Summary of experience of melanoma patients treated with BRAF/MEK inhibitors according to Polish National Drug Reimbursement Program Guidelines

Introduction. Combined inhibition of BRAF and MEK improved progression-free survival and overall survival in patients with BRAFV600-mutation-positive metastatic melanoma. We conducted a retrospective study on real-life patients with BRAF-mutant melanoma treated with BRAF/MEK inhibitors. Patients and methods. Patients with untreated, unresectable stage IIIC/IV melanoma positive for the BRAFV600 mutation were treated with dabrafenib/trametinib or vemurafenib/cobimetinib. All patients received BRAF/MEK inhibitors as first-line therapy according to Polish National Drug Reimbursement Program Guidelines. Median follow-up time was 41 months. For the survival analysis, the Kaplan-Meier estimator was used with log-rank tests for univariate comparisons. Results. A total of 95 patients were included (48 women and 47 men; median age: 55 years). 80 patients received dabrafenib/trametinib and 15 received vemurafenib/cobimetinib. Overall, 12 patients continued therapy after the cutoff date. The objective response rate was 71%, including six patients (6%) with a complete response and 62 patients (65%) with a partial response. Median progression-free survival was 10 months and median overall survival was 15 months. High LDH level, ECOG > 0, stage M1c-M1d and three or more metastatic organ sites negatively impacted PFS and OS. Higher adverse event rate was reported in patients receiving vemurafenib/cobimetinib (87%) as compared to patients treated with dabrafenib/trametinib (64%). Overall, grade 3-4 toxicity was reported in 20% of patients. The most frequent adverse events in the dabrafenib/trametinib group were pyrexia, fatigue, nausea and arthralgia. In the vemurafenib/cobimetinib group, the most frequent adverse events were skin toxicity (rash, photosensitivity), arthralgia, myalgia and diarrhea. Conclusions. Despite the high response rate to BRAF and MEK inhibitor therapy, the overall survival is lower in clinical practice than observed in clinical trials. This difference may be explained by a more heterogeneous patient population seen in routine clinical practice, with more advanced disease and comorbidities.