Continuous combination of MAPKi and anti-PD-(L)1 is currently tested in several trials to improve outcome of BRAFV600 mutated melanoma patients (pts). However, a major obstacle for continuous combination is the high frequency of grade 3/4 treatment-related adverse events (TRAE). We showed that short‐time MAPKi induces T cell infiltration and is synergistic with anti-PD‐1 in mice. In pts we found increased T cell infiltration upon D+T after short-term MAPKi, while this was frequently below baseline levels after >2 weeks (W) MAPKi. The aim of this phase 2b study was to identify the optimal duration of D+T in combination with PEM.
Treatment-naïve BRAFV600E/K mutant advanced melanoma pts (n=32) started PEM 200mg Q3W and were randomized in W6 to continue PEM only (cohort 1), or to receive in addition intermittent D 150 mg BID + T 2mg QD for 2 x 1W (cohort 2), 2 x 2W (cohort 3), or continuous for 6W (cohort 4). All cohorts continued PEM for up to 2 years. Primary endpoints were safety and treatment adherence. Secondary endpoints were objective response rate (ORR, RECIST 1.1) at week 6, 12, and 18 compared to baseline, and PFS.
Of the 32 pts enrolled, 4 (13%) had LDH>ULN and 16 (50%) had M1c disease. So far, 26 pts completed the first 18W and were evaluable for toxicity and response. Grade 3/4 TRAE within the first 18W were observed in 0%, 14%, 33%, and 50% of pts in cohort 1, 2, 3, and 4, respectively. All planned D+T was given in 86%, 50%, and 33% of pts in cohort 2, 3, and 4. Most pts needed to interrupt D+T due to fever. D+T was discontinued in 1 pt in cohort 2 due to myalgia, 3 in cohort 3 due to fever (2x) and mucositis, and 3 pts in cohort 4 due to fever and liver toxicity. PEM was stopped in 1 pt in cohort 2 due to myalgia and interrupted in 2 pts in cohort 3 due to mucositis and liver toxicity and 3 in cohort 4 due to liver toxicity. ORR at W6, W12, and W18 were 29%, 57%, and 57% in cohort 1, 29%, 71%, and 71% in cohort 2, 33%, 50%, and 83% in cohort 3 and 0%, 50%, and 50% in cohort 4.
IMPemBra indicates that PEM + intermittent D+T for 2x 1W or 2x 2W are promising combinations in terms of safety and feasibility, warranted to be tested in subsequent trials.
Clinical trial identification