Treatment of tumors harboring non-V600 mutations is challenging because of functional heterogeneity and lack of knowledge regarding their clinical significance and response to targeted agents. This study was done to check the functional heterogeneity and provide knowledge regarding their clinical significance and response to targeted agents.

305 unique BRAF mutations were identified. Missense mutations were most common. F468S and N581Y were identified as novel activating mutations. Class 1 to 3 mutations had higher clonality than mutations of unknown class. Three patients were treated with MEK with or without BRAF inhibitors. The patient with the L597R mutation had a durable response. Trametinib with or without dabrafenib, LXH254, and lifirafenib had more potent inhibition of BRAF non–V600-mutant NSCLC cell lines than other inhibitors, comparable with the inhibition of BRAF V600E cell line.

In BRAF-mutant NSCLC, clonality is higher in known functional mutations and may allow identification of variants of unknown significance that are more likely to be oncogenic drivers. This study concluded that certain non-V600 mutations are responsive to MEK and BRAF inhibitors. This integration of genomic profiling and drug sensitivity may guide the treatment for BRAF-mutant NSCLC.

Reference: https://www.jto.org/article/S1556-0864(20)30466-4/fulltext