TY - JOUR
T1 - Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR)
T2 - a multicentre, open-label, single-arm, phase 2, basket trial
AU - Wen, Patrick Y.
AU - Stein, Alexander
AU - van den Bent, Martin
AU - de Greve, Jacques
AU - Wick, Antje
AU - de Vos, Filip Y. F. L.
AU - von Bubnoff, Nikolas
AU - van Linde, Myra E.
AU - Lai, Albert
AU - Prager, Gerald W.
AU - Campone, Mario
AU - Fasolo, Angelica
AU - Lopez-Martin, Jose A.
AU - Kim, Tae Min
AU - Mason, Warren P.
AU - Hofheinz, Ralf-Dieter
AU - Blay, Jean-Yves
AU - Cho, Daniel C.
AU - Gazzah, Anas
AU - Pouessel, Damien
AU - Yachnin, Jeffrey
AU - Boran, Aislyn
AU - Burgess, Paul
AU - Ilankumaran, Palanichamy
AU - Gasal, Eduard
AU - Subbiah, Vivek
N1 - Funding Information: This trial was originally designed and sponsored by GlaxoSmithKline. Novartis Pharmaceuticals Corporation is the current sponsor of the trial. The authors thank the patients participating in this clinical trial and their families, as well as the staff at each participating institution that assisted with the study. Medical writing and editorial assistance was provided by Shruti Shah (Novartis), Sharol Janice Rodrigues (Novartis), and Laura Hilditch (Articulate Science), which was funded by Novartis Pharmaceuticals Corporation in accordance with Good Publication Practice guidelines (http://www.ismpp.org/gpp3). The authors thank James Garrett and Kitty Wan (Novartis NPC) for their contributions to the statistical biomarker analysis, Catarina Campbell and Mukta Joshi (Novartis NIBR) for their contributions to the DNA sequencing analysis, and Maurizio Voi (Novartis NPC) for contributions to this study. Support with the Bayesian study design and analysis was provided by Berry Consultants LLC. Funding Information: This trial was originally designed and sponsored by GlaxoSmithKline. Novartis Pharmaceuticals Corporation is the current sponsor of the trial. The authors thank the patients participating in this clinical trial and their families, as well as the staff at each participating institution that assisted with the study. Medical writing and editorial assistance was provided by Shruti Shah (Novartis), Sharol Janice Rodrigues (Novartis), and Laura Hilditch (Articulate Science), which was funded by Novartis Pharmaceuticals Corporation in accordance with Good Publication Practice guidelines ( http://www.ismpp.org/gpp3 ). The authors thank James Garrett and Kitty Wan (Novartis NPC) for their contributions to the statistical biomarker analysis, Catarina Campbell and Mukta Joshi (Novartis NIBR) for their contributions to the DNA sequencing analysis, and Maurizio Voi (Novartis NPC) for contributions to this study. Support with the Bayesian study design and analysis was provided by Berry Consultants LLC. Publisher Copyright: © 2022 Elsevier Ltd
PY - 2022/1/1
Y1 - 2022/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85121901207&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/S1470-2045(21)00578-7
DO - https://doi.org/10.1016/S1470-2045(21)00578-7
M3 - Article
C2 - 34838156
SN - 1470-2045
VL - 23
SP - 53
EP - 64
JO - The Lancet Oncology
JF - The Lancet Oncology
IS - 1
ER -