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Clinical Trial
. 2024 Nov 4;26(11):2074-2083.
doi: 10.1093/neuonc/noae116.

Encorafenib and binimetinib followed by radiotherapy for patients with BRAFV600-mutant melanoma and brain metastases (E-BRAIN/GEM1802 phase II study)

Iván Márquez-Rodas  1 , Ana Álvarez  2 , Ana Arance  3 , Izaskun Valduvieco  4 , Miguel-Ángel Berciano-Guerrero  5 , Raquel Delgado  6 , Ainara Soria  7 , Fernándo Lopez Campos  8 , Pedro Sánchez  9 , Jose Luis Romero  10 , Juan Martin-Liberal  11 , Anna Lucas  12 , Roberto Díaz-Beveridge  13 , Antonio-José Conde-Moreno  14 , Maria Del Carmen Álamo de la Gala  15 , Almudena García-Castaño  16 , Pedro José Prada  17 , María González Cao  18 , Enrique Puertas  19 , Joana Vidal  20 , Palmira Foro  21 , Carlos Aguado de la Rosa  22 , Juan Antonio Corona  23 , Pablo Cerezuela-Fuentes  24 , Paco López  25 , Pablo Luna  26 , Neus Aymar  27 , Teresa Puértolas  28 , Pilar Sanagustín  29 , Alfonso Berrocal  30
Affiliations
Clinical Trial

Encorafenib and binimetinib followed by radiotherapy for patients with BRAFV600-mutant melanoma and brain metastases (E-BRAIN/GEM1802 phase II study)

Iván Márquez-Rodas et al. Neuro Oncol. .

Abstract

Background: Encorafenib plus binimetinib (EB) is a standard-of-care treatment for advanced BRAFV600-mutant melanoma. We assessed the efficacy and safety of encorafenib plus binimetinib in patients with BRAFV600-mutant melanoma and brain metastasis (BM) and explored if radiotherapy improves the duration of response.

Methods: E-BRAIN/GEM1802 was a prospective, multicenter, single-arm, phase II trial that enrolled patients with melanoma BRAFV600-mutant and BM. Patients received encorafenib 450 mg once daily plus binimetinib 45 mg BID, and those who achieved a partial response or stable disease at first tumor assessment were offered radiotherapy. Treatment continued until progression. Primary endpoint was intracranial response rate (icRR) after 2 months of EB, establishing a futility threshold of 60%.

Results: The study included 25 patients with no BM symptoms and 23 patients with BM symptoms regardless of using corticosteroids. Among them, 31 patients (64.6%) received sequential radiotherapy. After 2 months, icRR was 70.8% (95% CI: 55.9-83.1); 10.4% complete response. Median intracranial progression-free survival (PFS) and OS were 8.5 (95% CI: 6.4-11.8) and 15.9 (95% CI: 10.7-21.4) months, respectively (8.3 months for icPFS and 13.9 months OS for patients receiving RDT). Most common grades 3-4 treatment-related adverse event was alanine aminotransferase (ALT) increased (10.4%).

Conclusions: Encorafenib plus binimetinib showed promising clinical benefit in terms of icRR, and tolerable safety profile with low frequency of high-grade TRAEs, in patients with BRAFV600-mutant melanoma and BM, including those with symptoms and need for steroids. Sequential radiotherapy is feasible but it does not seem to prolong response.

Keywords: brain metastasis; encorafenib and binimetinib; melanoma; radiotherapy; targeted therapy.

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Conflict of interest statement

IMR declares advisory roles: Amgen, BMS, GSK, Novartis, MSD, Roche, Celegene, Pierre Fabre, Highlight Therapeutics, Regeneron, Sanofi, Merck Serono, Astra Zeneca, BiolineRx, and Sun Pharma. MABG declares advisory roles: BMS, Eisai, Ipsen, Lilly, MSD, Novartis, Pharmamar, and Pierre Fabre. AA declares advisory roles: BMS, MSD, Novartis, Pierre Fabre, Biontech. JML declares lecture fees from Astellas, Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Sanofi; advisory fees from Bristol-Myers Squibb, Highlight Therapeutics, Novartis, Pierre Fabre, Roche, Sanofi; and travel grants from Bristol-Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Pfizer, Roche, and Ipsen. JV declares lecture fees from Merck, Amgen, Bristol-Myers Squibb, Novartis and Pierre Fabre: advisory fees from Bristol-Myers Squibb and Amgen outside the submitted work. FLC declares lecture fees from Astellas, Bristol-Myers Squibb, Janssen, Bayer; advisory fees from Astellas, Bristol-Myers Squibb, Janssen, and Bayer. PC declares lecture fees from Merck and Novartis and advisory fees from Pierre Fabre outside the submitted work. CAR declares advisory fees from: MSD, Astra Zeneca, Sanofi; lecture fees: BMS, Novartis, Roche, Merck Serono, Pfizer, Pierre Fabre, and travel grants from Pierre Fabre. All the remaining coauthors declare that they have no conflicts of interest.

Figures

Figure 1.
Figure 1.
Confirmed maximum reduction in intracranial target lesion (at any time) in patients with symptomatic and asymptomatic brain metastasis. Dashed red lines at 20% and –30% represent the threshold of progression and partial response respectively. Crosses mark patients who were receiving corticosteroids at baseline. 1 patient was not evaluated for response.
Figure 2.
Figure 2.
Kaplan–Meier graphs showing intracranial PFS (A), extracranial PFS (B), and OS (C) in the overall population. Median survivals for each subgroup are included in the graph. Censored patients are marked with a cross line. Dashed lines represent the 50% rate of events.
Figure 3.
Figure 3.
Most common treatment-related adverse events. Bars represent the percentage of patients who experience each event type. Numbers within the bar show the number of patients who had each event. The minimum frequency threshold used for the figure is 10%.
See this image and copyright information in PMC

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