Dabrafenib plus trametinib in patients with BRAF V600E -mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial.

Background: Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAF ^V600E mutation-positive high-grade glioma and low-grade glioma.
Methods: This study is part of an ongoing open-label, single-arm, phase 2 Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and academic cancer centres in 13 countries (Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, South Korea, Spain, Sweden, and the USA). The study enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients with BRAF ^V600E mutation-positive high-grade glioma and low-grade glioma received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until unacceptable toxicity, disease progression, or death. In the high-grade glioma cohort, patients were required to have measurable disease at baseline using the Response Assessment in Neuro-Oncology high-grade glioma response criteria and have been treated previously with radiotherapy and first-line chemotherapy or concurrent chemoradiotherapy. Patients with low-grade glioma were required to have measurable non-enhancing disease (except pilocytic astrocytoma) at baseline using the Response Assessment in Neuro-Oncology low-grade glioma criteria. The primary endpoint, in the evaluable intention-to-treat population, was investigator-assessed objective response rate (complete response plus partial response for high-grade glioma and complete response plus partial response plus minor response for low-grade glioma). This trial is ongoing, but is closed for enrolment, NCT02034110.
Findings: Between April 17, 2014, and July 25, 2018, 45 patients (31 with glioblastoma) were enrolled into the high-grade glioma cohort and 13 patients were enrolled into the low-grade glioma cohort. The results presented here are based on interim analysis 16 (data cutoff Sept 14, 2020). In the high-grade glioma cohort, median follow-up was 12·7 months (IQR 5·4-32·3) and 15 (33%; 95% CI 20-49) of 45 patients had an objective response by investigator assessment, including three complete responses and 12 partial responses. In the low-grade glioma cohort, median follow-up was 32·2 months (IQR 25·1-47·8). Nine (69%; 95% CI 39-91) of 13 patients had an objective response by investigator assessment, including one complete response, six partial responses, and two minor responses. Grade 3 or worse adverse events were reported in 31 (53%) patients, the most common being fatigue (five [9%]), decreased neutrophil count (five [9%]), headache (three [5%]), and neutropenia (three [5%]).
Interpretation: Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAF ^V600E mutation-positive recurrent or refractory high-grade glioma and low-grade glioma, with a safety profile consistent with that in other indications. BRAF ^V600E testing could potentially be adopted in clinical practice for patients with glioma.
Funding: Novartis.
Competing Interests: Declaration of interests PYW reports research support from Agios, AstraZeneca/MedImmune, Bayer, Celgene, Eli Lilly, Genentech/Roche, Kazia Therapeutics, MediciNova, Merck, Novartis, Nuvation Bio, Oncoceutics, Vascular Biogenics, and VBI Vaccines; and has an advisory or board member role in Agios, AstraZeneca, Bayer, Black Diamond, Boston Pharmaceuticals, ElevateBio, Imvax, Karyopharm Therapeutics, Merck, Mundipharma, Novartis, Novocure, Nuvation Bio, Prelude Therapeutics, QED Therapeutics, Sapience, Vascular Biogenics, VBI Vaccines, and Voyager. AS reports grants or research support from Bristol Myers Squibb, German Cancer Aid, Merck KGaA, Roche, Sanofi, and Servier; has advisory or board member role in Amgen, Bristol Myers Squibb, Celgene, Merck KGaA, Merck Sharp & Dohme, Roche, Sanofi, and Servier; and speaker's bureau participation in Amgen, Bristol Myers Squibb, Merck KGaA, Roche, Sanofi, and Servier. MvdB has a consultant or independent role in Agios, CarThera, Celgene, Genenta, Karyopharm Therapeutics, and Nerviano Medical Sciences. FYFLdV reports grants or research support from AbbVie, BioClin Therapeutics, Bristol Myers Squibb, GlaxoSmithKline, Novartis, Octimet Oncology NV, and Vaximm; has an advisory or board member role in Bristol Myers Squibb; and received travel support from Roche Genentech. NvB reports grants or research support and has an advisory or board member role in Novartis; and recieves honorarium from Novartis and Takeda. GWP reports honoraria and being an advisory or board member in Amgen, Bayer, Bristol Myers Squibb, Eli Lilly, Merck, Merck Sharp & Dohme, Roche, Sanofi, Servier, and Taiho Pharma. MC reports honoraria and advisor or consultant role in AbbVie, Accord, AstraZeneca, GT1, Novartis, Pierre