The IMPemBra trial, a phase II study comparing pembrolizumab with intermittent/short‐term dual MAPK pathway inhibition plus pembrolizumab in melanoma patients harboring the BRAFV600 mutation.
Authors: Elisa A. Rozeman, Judith M. Versluis, Karolina Sikorska, Ruben Lacroix, Lindsay G Grijpink-Ongering, Birthe Heeres, Bart A. Van De Wiel, Petros Dimitriadis, Ayşegül Sari, Stijn Heijmink, Pia Kvistborg, Daan van den Broek, Annegien Broeks, Jan Willem de Groot, Sofie Wilgenhof, Marieke Anne Vollebergh, Johannes V. Van Thienen, John B. A. G. Haanen, Christian U. Blank
Journal: Journal of Clinical Oncology (2020)

10021 Background: Continuous combination of MAPK inhibition (MAPKi) and anti-PD-(L)1 has been investigated by several trials to improve outcome of BRAFV600 mutated melanoma patients. A major obstacle for continuous combination is the high frequency (~60%) of grade 3-4 treatment-related adverse events (TRAE) for which many patients need to discontinue (~40%). In a preclinical model we showed that short‐time MAPKi induces T cell infiltration and is synergistic with anti-PD‐1. In patients T cell infiltration increased after short-term MAPKi, while after &gt; 2 weeks this was often diminished. The aim of this phase 2b study was to identify the optimal duration of MAPKi with dabrafenib (BRAFi) + trametinib (MEKi) in combination with pembrolizumab (anti-PD-1) in terms of safety, feasibility and immune-activating capacity. Methods: Treatment-naïve BRAFV600E/K mutant advanced melanoma patients started pembrolizumab (PEM) 200mg Q3W and were randomized in week 6 to continue PEM only (cohort 1) or to receive in addition intermittent dabrafenib (D) 150 mg BID + trametinib (T) 2mg QD for 2 x 1 week (cohort 2), 2 x 2 weeks (cohort 3), or continuous for 6 weeks (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, 18 compared to baseline and PFS. Results: Between June 2016 and August 2018, 32 patients have been included; 56% were male, 50% had M1c disease and the majority had a BRAFV600E mutation (81%) and a baseline LDH level &gt; ULN (87%). Grade 3-4 TRAE were observed in 12%, 12%, 50%, and 62% of patients in cohort 1, 2, 3, and 4, respectively. All planned D+T was given in 88%, 63%, and 38% of patients in cohort 2, 3, and 4. Most patients needed to interrupt or discontinue D+T due to fever or elevated liver enzymes. ORR at week 6, week 12, and week 18 were 38%, 62%, and 62% in cohort 1, 25%, 62%, and 75% in cohort 2, 25%, 50%, and 75% in cohort 3 and 0%, 62%, and 50% in cohort 4. After a median follow-up of 17.4 months, the median PFS of patients treated with PEM monotherapy was 10.6 months compared to 27.0 months for patients treated with PEM and short-term/intermittent D+T (p = 0.13). Conclusions: Combination of PEM plus intermittent D+T seems more feasible and tolerable than continuous triple therapy. Intermittent short-time combination therapy might be equally effective, enables therapy with MAPKi as a second line, and therefore warrants further investigation in a larger patient cohort. Clinical trial information: NCT02625337.