Comparison of real-world effectiveness of all approved BRAF/MEK inhibitor combinations in <i>BRAF</i> -mutant melanoma patients.

Abstract

e21525 Background: Currently, three distinct combinations of BRAF and MEK inhibitors (BRAFi/MEKi) are approved for treatment of advanced melanoma patients. However, they have not been compared in a head-to-head trial. Objective of this study was to investigate if selection of BRAF/MEK inhibitors combination impacted progression-free survival (PFS) in real-world setting. Methods: This was a multi-centre, retrospective study, conducted in major melanoma centres in Poland. Only patients treated in routine clinical practice (not clinical trials) were included. Multivariable Cox proportional hazards (PH) regression model was created to assess prognostic impact of the selected variables. Results: A total number of 790 BRAF -mutant melanoma patients received BRAFi/MEKi as first-line systemic therapy in advanced metastatic/unresectable setting. Dabrafenib + trametinib (D+T) was used in 497 (62.9%) patients, encorafenib + binimetinib (E+B) in 146 patients (18.5%) and vemurafenib + cobimetinib (V+C) in 147 patients (18.6%). Table 1 provides baseline clinical characteristics and overall response rates (ORR). Median PFS was 8.11 (95% CI: 7.33 – 9.33) months in patients treated with D+T, 10.35 (7.95 – 12.42) months in patients treated with E+B and 8.71 (7.13 – 11.14) in patients treated with V+C. Median overall survival since the start of treatment was 14.1 (12.6 – 15.6) months, 14.7 (12.6 – 21.7) and 12.2 (10.7 – 16) months respectively. Multivariate Cox model included BRAFi/MEKi, baseline melanoma stage, age and gender as covariates, while lactate dehydrogenase level and ECOG score were used as stratification variables due to failure to meet PH assumption. Melanoma stage and age were the only significant prognostic factors with hazard ratio (HR) of 4.48 (2.34– 8.57; p &lt; 0.001) in M1d patients, 2.41 (1.34 – 4.33; p = 0.003) in M1c patients, 2.08 (1.03 – 4.18; p = 0.04) in M1b patients and 0.74 (0.3 – 1.83; 0.511) in unresectable stage III patients compared to M1a patients as reference and HR 1.01 (1-1.03; p = 0.044) for age (continuous). Importantly, combination of BRAFi/MEKi was not a significant prognostic factor, with HR of 0.86 (0.52 – 1.42; p = 0.552) in E+B patients and 0.90 (0.53 – 1.50; p = 0.676) in V+C patients compared to D+T patients. Conclusions: In this retrospective analysis of real-world patients, type of used BRAFi/MEKi combination was not a significant prognostic factor, suggesting similar clinical activity of these combinations. These results require validation in randomized, prospective studies. Combination D+T E+B V+C Number of patients 497 146 147 TNM: M1c 189 (38%) 52 (35.6%) 50 (34%) TNM: M1d 135 (27.2%) 40 (27.4%) 48 (32.7%) TNM: M1a 65 (13.1%) 23 (15.8%) 21 (14.3%) TNM: M1b 70 (14.1%) 21 (14.4%) 21 (14.3%) TNM: stage III unresectable 33 (6.6%) 9 (6.2%) 7 (4.8%) ECOG: 1+ 359 (72.2%) 112 (76.7%) 98 (66.7%) ECOG: 0 122 (24.5%) 34 (23.3%) 49 (33.3%) ORR 245 (49.3%) 91 (62.3%) 85 (57.8%)