Abstract 4122: Occurrence of BRAF class II and III alterations is common across solid tumors and is associated with inferior clinical outcomes in NSCLC and melanoma

Abstract

Abstract Background: Oncogenic BRAF alterations can be categorized by their distinct structural and signaling properties which lead to activation of the MAPK pathway: class I - kinase active signaling of BRAF mutant monomers; class II - kinase active signaling of BRAF mutant dimers; and class III - kinase impaired BRAF that signals via RAS-dependent, heterodimers containing wild-type RAF. There are currently no approved BRAF targeted therapies for patients whose tumors bear BRAF class II or III alterations. This research utilizes the GuardantINFORM࣪ clinical-genomic database to assess the real-world occurrence and outcomes of patients with oncogenic BRAF alterations by distinct classes across solid tumors.​ Methods: This observational study utilized a database containing clinical and genomic data from ~160,000 cancer patients with ctDNA profiling by the Guardant360 assay. Patients were categorized using a broad list of known and putative class I, II or III BRAF alterations compiled from published sources. Patients were stratified by BRAF mutant class for real-world overall survival analyses. Results: The analysis identified a cohort of over 5,890 patients with oncogenic BRAF alterations. Class II and III alterations were present in more than 2% of all ctDNA positive patients and made up approximately 55% of all the oncogenic BRAF alterations. Class II and III accounted for 65%, 30% and 20% of oncogenic BRAF alterations in NSCLC, CRC and melanoma respectively. NSCLC and melanoma patients with class II or III BRAF alterations experienced shorter overall survival relative to patients with class I alterations. Conclusions: The analysis of this large real-world dataset identified a substantial number of cancer patients with BRAF class II and III alterations. NSCLC and melanoma patients with BRAF class II and III alterations experienced inferior clinical outcomes and represent a population that could benefit from novel targeted therapies. Overall survival in NSCLC and melanoma patients with BRAF class I, II or III alterations Cohort Median OS Months (%95 CI) Unadjusted P-value Class I Class II Class III I vs II I vs III II vs III NSCLC (n=938) 44.8 (37.5,52.8) 34.4 (27.5,41.5) 32.3 (28.4,40.9) 0.006 0.0126 0.6611 Melanoma (n=333) 46.5 (42.3,65.5) 28.5 (8.6,30.3) 30.5 (12.5,73.8) 0.0008 0.0165 0.6529 Citation Format: Paul L. Severson, Elifnur Yay Donderici, Nicole Zhang, Aleksandra Franovic, Nichol Miller, Eric Martin, Eric Murphy, Richard Williams. Occurrence of BRAF class II and III alterations is common across solid tumors and is associated with inferior clinical outcomes in NSCLC and melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4122.