Results from a retrospective study showed that most patients with advanced BRAF-mutant melanoma receiving combination therapy with a BRAF and a MEK inhibitor following immune checkpoint blockade required dose modifications, and nearly one-third required hospitalization due to an adverse reaction.

BRAK/MEK inhibitor combination therapy and programmed cell death 1 (PD-1) inhibitor therapy are both options for the first-line treatment of patients with BRAF-mutant advanced melanoma. While no clinical trials have directly compared the efficacy and safety of these 2 treatment approaches in the first-line setting, the latter is often preferred due to reports of long-term disease control in some patients. Although BRAF/MEK inhibitor combination therapy is often used in the second-line setting, prospective clinical trials of this treatment regimen were performed in patients without exposure to immune checkpoint inhibitor therapy.

Because recently published case reports and case series have reported severe adverse reactions in patients receiving these therapies in this sequence, this retrospective study of patients receiving BRAF/MEK inhibitor combination therapy following PD-1 inhibition was undertaken.

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Data for a retrospective cohort of 78 patients with BRAF-mutant advanced melanoma treated with the combination of BRAF/MEK inhibitors following anti-PD-1–based therapy were obtained from 4 tertiary care centers in the United States and Australia.

Immune checkpoint inhibitor therapy included the combination of nivolumab and ipilimumab, anti–PD-1 therapy alone, and sequential anti–PD-1 therapy and ipilimumab in 40%, 32%, and 28% of patients, respectively. The combination of dabrafenib plus trametinib was received by 86% of patients, with the remaining 14% receiving either vemurafenib plus cobimetinib or encorafenib and binimetinib. The median interval between last dose of anti–PD-1–based therapy and administration of BRAF/MEK inhibitor therapy was 34 days.

A major finding of this study was the need for at least 1 BRAF/MEK inhibitor dose modification(s) (defined as a treatment break, dose reduction, or planned intermittent dosing due to an adverse event) in 83% of patients. The median time to first dose modification was 14 days, with over two-thirds of first dose modifications involving pyrexia. Other common adverse events included rash, fatigue and weakness, aspartate aminotransferase and alanine aminotransferase elevation, nausea and vomiting, and myopathy and myalgia.

Patients who were not receiving steroids (no vs yes; P =.002) or who initiated BRAF/MEK inhibitor combination therapy fewer than 90 days following the last dose of anti-PD-1–based therapy (<90 days vs ≥90 days; P =.030) were more likely to require a dose modification in BRAF/MEK inhibitor combination therapy. For 31% of patients undergoing a dose modification, hospitalization was required for an adverse event.

“Patients should be counseled that it often will be difficult to tolerate BRAF-MEK inhibition after anti–PD-1–based therapy,” the authors wrote.

For the subgroup of patients who had not received previous BRAF inhibitor therapy, median time on BRAF/MEK combination therapy and median overall survival (OS) were 5.8 months and 15.6 months, respectively.

Although it is not possible to make direct comparisons, the study authors pointed out that median progression-free survival was 11 months to 12 months and median OS was 22 months to 25 months in phase 3 trials of first-line vemurafenib/combimetinib and dabrafenib/trametinib in patients with advanced melanoma.

“It is not clear whether the increased dose interruptions and reductions underlie this decrease in efficacy or whether microenvironmental features associated with PD-1 resistance also promote cross-resistance to BRAF-MEK inhibition,” the authors noted.


  1. Saab KR, Mooradian MJ, Wang DY, et al. Tolerance and efficacy of BRAF plus MEK inhibition in patients with melanoma who previously have received programmed cell death protein 1-based therapy. Cancer. 2019;125(6):884-891.