Diversity of BRAF mutations in non-small cell lung cancer and implications on treatment

The optimal treatment sequence in non-small cell lung cancer harboring class I BRAF mutations and atypical BRAF variants remains unclear. To better characterize therapeutic strategy, we retrospectively evaluated a multi-institutional cohort of BRAF-mutant NSCLC patients (n = 97) and an independent clinico-genomic database (n = 342), performed structural modeling, and conducted chemical screens of BRAF-mutant cell lines. Patients with class I BRAF mutation treated with BRAF-MEK inhibitors at any line of therapy had significantly greater median overall survival compared to those who did not receive BRAF-MEK inhibitors (40 vs 10 months, Log-rank p = 0.043). There, however, was no significant survival difference between patients treated with immune checkpoint inhibitors versus those not treated. Tumors with class II or III BRAF variants were significantly more likely to harbor concurrent MAPK pathway alterations relative to class I (Chi-Square p < 10^-4). Cell line studies identified genetic dependency on BRAF in class II cell lines without sensitivity to BRAF inhibitors, and dependency on EGFR in class III cell lines.