BRAF inhibitor acquired resistance: A multicenter meta-analysis of the spectrum and clinical implications of resistance mechanisms.

9008 Background: Acquired resistance (AR) to BRAF inhibitors (BRAFi) in melanoma is a near-universal phenomenon driven by numerous genetic and non-genetic alterations. Clinical implications of these AR mechanisms have not been described in a large cohort. We assessed the spectrum of BRAFi AR mechanisms and their associated timing of onset, pattern of disease progression (DP), and clinical outcomes. Methods: We compiled clinical and genetic data from 100 patients (pts) with 132 melanoma samples obtained at BRAFi DP from three previously published studies of BRAFi resistance. Whole exome sequencing and/or PCR-based genetic testing were performed on all samples. Associations between AR mechanisms and clinical features/outcomes were assessed with multivariate logistic regression models. Results: In 132 DP samples, putative AR mechanisms were identified in 58%, including NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAFV600E/K amplifications (13%), MEK1/2 mutations (7%), and non-MAPK pathway alterations (11%). Marked heterogeneity was observed within tumors and patients. BRAFV600E/K amplifications and non-MAPK alterations often co-occurred with other genetic changes, whereas NRAS mutations, MEK1/2 mutations, and BRAF splice variants largely arose in isolation (p = 0.02). Of 19 pts with ≥ 2 DP biopsies, identified AR mechanisms were concordant in only 1 pt (5%). NRAS mutations were associated with vemurafenib use (p = 0.045) and baseline intracranial metastases (p = 0.036). Progression-free survival and patterns of DP were similar across AR mechanisms. The median survival after DP was 6.9 months, and subsequent responses to combined BRAF/MEK inhibition were uncommon (2/15; 13%); no patients responded to ipilimumab (0/24). Post-progression outcomes did not correlate with specific BRAFi AR mechanisms. Conclusions: This is the largest study of acquired BRAFi resistance in pts with BRAF mutant melanoma. Despite marked heterogeneity of AR mechanisms within pts and tumors, NRAS mutations were associated with vemurafenib use and intracranial disease. Further investigation into non-genetic AR mechanisms and immune features of BRAFi progression is warranted.