Outcome of adjuvant BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600K– compared to V600E-mutated melanoma.

Abstract

9576 Background: Patients with resected stage III BRAF V600 mutated melanoma can be treated with combined dabrafenib and trametinib (D/T) with significant improvement of recurrence-free survival (RFS). The results of the pivotal Combi-AD study showed overall survival (OS) improvement only for patients with BRAF V600E mutations, while for V600K there was even an OS impairment as compared to placebo, although not statistically significant. Methods: We analysed EUMelaReg data for patients with adjuvant D/T therapy for resected stage III melanoma. Only patients with V600E and V600K mutations were selected, where n=93 from a total of 1,033 patients (9.0 %) harboured V600K. Results: Demographics of patients with V600K mutations differed significantly for age (67 vs. 58 years, p <0.001) and a higher proportion of males (67.0% vs. 54.6%, p=0.03) at baseline. Other baseline variables, including substage, were not significantly different. One year of treatment was completed in 51.6% for V600K, and 62.8% for V600E, respectively, while with V600K mutations 22.6% of the patients stopped for toxicity (vs. 18.8% with V600E), and 10.8% for disease recurrence (vs. 6.9%), which was not statistically significant. After a median follow-up of 41.7 (V600K) and 41.2 (V600E) months, Kaplan-Meier analysis estimated 4-year overall survival of 75.7% for V600K compared to 77.8% for V600E. The 4-y-RFS estimates were 48.3% for V600K and 47.0% for V600E. These differences were not statistically significant. Cox regression analysis revealed no different results when adjusted for demographic co-variates, including age and sex, for RFS and OS, respectively. Conclusions: It appears that V600E and V600K mutations are not associated with a different outcome from adjuvant treatment with combined D/T. The findings offer no explanation for differences found in the Combi-AD trial, although part of these differences also resulted from a different natural course of V600K mutated melanomas the placebo group. A longer follow-up will help to further confirm these results and also analyse the possible role of further treatments in the metastatic setting. Baseline characteristics and outcome. V600E(N=940) V600K(N=93) P-value SEX 0.035 Female 426 (45.3%) 31 (33.3%) Male 514 (54.7%) 62 (66.7%) AGE <0.001 Mean (SD) 57.4 (13.8) 65.6 (11.9) Median [Min, Max] 58.0 [17.0, 90.0] 67.0 [28.0, 87.0] ECOG 0.1 0 846 (90.0%) 82 (88.2%) 1 51 (5.4%) 8 (8.6%) 2 5 (0.5%) 2 (2.2%) Baseline Stage 0.34 III 8 (0.9%) 1 (1.1%) IIIA 126 (13.4%) 7 (7.5%) IIIB 293 (31.2%) 29 (31.2%) IIIC 470 (50.0%) 54 (58.1%) IIID 43 (4.6%) 2 (2.2%) STAGE III DIAGNOSIS TYPE 0.96 Primary Diagnosis 679 (72.2%) 68 (73.1%) Relapse 260 (27.7%) 25 (26.9%) SUBTYPE 0.06 SSM 358 (38.1%) 26 (28.0%) NMM 315 (33.5%) 44 (47.3%) NOS 207 (22.0%) 18 (19.4%) MUP 49 (5.2%) 4 (4.3%) OUTCOME 4-Year RFS (95%-CI) 0.47 (0.43; 0.51) 0.48 (0.38; 0.61) 0.94 4-Year OS (95%-CI) 0.78 (0.75; 0.81) 0.76 (0.65; 0.88) 0.94