V600E/V600K Mutations versus Nonstandard Alterations: Prognostic Implications and Therapeutic Outcomes.

BRAF and MEK inhibitors are standard of care for V600E/K-mutated melanoma, but the benefit of BRAF and/or MEK inhibitors for nonstandard alterations for melanoma and other cancers is unclear. Patients with diverse malignancies whose cancers had undergone next-generation sequencing were screened for alterations. Demographics, treatment with BRAF and/or MEK inhibitors, clinical response, progression-free survival (PFS), and overall survival (OS) were determined from review of the electronic medical records for patients with standard V600E/K versus nonstandard alterations. A total of 213 patients with alterations (87 with nonstandard alterations) were identified; OS from diagnosis was significantly worse with nonstandard versus standard alterations, regardless of therapy [HR (95% confidence interval), 0.58 (0.38-0.88); = 0.01]. Overall, 45 patients received BRAF/MEK-directed therapy (eight with nonstandard alterations); there were no significant differences in clinical benefit rate [stable disease ≥6 months/partial/complete response (74% vs. 63%; = 0.39) or PFS ( = 0.24; vs. others)]. In conclusion, patients with nonstandard versus standard alterations ( V600E/K) have a worse prognosis with shorter survival from diagnosis. Even so, 63% of patients with nonstandard alterations achieved clinical benefit with BRAF/MEK inhibitors. Larger prospective studies are warranted to better understand the prognostic versus predictive implication of standard versus nonstandard alterations.