Encorafenib plus Binimetinib in patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma: First data of the multicenter, multinational, prospective, non-interventional longitudinal study BERINGMELANOMA.
Authors: Richtig Erika , Gutzmer Ralf , Loquai Carmen , Utikal Jochen , Hoeller Christoph , Stadler Rudolf , Forschner Andrea , Hassel Jessica Cecile , Goeppner Daniela , Fluck Michael , Haferkamp Sebastian , Kaatz Martin , Welslau Manfred , Dummer Reinhard , Von Moos Roger Anton Fredy , Schmidt Andrea , Milde Laura , Michielin Olivier , Schadendorf Dirk 
Published: June 2021

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Background: For the treatment of advanced BRAFV600-mutated melanoma, targeted therapy (BRAF/MEK-inhibition) is a standard of care. Encorafenib + binimetinib (EB) were approved in the EU in Sep 2018 and in Switzerland in Nov 2019, based on positive results from COLUMBUS (NCT01909453), with a median progression-free survival (PFS) of 14.9 mo (4-year PFS: 26%) and overall survival (OS) of 33.6 mo (4-year OS: 39%). As data from controlled trials are based on selected populations, BERINGMELANOMA investigates the use of EB under real-world conditions in a broader population. Methods: BERINGMELANOMA is an ongoing, multi-national, multi-center, prospective, longitudinal, non-interventional study. It analyzes the effectiveness, quality of life and tolerability of EB-treatment under real-world conditions (primary endpoint: 1-year PFS-rate), focusing on the first- (1L) and second-line setting and including an evaluation of the impact of prognostic factors. The project aims to enroll up to 750 patients (pts) in a total of 80 German, Austrian and Swiss sites with a study duration of 8 yrs. So far, from Oct 2019 to Jan 2021, 153 pts have been included. Pts with prior BRAF-/MEK-inhibition (except adjuvant use completed > 6 mo) and > 1 prior treatment line were excluded. Results: Here we present the first planned interim analysis based on the initial 100 enrolled pts (91 treated / 89 evaluable; median follow-up: 8.1 mo). This analysis set shows a median age of 63.0 yrs (range 29.0-88.0), 52% of pts were female. 81% presented with distant metastases (brain: 31%), with an involvement of ≥3 organ systems in 51% and an elevated LDH in 42%. 54% of pts underwent prior systemic therapy (adjuvant: 28%; 1L: 24%, with ipilimumab + nivolumab as main 1L-treatment: 52%). EB was mainly administered in the 1L-setting (65%). Main reasons for EB-selection were: physician's preference (37%), efficacy (34%), quality of life (21%). Median estimated EB treatment duration was 12.7 mo (95%CI 8.3-NE), median relative dose intensity was 100% for both drugs. Treatment adaptations were required in 34% of pts. Adverse events (AE) were reported in 76% of pts (grade 3/4: 26%). Main AE (≥10%, all grades) were: nausea (18%), diarrhea (17%), CK increase (15%), fatigue (11%), gamma-GT increase (11%). No fatal toxicities were observed. Conclusions: This first interim analysis of BERINGMELANOMA shows an investigation of EB in a real-world population with advanced disease. Despite the poorer prognosis configuration as compared to the pivotal study, the observed treatment duration and tolerability profile are largely consistent with data derived from COLUMBUS without any new safety signals. The second interim analysis will be performed after enrollment of 200 pts and will include an initial analysis of effectiveness data. Clinical trial information: NCT04045691.