IMPemBra: a phase 2 study comparing pembrolizumab with intermittent/short-term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation.

Background: Continuous combination of MAPK pathway inhibition (MAPKi) and anti-programmed death-(ligand) 1 (PD-(L)1) showed high response rates, but only limited improvement in progression-free survival (PFS) at the cost of a high frequency of treatment-related adverse events (TRAE) in patients with BRAF ^V600 -mutated melanoma. Short-term MAPKi induces T-cell infiltration in patients and is synergistic with anti-programmed death-1 (PD-1) in a preclinical melanoma mouse model. The aim of this phase 2b trial was to identify an optimal regimen of short-term MAPKi with dabrafenib plus trametinib in combination with pembrolizumab.
Methods: Patients with treatment-naïve BRAF ^V600E/K -mutant advanced melanoma started pembrolizumab 200 mg every 3 weeks. In week 6, patients were randomized to continue pembrolizumab only (cohort 1), or to receive, in addition, intermittent dabrafenib 150 mg two times per day plus trametinib 2 mg one time per day for two cycles of 1 week (cohort 2), two cycles of 2 weeks (cohort 3), or continuously for 6 weeks (cohort 4). All cohorts continued pembrolizumab for up to 2 years. Primary endpoints were safety and treatment-adherence. Secondary endpoints were objective response rate (ORR) at week 6, 12, 18 and PFS.
Results: Between June 2016 and August 2018, 33 patients with advanced melanoma have been included and 32 were randomized. Grade 3-4 TRAE were observed in 12%, 12%, 50%, and 63% of patients in cohort 1, 2, 3, and 4, respectively. All planned targeted therapy was given in 88%, 63%, and 38% of patients in cohort 2, 3, and 4. ORR at week 6, 12, and 18 were 38%, 63%, and 63% in cohort 1; 25%, 63%, and 75% in cohort 2; 25%, 50%, and 75% in cohort 3; and 0%, 63%, and 50% in cohort 4. After a median follow-up of 43.5 months, median PFS was 10.6 months for pembrolizumab monotherapy and not reached for patients treated with pembrolizumab and intermittent dabrafenib and trametinib (p=0.17). The 2-year and 3-year landmark PFS were both 25% for cohort 1, both 63% for cohort 2, 50% and 38% for cohort 3 and 75% and 60% for cohort 4.
Conclusions: The combination of pembrolizumab plus intermittent dabrafenib and trametinib seems more feasible and tolerable than continuous triple therapy. The efficacy is promising and appears to be favorable over pembrolizumab monotherapy.
Trial Registration Number: NCT02625337.
Competing Interests: Competing interests: All authors declare no direct conflicts with this work. For unrelated conflicts, EAR, JMV, KS, EPH, PD, DR, RL, LGG-O, ML-Y, BCH, CF, AS, SWTPJH, AB, JWBdG, MAV and JVvT report no competing interests. BAvdW reports an advisory role for BMS. DvdB reports expert testimony and honoraria from Roche Diagnostics, both paid to the institution. JBAGH reports an advisory role for Achilles Therapeutics, BioNTech, Bristol-Myers Squibb, Immunocore, Instil Bio, Iovance Biotherapeutics, Ipsen, Molecular Partners, MSD Oncology, Neogene Therapeutics, Novartis, PokeAcel, Roche/Genentech, Sanofi, Third Rock Ventures and T-Knife; has received research funding, paid to the institute, from Amgen, Asher Biotherapeutics, BioNTech, Bristol-Myers Squibb, MSD, Neon Therapeutics, Novartis; and is stock owner of Neogene Therapeutics. SW reports serving on advisory boards for Eisai, Bristol-Myers Squibb, Pfizer, Novartis and Pierre Fabre all paid to the institution. CUB reports advisory roles for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures, research funding from BMS, Novartis, Nanostring, and 4SC, co-founder, shareholder and advisor of Immagene B.V and co-founder of Signature Oncology.
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