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

摘要

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 post–programmed 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.