BRAF Mutation Class and Clinical Outcomes—Letter

We read with great interest the recent article by Dagogo-Jack and colleagues, wherein they interrogated the clinical outcomes of patients with lung cancer whose tumors expressed different classes of BRAF mutations (1). Clinicians are increasingly requesting next-generation sequencing analyses of BRAF for patients with advanced NSCLC, colorectal cancer, and melanoma. As such, they are identifying more patients whose tumors express non-V600 BRAF mutations. Until recently, the prognostic and therapeutic relevance of these mutations was poorly understood (2). Dagogo-Jack and colleagues have published the largest and most comprehensive clinical dataset to date, derived from patients with BRAF-mutant NSCLC, including both non-V600 (class 2 and 3) and V600 (class 1) mutations. We congratulate the authors on this work, as it has contributed greatly to the field; but as with any well-conceived research project, their results yield more questions that have yet to be answered.

Dagogo-Jack and colleagues found that patients with class 2 or 3 BRAF mutations have shorter survival times than patients with class 1 BRAF mutations. In concordance with these data, we found that patients with advanced melanoma with class 2 or 3 BRAF mutations (and/or NRAS mutations) also have shorter survival compared with those with class 1 BRAF mutations (3). We have reported that subsets of class 2 BRAF-mutant melanomas are sensitive to MAPK inhibition (3). As such, we expect that class 2 BRAF-mutant NSCLC may also be sensitive to a similar therapeutic approach. We note that Dagogo-Jack and colleagues describe 6 patients with NSCLC with class 2 and class 3 BRAF-mutant tumors treated with MAPK-targeted agents. We would like to know more about these patients; in particular, which BRAF-specific mutations they expressed, which targeted therapies they received, and whether they experienced durable clinical responses.

There is now a growing body of evidence demonstrating that class 2/3 BRAF mutations are associated with an aggressive clinical course in NSCLC and melanoma (1–3). These are actionable mutations and effective targeted therapies are thus warranted. Different strategies have been proposed on the basis of BRAF mutation class, including single-agent ERK inhibition (4), combined BRAF + MEK inhibition (3), and MEK + receptor-tyrosine kinase inhibition (5). However, none of these strategies have been robustly assessed in the clinic thus far. Moreover, due to the relative rarity and wide variety of non-V600 BRAF mutations, the possibility of developing a randomized controlled trial for any targeted modality represents a significant challenge. Consolidating research efforts to identify the most promising strategies will be critical to the successful clinical development of effective targeted therapies for patients with non-V600 BRAF mutations. As such, we feel strongly that the ongoing publication of (even anecdotal) reports of therapeutic outcomes with MAPK-targeted therapies in these patients is necessary.

See the Response, p. 3189