BRAF fusions in clinically advanced non

Background: Although far less common than BRAF V600E base substitutions (subs) classically associated with melanomas and colorectal carcinomas, BRAF subs occur in 1-2% of non-small cell lung cancer (NSCLC). BRAF fusions are emerging treatment targets for Spitzoid melanomas and other solid tumors. The frequency of BRAF fusions and targeting potential in NSCLC has not been widely described. Methods: Hybridization capture-based comprehensive genomic profiling (CGP) was performed on 17,128 NSCLC FFPE samples sequenced to a mean coverage depth of > 550X for up to 315 cancer-related genes plus 37 introns from 19 genes frequently rearranged in cancer. Genomic alterations (GA) included short variant (SV) base subs and insertions/deletions, copy number alterations, and rearrangements/fusions. Tumor mutational burden (TMB; mut/Mb) was calculated on up to 1.1 Mb of sequenced DNA. Results: BRAF fusions were identified in 42/17,128 (0.2%) NSCLC profiled. Median patient age was 67 (range 44-93 yrs). Of the BRAF fusion positive NSCLC, 55% were female. Biopsies were obtained from primary lung tumor (48%) and metastatic sites (52%). The most frequent 5’ partners were AGK, DOCK4, and TRIM24. Multiple novel BRAF fusions were identified. The genes most frequently co-altered with BRAF fusions were TP53(67%), CDKN2A(31%), EGFR (29%) and CDKN2B (26%). Overall TMB in the BRAFfusion positive cohort was low (median 3.8 mut/Mb), although 3/42 cases (7%) had > 20 mut/Mb. Of the BRAF fusion driven NSCLC, 10 cases (24%) featured EGFR SV alterations. Two BRAF fusion/EGFR SV cases featured primary exon 19 deletion and T790M mutation. Examples of BRAF fusion driven NSCLC responding to a combination of BRAFand MEK inhibitors (MEKi) will be presented. Conclusions: NSCLC BRAF fusions are a rare GA that may be associated with acquired resistance in a subset of EGFR-mutated NSCLC progressing on anti-EGFR TKI therapies. Given clinical evidence for the activity of targeted therapy approaches, molecular eligibility for clinical trials of MEKi should include these variants. The clinical evidence for responsiveness of BRAF fusion driven NSCLC provides an opportunity to personalize treatments and improve clinical outcomes for patients.