Patrick Y Wen1, Alexander Stein2, Martin van den Bent3, Jacques De Greve4, Antje Wick5, Filip Y F L de Vos6, Nikolas von Bubnoff7, Myra E van Linde8, Albert Lai9, Gerald W Prager10, Mario Campone11, Angelica Fasolo12, Jose A Lopez-Martin13, Tae Min Kim14, Warren P Mason15, Ralf-Dieter Hofheinz16, Jean-Yves Blay17, Daniel C Cho18, Anas Gazzah19, Damien Pouessel20, Jeffrey Yachnin21, Aislyn Boran22, Paul Burgess23, Palanichamy Ilankumaran22, Eduard Gasal22, Vivek Subbiah24. 1. Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: patrick_wen@dfci.harvard.edu. 2. Department of Internal Medicine II (Oncology Center), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 3. Brain Tumor Center and Department of Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands. 4. University Hospital Vrije Universiteit Brussel, Brussels, Belgium. 5. Department of Neurology, University of Heidelberg, National Center for Tumor Diseases, Heidelberg, Germany. 6. Department of Medical Oncology, University Medical Center Utrecht, University Utrecht, Utrecht, Netherlands. 7. University Medical Center Freiburg, Freiburg, Germany; Department of Hematology and Oncology, Medical Center, University of Schleswig-Holstein, Lübeck, Germany. 8. Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands. 9. Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. 10. Department of Medicine I, AKH Wien, Medical University of Vienna, Vienna, Austria. 11. Institut de Cancérologie de l'Ouest, Saint-Herblain, France. 12. Department of Medical Oncology, Ospedale San Raffaele IRCCS, Milan, Italy. 13. 12 de Octubre University Hospital & Research Institute, Madrid, Spain. 14. Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. 15. University Health Network, University of Toronto, Toronto, ON, Canada. 16. University Hospital of Mannheim, Mannheim, Germany. 17. Center Leon Berard & University Claude Bernard Lyon I, Lyon, France. 18. New York Medical College, Valhalla, New York, NY, USA. 19. Gustave Roussy Cancer Institute, Villejuif, France. 20. Department of Medical Oncology & Clinical Research Unit, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France. 21. Karolinska University Hospital, Theme Cancer, Center for Clinical Cancer Studies, Solna, Sweden. 22. Global Drug Development, Oncology Development Unit, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. 23. Global Drug Development, Oncology Development Unit, Novartis Pharma AG, Basel, Switzerland. 24. Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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 BRAFV600E 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 BRAFV600E 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 BRAFV600E mutation-positive recurrent or refractory high-grade glioma and low-grade glioma, with a safety profile consistent with that in other indications. BRAFV600E testing could potentially be adopted in clinical practice for patients with glioma. FUNDING: Novartis.
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 BRAFV600E 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 BRAFV600E 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 BRAFV600E mutation-positive recurrent or refractory high-grade glioma and low-grade glioma, with a safety profile consistent with that in other indications. BRAFV600E testing could potentially be adopted in clinical practice for patients with glioma. FUNDING: Novartis.
Authors: A M Zeitlberger; P M Putora; S Hofer; P Schucht; D Migliorini; A F Hottinger; U Roelcke; H Läubli; P Spina; O Bozinov; M Weller; M C Neidert; T Hundsberger Journal: J Neurooncol Date: 2022-04-29 Impact factor: 4.130
Authors: Drew Pratt; Zied Abdullaev; Antonios Papanicolau-Sengos; Courtney Ketchum; Pavalan Panneer Selvam; Hye-Jung Chung; Ina Lee; Mark Raffeld; Mark R Gilbert; Terri S Armstrong; Peter Pytel; Ewa Borys; Joshua M Klonoski; Matthew McCord; Craig Horbinski; Daniel Brat; Arie Perry; David Solomon; Charles Eberhart; Caterina Giannini; Martha Quezado; Kenneth Aldape Journal: Acta Neuropathol Date: 2022-02-01 Impact factor: 17.088
Authors: Alberto Picca; David Guyon; Orazio Santo Santonocito; Capucine Baldini; Ahmed Idbaih; Alexandre Carpentier; Antonio Giuseppe Naccarato; Mario Caccese; Giuseppe Lombardi; Anna Luisa Di Stefano Journal: Cancers (Basel) Date: 2022-02-22 Impact factor: 6.639