Class II and class III BRAF mutations in patients with advanced non-small cell lung cancer (NSCLC): Clinical characteristics, mutation patterns, and survival outcomes.

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e21204 Background: Class II and class III BRAF mutations (i. e., non-V600X) in NSCLC differ from V600E in terms of dimerization and KRAS-dependency. Whereas V600X is effectively targetable by combined BRAF- and MEK-inhibition, no specific targeted approach for non-V600X exists, and a comprehensive description of the patient group is lacking. This retrospective cohort analysis presents clinical and genomic characteristics of a large cohort of patients with advanced BRAF nonV600X mutant lung cancer. Methods: Molecular data of 1411 lung cancer patients staged IIIb/IV and harboring BRAF mutations were linked to hospital registry data in the NGM (Network Genomic Medicine) database. Biospecimens were analyzed using next-generation sequencing (NGS). Results: 721 patients with BRAF non-V600X mutations were identified, of whom 10.5% had been diagnosed with squamous cell carcinoma (SCC) and 89.5% had non-squamous histology. Median age at diagnosis was 66 years (range: 34-81) and the cohort comprised 409 (56.7%) men and 312 (43.3%) women. 301 (41.8%) of the BRAF non-V600X alterations detected in this cohort are “activators” in the MAPK pathway (class II, including G469A/V/R, G464A/E/L/V, K601E/N, L597Q/R/V), while 310 (43.0%) function as “amplifiers” (class III, including mutants such as D594A/G/H/N, G466A/E/V, G469E, N581I/S/T in this cohort). While 21.5 % (155; SCC: 12.3%; non-SCC: 22.9%) of patients did not have any co-occurring mutations (55.6% of SCC and 37.1% of non-SCC patients respectively), TP53 was the most frequent co-mutation, detected in 56.6% (SCC: 74.0%; non-SCC: 53.8%) of patients. 16.4% (118) exhibited a KRAS co-mutation (SCC: 4; non-SCC: 109). A preliminary survival analysis suggests no significant difference in overall survival between these broad classes (HR 0.92, 95%-CI 0.62, 1.36). Conclusions: The study highlights the heterogeneity of patients with BRAF class II and class III regarding histology and co-mutational status, with both classes equally frequent. A more granular investigation of non-V600X alterations and their associated clinical outcomes under different treatment approaches is ongoing.