Efficacy of dabrafenib (D) trametinib (T) plus spartalizumab (S) by baseline site of metastases in patients (pts) with previously untreated BRAF V600-mutant unresectable or metastatic melanoma: Post hoc analysis of phase III COMBI-i trial

Pts with high tumour burden may benefit from adding anti-PD-1 to targeted therapy.1 Although COMBI-i trial (NCT02967692) did not meet its primary endpoint for overall population, progression-free survival (PFS) was significantly longer with S (anti-PD-1) +DT vs placebo (PBO)+DT in pts with ≥3 metastatic (met) sites (hazard ratio [HR]=0.63; 95% confidence interval [CI] 0.46–0.87).2 This post hoc analysis of COMBI-i examined S+DT vs PBO+DT based on met site. In COMBI-i part 3, eligible pts were randomised 1:1 to receive either S+DT (n=267) or PBO+DT (n=265) until progression or unacceptable toxicity.2 Post hoc analysis of PFS and overall survival (OS) was performed in pts with >2/>3 met sites and in pts with adrenal/bone/lung/liver mets at baseline. PFS and OS were summarised descriptively using Kaplan–Meier methods; HRs were estimated using cox regression models. At data cut off on 01 July 2020, median follow-up for COMBI-i part 3 was 27.2 months.2 Among 531 pts with mets at baseline, n=179 had >2 met sites, n=93 had >3 met sites. Mets at baseline were reported in lung (n=250), liver (n=157), bone (n=57) and adrenal glands (n=33). In pts with >3 met sites, S+DT showed benefit vs PBO+DT in terms of PFS (HR=0.40; 95% CI 0.25–0.65) and OS (HR=0.50; 95% CI 0.28–0.87). Pts with >3 met sites and elevated lactate dehydrogenase (LDH) had longer PFS (HR=0.43; 95% CI 0.24–0.77) and OS (HR=0.42; 95% CI 0.21–0.84) with S+DT vs PBO+DT. Similar results were seen in pts with >2 met sites. PFS was longer with S+DT vs PBO+DT in pts with adrenal (HR=0.20; 95% CI 0.07–0.57), bone (HR=0.45; 95% CI 0.24–0.84) and lung mets (HR=0.59; 95% CI 0.43–0.80); 95% CIs for HR for PFS crossed 1 in pts with liver mets (HR=0.85) or those with isolated lung mets (n=33; HR=1.27). Pts with >2 or >3 met sites with or without raised LDH derived benefit from adding S to DT, as did pts with lung, bone and adrenal involvement at baseline. Number and site of mets may be a useful guide for patient selection for triplet therapy. 1. Kim et al Front Immunol;11:629722. 2. Dummer et al JCO 2022;JCO2101601.