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: Three-year survival data and translational analyses.
Authors: Rozeman Elisa A. , Versluis Judith M. , Hoefsmit Esmée P , Dimitriadis Petros , Grijpink-Ongering Lindsay G. , Sikorska Karolina , van de Wiel Bart A. , Heeres Birthe C , Flohil Claudi , Kvistborg Pia , van den Broek Daan , Broeks Annegien , de Groot Jan Willem , Wilgenhof Sofie , Vollebergh Marieke A. , van Thienen Johannes V. , Haanen John B. A. G. , Blank Christian U. 
Published: June 2022

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Background: Continuous combination of MAPK pathway inhibition (MAPKi) and anti-PD-(L)1 showed high response rates, but also high frequency of treatment-related adverse events (TRAE) in BRAFV600-mutated melanoma patients (pts). Short‐time MAPKi already induces T cell infiltration in pts and was synergistic with anti-PD‐1 in a pre-clinical model. This phase 2b trial aimed to identify the optimal duration of MAPKi with dabrafenib + trametinib (D+T) in combination with pembrolizumab (PEM). We have previously shown that no SUSARs were observed, toxicity was related to duration of D+T, and response rates increased after addition of D+T. Here we present 3-year PFS and OS data and results of translational analyses. Methods: In IMPemBra, pts with treatment-naïve BRAFV600E/K mutant advanced melanoma started with PEM 200mg Q3W. After 2 cycles, pts were randomized to continue PEM only (cohort 1) or to receive in addition intermittent dabrafenib 150 mg BID + trametinib 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, treatment adherence and immune-activating capacity of the different regimens. Secondary endpoints were objective response rate (ORR) and PFS, OS was an exploratory endpoint. For survival analyses, pts that received D+T (cohort 2-4) were pooled. Results: Thirty-two pts were randomized, 56% were male, 53% had M1c disease and 88% had a LDH level < ULN. No new grade 3-4 TRAE were observed; frequencies were 12%, 12%, 50% and 62% for pts in cohort 1, 2, 3 and 4, respectively. ORRs were 75% in cohort 1 and 2, and 88% in cohort 3 and 4. The frequency of PD1+CD8+ T cells in peripheral blood decreased slightly during treatment and there were no differences between cohorts. In cohort 1 and 2, an increase in IFNγ signature in tumor biopsies was already observed after 6 weeks of PEM, in cohort 3-4 an increase in IFNγ signature was observed in week 9, after addition of D+T. The same pattern was observed for CD8+ T cell infiltration and PD-L1 expression. After a median follow-up of 43.5 months, the median PFS of pts treated with PEM monotherapy was 10.6 months versus 32.3 months for pts treated with PEM plus D+T (p = 0.19). The 3-year PFS rates were 25.0% and 50.0% respectively. Median OS was 40.5 months in the PEM pts and not reached for pts treated with PEM plus D+T (p = 0.32); 3-year OS rates were 62.5% and 70.8% respectively. Conclusions: IMPemBra demonstrated that short-term addition of intermittent D+T to PEM seems a more feasible, tolerable and an effective alternative for the continuous triple combination. In addition, it gives the opportunity to treat with second line targeted therapy after disease progression. Therefore, this regimen should be considered for further investigation in a larger cohort. Clinical trial information: NCT02625337.