Sequencing Treatment in BRAF V600 Mutant Melanoma: Anti-PD-1 Before and After BRAF Inhibition

Abstract

Novel agents targeting immune checkpoint molecules or mutated BRAF are active therapeutic options for patients with BRAF-mutant melanoma. However, the most effective first-line treatment and the optimal sequencing of these agents have not been well characterized. To explore this, we retrospectively assessed 114 patients from 4 centers with advanced, BRAF-mutant melanoma who received anti-programmed cell death-1 (PD-1)/PD-L1 antibodies. We evaluated clinical outcomes, including objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) to initial and subsequent therapies in patients that received anti-PD-1 first (n=56) versus those that received BRAF±MEK inhibitors (BRAFi) first (n=58). Median OS was similar between these groups (27.5 vs. 40.3 mo, P=0.71). Patients who progressed on anti-PD-1 during the study timeframe had worse outcomes after starting subsequent BRAFi than those who had not received prior anti-PD-1 (median PFS 5 vs. 7.4 mo, median OS 10.6 vs. 40.3 mo). Similarly, patients who previously progressed on BRAFi had seemingly inferior outcomes after starting anti-PD-1 compared with those without prior BRAFi, including ORR (25% vs. 41%), median PFS (2.8 vs. 10.6 mo) and median OS (8.2 vs. 27.6 mo). Notably, patients who benefited >6 months from BRAFi had superior ORR to subsequent anti-PD-1 compared with those with more rapid progression (<6 mo) on BRAFi (34% vs. 15%, P=0.04). We conclude that either BRAFi or anti-PD-1 may be effective regardless of treatment sequence in patients with BRAF-mutant melanoma, but clinical outcomes to front-line therapy are superior. In addition, we suggest a shared "responder phenotype" between BRAFi and anti-PD-1.

Primary Resistance to PD-1-Based Immunotherapy—A Study in 319 Patients with Stage IV Melanoma

“…In our cohort, patients with BRAFV600E/K mutation received predominantly targeted therapy, and in this subgroup, 63% of patients had a response (CR or PR). This was slightly higher than previously published [43], but in our cohort, only 21 patients with BRAFV600E/K mutation received second-line therapy, and therefore the outcomes need to be interpreted cautiously. Nevertheless, our group and others have already demonstrated that patients with BRAFV600E/K first-line immunotherapy followed by targeted therapy, similar to what patients in this cohort received, seem to have better outcomes than the inverse sequence [44,45].…”

Current Advances in the Treatment of BRAF-Mutant Melanoma

“…The sequence of treatment for a patient with targeted therapy and immune therapy is not well established. Starting a patient on a BRAF inhibitor or anti-PD1 inhibitor is effective regardless of the treatment order, but more randomized controlled trials are required to address and establish the superiority and sequencing of one therapy over the other [67,68]. Studies have also shown that the efficacy of immunotherapy is improved in previously untreated patients compared to patients who have single agent immunotherapy failure or failure to targeted therapy [69].…”

Utility of PD-L1 immunohistochemistry assays for predicting PD-1/PD-L1 inhibitor response

“…BRAF and MEK mutations contribute to dysfunction of the Ras-Raf-MEK-ERK Map kinase mutations that are present in greater than 90% of melanomas. Specific BRAF mutations when pretreated with Dabrafenib have been associated with reduced response to PD-1/PD-L1 inhibition in melanoma [53–55]. However, when Dabrafenib was combined with MEK suppressor Tremelimumab, an improved response to PD-L1 inhibition was noted [55, 56].…”