The treatment landscape for patients with advanced (unresectable or metastatic) melanoma has changed dramatically over the last 5-10 years with the availability of targeted therapies and immune checkpoint inhibitors (ICIs). Around half of all melanomas harbor mutations in the BRAF gene, with V600E/K being the most common mutation. The standard of care for patients with BRAF mutation-positive advanced melanoma has shifted from single-agent BRAF inhibition to combination therapy with BRAF and MEK inhibitors (BRAFi; MEKi) as well as immunotherapy. However, the optimal sequencing of targeted and immunotherapy regimens for maximum efficacy and tolerability in patients with BRAF V600E/K mutation-positive advanced melanoma is still a matter of debate.

A recent publication describes a post-hoc subgroup analysisof pooled data from 3 multinational, multicenter studies: KEYNOTE-001, KEYNOTE-002 and KEYNOTE-006, with the objective of assessing whether BRAF V600E/K mutation status or previous BRAFi therapy with or without MEKi affected patients’ response to the PD-1 inhibitor, pembrolizumab. The analysis included data from 1,558 patients with advanced melanoma and known BRAF mutation status, who had all received pembrolizumab, and some who had also received BRAFi with or without MEKi. The primary endpoints, which were objective response rate (ORR), 4-year progression free survival (PFS) rate and 4-year overall survival (OS) rate, were compared between subgroups. For patients with BRAF wild type (wt) melanoma, the ORR was 39.8% versus 34.3% for BRAF mutant melanoma, the 4-year PFS rate was 22.9% and 19.8%, respectively, and the 4-year OS rate was 37.5% and 35.1%. In patients who had, or had not, received prior BRAFi, with or without MEKi therapy, ORR was 28.4% versus 44.2%, 4-year PFS rate was 15.2% versus 27.8%, and 4-year OS rate was 26.9% versus 49.3%, respectively. One theory for the lower response and survival rates in patients who had been previously treated with BRAFi with/without MEKi, was the imbalance in baseline characteristics between the two groups. A higher number of patients who had previously received targeted therapy had baseline characteristics that indicated a worse prognosis, such as PD-L1 negative tumors, elevated lactate dehydrogenase (LDH) levels, higher Eastern Cooperative Oncology Group (ECOG) performance status, larger baseline tumors and lower albumin levels. There was no meaningful difference in the safety profile among patients treated with pembrolizumab in the four subgroups.

Overall, the results of this post hoc pooled subgroup analysis indicate that the PD-1 inhibitor may provide clinical benefit in patients who are BRAF wt or BRAF mutant, and in patients whowere, or were not, previously treated with targeted therapy, and support its use in the treatment of patients regardless of BRAF mutation status or previous therapy. Ongoing randomized clinical trials of immunotherapy and targeted therapy for patients with BRAF V600E/K-mutated advanced melanoma may further clarify optimal sequencing. Indeed, in the phase III IMspire trial that compared the PD-L1 inhibitor, atezolizumab plus BRAFi/MEKi combination of vemurafenib/cobimetinib, with placebo plus vemurafenib/cobimetinb, the addition of immunotherapy to targeted therapy demonstrated a PFS benefit of 5 months. In July 2020, the United States Food and Drug Administration (FDA) approved this combination for the first-line treatment of patients with BRAF-V600 unresectable, mutation-positive advanced melanoma. For more details on this approval see ACE OncoBlog, 14 August. 

Reference

Puzanov I, et al. JAMA Oncology 2020; 6(8):1256-1264