%), nausea (36%), fatigue (33%), diarrhea (33%) and chills (33%).
Eighty-six patients discontinued treatment due to adverse events, the most common of which were pyrexia, decreased ejection fraction, increased alanine transaminase, increased aspartate transaminase, increased blood creatinine, chills, peripheral edema and hyponatremia.
Patients who received the combination regimen for 36 months or more (n = 50; 9%) experienced incidences of adverse events most frequently at 6 months of treatment, declining thereafter. For instance, the rate of pyrexia among these patients was 60% between months 0 to 6 of treatment compared with 12% at months 30 to 36. Similarly, the rate of fatigue decreased from 38% to 6%, and chills decreased from 38% to 2%.
Patients with and without a pyrexia event demonstrates similar median PFS (11.1 months for both) and OS (29.1 months vs. 26 months).
Researchers observed a lower frequency of dose reductions or interruptions over time in patients on treatment. Frequencies of dose reductions and interruptions also were similar regardless of best response. Researchers noted median treatment duration was longest for patients with complete response (36.2 months; range, 2.3-47.3) and shortest for patients with progressive disease (3.1 months; range, 1.1-34.3).
“These trends may be expected since patients requiring dose modifications and/or not responding are more likely to discontinue therapy,” the researchers wrote.
“These results confirm that long-term tolerability of dabrafenib plus trametinib is achievable in patients with BRAF V600–mutant melanoma,” they added. – by Kristie L. Kahl
Grob JJ, et al. Pooled Analysis of Safety With Extended 3-Year Follow-Up Across Combination Dabrafenib and Trametinib Phase 3 Trials. Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; March 24-25, 2017; New York.
Disclosures: Grob reports a consultant role with Novartis. Please see the abstract for a list of all other researchers’ relevant financial disclosures.