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

Abstract

BRAF and MEK inhibitors are standard of care for BRAF V600E/K-mutated melanoma, but the benefit of BRAF and/or MEK inhibitors for nonstandard BRAF alterations for melanoma and other cancers is unclear. Patients with diverse malignancies whose cancers had undergone next-generation sequencing were screened for BRAF 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 BRAF V600E/K versus nonstandard BRAF alterations. A total of 213 patients with BRAF alterations (87 with nonstandard alterations) were identified; OS from diagnosis was significantly worse with nonstandard BRAF versus standard alterations, regardless of therapy [HR (95% confidence interval), 0.58 (0.38-0.88); P = 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%; P = 0.39) or PFS (P = 0.24; BRAF V600E/K vs. others)]. In conclusion, patients with nonstandard versus standard BRAF alterations (BRAF V600E/K) have a worse prognosis with shorter survival from diagnosis. Even so, 63% of patients with nonstandard BRAF 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 BRAF alterations.

Figure 1:

Consort diagram for the study. Only patients included in the PREDICT protocol were assessable for response.

Figure 2:

Progression-free survival for standard BRAF mutations (V600E and V600K) as compared to other BRAF alterations treated with BRAF or MEK inhibitors. Start date was course 1 day 1 of BRAF or MEK inhibitor therapy. There were no significant differences in progression-free survival found. Patients were censored if therapy was switched in the absence of progression at the date of the last set of scans. Patients who were lost to follow-up or underwent curative surgery were also censored at the date of the last set of scans. Patients who died without progression were censored at the date of death.

Figure 3:

Overall survival according to BRAF alteration status. A. Overall survival for standard BRAF mutations (V600E and V600K) as compared to other BRAF alterations treated with BRAF or MEK inhibitors. Start date was course 1 day 1 of BRAF and/or MEK inhibitor therapy. Patients with standard alterations had significantly improved overall survival. B. Overall survival from time of diagnosis for standard BRAF mutations (V600E and V600K) as compared to other BRAF alterations for all patients with BRAF alterations. Patients with unknown dates of death were censored at the last follow-up (office visit or phone call). Patients with standard BRAF alterations had significantly longer overall survival from diagnosis

Figure 4:

Time to metastatic disease from time of diagnosis for BRAF mutations (V600E and V600K) as compared to other BRAF alterations. Patient who did not develop metastatic disease were considered censored at the last follow-up (office visit or phone call) or at death. A. All patients with BRAF alterations, B. Patients treated with BRAF and/or MEK inhibitors.