Induction therapy with BRAF/MEK inhibitors versus upfront ipilimumab/nivolumab in poor prognostic advanced melanoma

BRAF/MEK inhibitor induction therapy (BRAF/MEK-i) followed by ipilimumab/nivolumab (IPI/NIVO) did not show benefit over upfront IPI/NIVO in unselected advanced melanoma patients in clinical trial setting. We investigated BRAF/MEK-i in subgroups of patients with advanced melanoma and poor prognostic characteristics. Patients with BRAF-mutant advanced melanoma treated with BRAF/MEK inhibitors (<120 days) followed by planned switch to IPI/NIVO or upfront IPI/NIVO between 2016 and 2023 were included from the nationwide Dutch Melanoma Treatment Registry. Progression-free survival (PFS) and overall survival (OS) were analyzed in propensity score-matched cohorts and subgroups (LDH 250–500 and >500U/L, symptomatic and asymptomatic brain metastases (BMs), liver metastases, ≥ 3 metastatic sites, and ECOG PS ≥ 2). We included 709 patients (187 BRAF/MEK-i and 522 upfront IPI/NIVO). In the matched cohort (n = 280), median PFS and OS were not statistically significantly different: 6.5 (95 %CI 5.3–8.1) and 20.0 (95 %CI 17.2–35.3) months for BRAF/MEK-i vs. 6.6 (95 %CI 4.3–11.3) and 54.0 (95 %CI 21.7–64.4) months for upfront IPI/NIVO. Upfront IPI/NIVO showed significantly improved PFS compared to BRAF/MEK-i for asymptomatic BMs (median 9.4 months (95 %CI 6.3–28.2) vs. 4.8 months (95 %CI 4.1–5.3); p < 0.01), and significantly improved OS for asymptomatic BMs (median 60.4 months (95 %CI 39.1-NR) vs. 16.2 months (95 %CI 11.7–31.8); p < 0.01), liver metastases (median 49.8 months (95 %CI 32.1–60.3) vs. 14.1 months (95 %CI 12.1–20.5); p < 0.01), LDH 250–500 U/L (median 52.7 months (95 %CI 35.1-NR) vs. 20.1 months (95 %CI 13.9–35.5); p = 0.03), and ≥ 3 metastatic sites (median 54.0 months (95 %CI 39.1-NR) vs. 16.7 months (95 %CI 13.8–24.8); p < 0.01). BRAF/MEK-i showed no significant benefit over upfront IPI/NIVO in matched and stratified analyses according to prognostic characteristics.