Fabre, Pfizer, Sanofi, and Servier; and speaker's bureau participation in Eli Lilly and Novartis. JAL-M is employed at PharmaMar; and reports advisory or board member role in Amgen, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Novartis, Merck Sharp & Dohme, Pfizer, PharmaMar, Pierre Fabre, and Roche; has a consultant or independent role in Chobani; is a stock shareholder (self-managed) in PharmaMar; is a co-founder, member of the Board of Directors, and former President of GETICA (Spanish Group–Cancer ImmunoBiotherapy); and receives travel support from Bayer, Bristol Myers Squibb, Daiichi Sankyo, Merck Serono, Merck Sharp & Dohme, Novartis, PharmaMar, and Roche. TMK reports grants or research support from AstraZeneca–KHIDI outside the submitted work; has a consultant or independent role in AstraZeneca, Boryung, Eli Lilly, Hanmi, Novartis, Roche–Genentech, Sanofi, and Takeda; and speaker's bureau participation in Takeda. WPM reports participation in GlaxoSmithKline, Ono Pharmaceuticals, Apotex, and Viatris advisory board outside the submitted work. J-YB reports grants or research support from AstraZeneca, Bayer, Bristol Myers Squibb, Deciphera, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, PharmaMar, and Roche; has an advisory or board member role in Innate Pharma; and receives honorarium from Bayer, Deciphera, Novartis, and Roche. DCC reports being a consultant for Amphivena Therapeutics, HUYA Bioscience, Nektar Therapeutics, Pfizer, PureTech, and Werewolf. AG is a principal investigator or sub-investigator in clinical trials for AbbVie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, arGEN-X BVBA, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Basilea Pharmaceutica International, Bayer Healthcare, BBB Technologies BV, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Celgene, Chugai Pharmaceutical, Clovis Oncology, Cullinan Apollo, Daiichi Sankyo, Debiopharm, Eisai, Eli Lilly, Exelixis, Faron Pharmaceuticals, Forma Therapeutics, GamaMabs, Genentech, GlaxoSmithKline, H3 Biomedicine, Hoffmann-La Roche, ImCheck Therapeutics, Innate Pharma, Institut de Recherche Pierre Fabre, Iris Servier, Janssen-Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharmaceutical Development, Lilly France, Loxo Oncology, Lytix Biopharma AS, Medicament, MedImmune, Menarini Ricerche, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners, Merck Sharp & Dohme-Chibret, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology NV, Oncoethix, Oncopeptides, Orion Pharma, Ose Pharma, Pfizer, PharmaMar, Pierre Fabre, Roche, Sanofi Aventis, Seattle Genetics, Sotio, Syros Pharmaceuticals, Taiho Pharma, Tesaro, and Xencor; receives research grants from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Janssen-Cilag, Merck, Novartis, Onxeo, Pfizer, Roche, and Sanofi; and receives non-financial support (drug supplied) from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, MedImmune, Merck, NH TherAguix, Onxeo, Pfizer, and Roche. DP reports an advisory or board member role in Astellas, AstraZeneca, Merck, Pfizer, and Sanofi; receives honorarium from Bristol Myers Squibb, Ipsen, Janssen, and Merck Sharp & Dohme; and receives travel and accommodation support from AstraZeneca, Janssen, and Pfizer. AB is an employee of Novartis and reports stock ownership in Novartis. PB is an employee of Novartis and reports stock ownership in Novartis and GlaxoSmithKline. PI is an employee of Novartis and reports stock ownership in Novartis. EG is a former employee of Novartis and reports stock ownership in Novartis and Innovent Biologics. VS reports grants or research support from AbbVie, Agensys, Alfasigma, Altum, Amgen, Bayer, Berghealth, Blueprint Medicines, Boston Biomedical, Boston Pharmaceuticals, D3 Pharma, Dragonfly Therapeutics, Exelixis, Fujifilm, Idera Pharmaceuticals, Incyte, Inhibrx, Loxo Oncology, MedImmune, MultiVir, National Comprehensive Cancer Network, NCI-Cancer Therapy Evaluation Program, Novartis, Pfizer, PharmaMar, Takeda, The University of Texas MD Anderson Cancer Center, and Turning Point Therapeutics; has an advisory or board member role in Eli Lilly, Helsinn, Incyte, Loxo Oncology, MedImmune, Novartis, QED Therapeutics, and R-Pharma US; is an Andrew Sabin Family Foundation Fellow at The University of Texas MD Anderson Cancer Center; receives financial support from The Jacquelyn A Brady Fund; receives the US National Institutes of Health grant R01CA242845; and is affiliated with University of Texas MD Anderson Cancer Center, which receives the US National Institutes of Health support grant P30 CA016672. All other authors declare no competing interests.
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