BRAF/MEK inhibitor rechallenge in patients with non-resectable or metastatic BRAF V600-mutated melanoma: A stratified, controlled, retrospective EUMelaReg multicenter study

Background: Therapeutic options for BRAF^V600-mutant melanoma in patients who progress on BRAF/MEK-inhibitors (BRAF/MEKi) and immune-checkpoint-inhibitor (ICI) therapy, are limited. We conducted a retrospective registry study to investigate post-ICI rechallenge with BRAF/MEKi, stratified by type of initial BRAF/MEKi therapy. Methods: This retrospective study analysed patients from the EUMelaReg registry, who received adjuvant or first-line (1 L) BRAF/MEKi in the advanced setting, followed by ICI therapy and were later retreated with BRAF/MEKi. Overall response rate (ORR) for rechallenge served as primary endpoint, disease-control rate (DCR), progression-free survival (PFS), and overall survival (OS) were further endpoints. A covariate-matched control group of patients who received BRAF/MEKi only after 1 L ICI failure was selected for comparison. Results: Among patients previously treated with adjuvant (n = 42) or non-adjuvant (n = 142) BRAF/MEKi, rechallenge after one interim ICI line resulted in ORRs of 26.2 % and 30.3 % and DCRs of 42.9 % and 61.8 %, respectively. Median PFS was 8.4 and 5.1 months, median OS 13.8 and 8.6 months, respectively. Overall, the rechallenge group had a 1-year OS of 43.2 %, lower than the matched control (58.9 %). The adjuvant subgroup was similar to control (55.4 %), while the advanced subgroup showed notably poorer survival (39.9 %). Subgroup analyses showed that both the pre-ICI response to BRAF/MEKi treatment and progressive disease prior to ICI were associated with outcome of the BRAF/MEKi rechallenge. Conclusion: Rechallenge with BRAF/MEKi therapy under real-world conditions for advanced melanoma provides a valid treatment option. For patients who received their initial BRAF/MEKi therapy as adjuvant therapy there seems to be only limited impairment of outcomes.