Dabrafenib Plus Trametinib in Patients With BRAF-Mutant Low-Grade and High-Grade Glioma (ROAR): A Multicentre, Open-Label, Single-Arm, Phase 2, Basket Trial

Authors

Patrick Y. Wen, Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: patrick_wen@dfci.harvard.edu.
Alexander Stein, Department of Internal Medicine II (Oncology Center), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Martin van den Bent, Brain Tumor Center and Department of Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands.
Jacques De Greve, University Hospital Vrije Universiteit Brussel, Brussels, Belgium.
Antje Wick, Department of Neurology, University of Heidelberg, National Center for Tumor Diseases, Heidelberg, Germany.
Filip Y. de Vos, Department of Medical Oncology, University Medical Center Utrecht, University Utrecht, Utrecht, Netherlands.
Nikolas von Bubnoff, University Medical Center Freiburg, Freiburg, Germany; Department of Hematology and Oncology, Medical Center, University of Schleswig-Holstein, Lübeck, Germany.
Myra E. van Linde, Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands.
Albert Lai, Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
Gerald W. Prager, Department of Medicine I, AKH Wien, Medical University of Vienna, Vienna, Austria.
Mario Campone, Institut de Cancérologie de l'Ouest, Saint-Herblain, France.
Angelica Fasolo, Department of Medical Oncology, Ospedale San Raffaele IRCCS, Milan, Italy.
Jose A. Lopez-Martin, 12 de Octubre University Hospital & Research Institute, Madrid, Spain.
Tae Min Kim, Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
Warren P. Mason, University Health Network, University of Toronto, Toronto, ON, Canada.
Ralf-Dieter Hofheinz, University Hospital of Mannheim, Mannheim, Germany.
Jean-Yves Blay, Center Leon Berard & University Claude Bernard Lyon I, Lyon, France.
Daniel C. Cho, New York Medical College, Valhalla, New York, NY, USA.Follow
Anas Gazzah, Gustave Roussy Cancer Institute, Villejuif, France.
Damien Pouessel, Department of Medical Oncology & Clinical Research Unit, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France.
Jeffrey Yachnin, Karolinska University Hospital, Theme Cancer, Center for Clinical Cancer Studies, Solna, Sweden.
Aislyn Boran, Global Drug Development, Oncology Development Unit, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Paul Burgess, Global Drug Development, Oncology Development Unit, Novartis Pharma AG, Basel, Switzerland.
Palanichamy Ilankumaran, Global Drug Development, Oncology Development Unit, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Eduard Gasal, Global Drug Development, Oncology Development Unit, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Vivek Subbiah, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Author Type(s)

Faculty

Award

Research Article with Highest Number of Citations for All Authors

DOI

10.1016/S1470-2045(21)00578-7

Journal Title

The Lancet. Oncology

First Page

53

Last Page

64

Document Type

Article

Publication Date

1-1-2022

Department

Medicine

Abstract

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 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 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 mutation-positive recurrent or refractory high-grade glioma and low-grade glioma, with a safety profile consistent with that in other indications. BRAF testing could potentially be adopted in clinical practice for patients with glioma. FUNDING: Novartis.

Recommended Citation

Wen, P. Y., Stein, A., van den Bent, M., De Greve, J., Wick, A., de Vos, F. Y., von Bubnoff, N., van Linde, M. E., Lai, A., Prager, G. W., Campone, M., Fasolo, A., Lopez-Martin, J. A., Kim, T. M., Mason, W. P., Hofheinz, R., Blay, J., Cho, D. C., Gazzah, A., Pouessel, D., Yachnin, J., Boran, A., Burgess, P., Ilankumaran, P., Gasal, E., & Subbiah, V. (2022). Dabrafenib Plus Trametinib in Patients With BRAF-Mutant Low-Grade and High-Grade Glioma (ROAR): A Multicentre, Open-Label, Single-Arm, Phase 2, Basket Trial. The Lancet. Oncology, 23 (1), 53-64. https://doi.org/10.1016/S1470-2045(21)00578-7