We appreciate the interest generated by our study on the impact of BRAF functional class on clinical outcomes in patients with NSCLC. In our analysis, responses to standard first-line chemotherapy were not durable for patients with class II and III BRAF mutations. We therefore agree that it is essential to develop alternative therapeutic strategies for this molecular subgroup. Inhibition of BRAF and coinhibition of BRAF/MEK have proven effective for lung cancers harboring class I mutations. Given the shared dependence on activation of the MAPK pathway, it is important to determine whether patients with class II and III tumors derive similar benefit from targeting MAPK signaling. Data demonstrating clinical activity of MAPK-directed therapies in class II and III BRAF-mutant lung cancers are lacking. In a small retrospective series that included 5 patients with class II or III BRAF-mutant (G466V, G469A, G469L, G596V, or K601E) NSCLC, only one patient responded to monotherapy with a BRAF inhibitor (1). These findings are consistent with preclinical studies suggesting limited efficacy of BRAF monomer inhibitors (e.g., vemurafenib and dabrafenib) against dimer-promoting BRAF variants (2, 3). These preclinical observations are supported by multiple clinical reports in melanoma demonstrating that resistance to BRAF inhibitors can result from acquired genetic alterations that facilitate RAF dimerization (4, 5). In our study, one patient with a class II K601E BRAF mutation received vemurafenib. The patient succumbed to his cancer within one week of initiating treatment.

In contrast to the limited activity of BRAF inhibitors, MEK inhibitors may be effective against class II and III BRAF mutants, at least based on preclinical studies (3, 6). Three patients in our study cohort—all with class III BRAF G466 mutations—received a MEK inhibitor (n = 1 trametinib and n = 2 selumetinib). Two patients achieved a best response of progressive disease and were taken off therapy within 1 month, one of which had cooccurring BRAF G466V and KRAS G12C mutations. The remaining patient achieved disease stabilization lasting 4 months. This suggests that while this strategy may not be broadly effective for lung cancers with class III BRAF mutations, it may provide short-term benefit for a subset of patients. Recently, efforts have turned away from repurposing existing drugs toward exploring the activity of novel RAF dimer inhibitors (7), pan-RAF inhibitors, or ERK inhibitors in a variety of MAPK-activated tumors (8), including those driven by non-V600E BRAF mutations. Two patients with class II BRAF mutations (K601E and L597Q) in our study cohort were enrolled in a phase I study of ulixertinib, an investigational ERK inhibitor (8). Both patients discontinued therapy due to early toxicity and were not evaluable for response.

Given the limited number of patients in our study who received therapies targeting the MAPK pathway, no definitive conclusions can be drawn regarding the activity of MAPK-directed therapies in class II and III BRAF-mutant NSCLC. Larger prospective studies are necessary to establish the therapeutic potential of these drugs in these molecular subsets. It will be imperative that these studies independently assess outcomes for patients with class II and III BRAF alterations as underlying biology may translate to differences in efficacy.

See the original Letter to the Editor, p. 3188

I. Dagogo-Jack is a consultant/advisory board member for Boehringer-Ingelheim and reports receiving other remuneration from Foundation Medicine. M.M. Awad reports receiving commercial research grants from Bristol-Myers Squibb, AstraZeneca/MedImmune, Genentech/Roche, and Lilly, and is a consultant/advisory board member for Bristol-Myers Squibb, Merck, AstraZeneca/MedImmune, Genentech/Roche, Syndax, Nektar, Foundation Medicine, and Blueprint Medicine. A.T. Shaw is a consultant/advisory board member for Pfizer, Novartis, Genentech/Roche, Ariad/Takeda, Chugai, Ignyta, Loxo, Bayer, Daiichi-Sankyo, Guardant, KSQ Therapeutics, Blueprint, Natera, and EMD Sereno.

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