Tolerance and efficacy of BRAF plus MEK inhibition in patients with melanoma who previously have received programmed cell death protein 1‐based therapy

Abstract

BACKGROUND: Combined BRAF and MEK inhibition (BRAF-MEK) is a standard therapy for patients with BRAF V600-mutant melanoma, but to the authors' knowledge, the tolerance, adverse event (AE) profile, and efficacy have not been well defined in the postprogrammed cell death protein 1 (PD-1) setting. METHODS: Patients with BRAF V600-mutant melanoma who received combined BRAF-MEK after prior PD-1-based therapy were assembled from 4 tertiary care centers in the United States and Australia. Dose modification was defined as a treatment break, dose reduction, or intermittent dosing. Rates of hospitalization and discontinuation due to AEs were collected, and overall survival (OS) was calculated using Kaplan-Meier methods from the time of the initiation of BRAF-MEK therapy. RESULTS: A total of 78 patients were identified as having received a BRAF-MEK regimen at a median of 34 days after the last dose of PD-1-based therapy. The majority of patients (86%) received the combination of dabrafenib and trametinib. Approximately 80% of patients had American Joint Committee on Cancer M1c or M1d disease. Sixty-five regimens (83%) had ≥1 dose modification. The median time to the first dose modification was 14 days; 86% occurred within 90 days and 71% involved pyrexia. Dose modifications were more common in patients receiving BRAF-MEK <90 days after the last dose of PD-1 and who were not receiving steroids. Of the dose modifications, 25 (31%) led to an AE-related hospitalization. Among 55 BRAF-naive patients, the median time receiving BRAF-MEK therapy was 5.8 months and the median OS was 15.6 months. CONCLUSIONS: The majority of patients receiving BRAF-MEK inhibition after PD-1 therapy require dose interruptions, and a significant minority require hospitalization for AEs. In this higher risk population, the median time receiving therapy and OS may be inferior to those presented in published phase 3 trials. Cancer 2019;125:884-891.

Comprehensive Clinical Trial Data Summation for BRAF-MEK Inhibition and Checkpoint Immunotherapy in Metastatic Melanoma

“…Such observations have predominately suggested that there may be a detriment to the ORR with immunotherapy (specifically ipilimumab) if it is administered after BRAF inhibition, but the reverse sequence does not influence the ORR with BRAF inhibition . Recently, however, a retrospective series of 78 patients with BRAF V600‐mutant melanoma receiving a BRAF‐MEK combination after PD‐1‐based therapy showed an 83% rate of BRAF‐MEK dose modification, 31% rate of adverse event‐related hospitalization, and median BRAF‐MEK therapy and OS durations of 5.8 and 15.6 months, respectively . Overall, the available retrospective data sets are small, and their findings should be considered on a less urgent level relative to patient‐specific factors and preferences.…”

Sequential Treatment With Targeted and Immune Checkpoint Therapy in Patients With BRAF Positive Metastatic Melanoma: The Importance of Timing?

“…However, these observations are based on small case series. Most recently concern has been raised about the tolerability and side effect profile of BRAF/MEK inhibition after anti-PD-1 therapy (19). Indeed, the authors speculated that the increased incidence of treatment interruptions may impact upon the rates of OS.…”

The Great Debate at “Melanoma Bridge”, Naples, December 7th, 2019

“…Anti-PD-1 s also show similar outcomes when used after progression on ipilimumab with or without BRAF inhibitors [27]. Moreover, switching from anti-PD-1 s to BRAF/MEK inhibitors can be associated with significant toxicity problems involving treatment interruption or dose reductions [40]. Thus, switching patients with SD has the potential of causing toxicity issues before such a change in systemic therapy is truly needed.…”