TY - JOUR
T1 - Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers
T2 - the phase 2 ROAR trial
AU - Subbiah, Vivek
AU - Kreitman, Robert J
AU - Wainberg, Zev A
AU - Gazzah, Anas
AU - Lassen, Ulrik
AU - Stein, Alexander
AU - Wen, Patrick Y
AU - Dietrich, Sascha
AU - de Jonge, Maja J A
AU - Blay, Jean-Yves
AU - Italiano, Antoine
AU - Yonemori, Kan
AU - Cho, Daniel C
AU - de Vos, Filip Y F L
AU - Moreau, Philippe
AU - Fernandez, Elena Elez
AU - Schellens, Jan H M
AU - Zielinski, Christoph C
AU - Redhu, Suman
AU - Boran, Aislyn
AU - Passos, Vanessa Q
AU - Ilankumaran, Palanichamy
AU - Bang, Yung-Jue
N1 - Funding Information:
The ROAR study was designed and data were analyzed by the sponsor (Novartis) in collaboration with the trial steering committee. Study funding was provided by Novartis. Writing and editorial assistance was provided by T. Jandoo, Novartis Healthcare Pvt. Ltd., India. The authors thank G. Gao for supporting data analysis for the manuscript. V.S., an Andrew Sabin Family Foundation Fellow at The University of Texas MD Anderson Cancer Center, acknowledges support from the Jacquelyn A. Brady Fund and is supported by National Institutes of Health grants R01CA242845 and R01CA273168. The MD Anderson Cancer Center Department of Investigational Cancer Therapeutics is supported by the Cancer Prevention and Research Institute of Texas (RP1100584), the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (1U01 CA180964), National Center for Clinical and Translational Sciences grant UL1 TR000371 and the MD Anderson Cancer Center Support Grant (P30 CA016672). This trial was originally designed and sponsored by GlaxoSmithKline. Novartis Pharmaceuticals Corporation is the current sponsor of the trial.
Funding Information:
The US Food and Drug Administration (FDA) granted an accelerated approval to dabrafenib (Tafinlar) plus trametinib (Mekinist) for the treatment of unresectable or metastatic solid tumors with a BRAFV600E mutation. The combination was approved for patients aged 6 years and older in whom the tumors progressed after prior treatment and who had no alternative treatment options. This approval was supported by the meaningful efficacy and safety for the combination in the Rare Oncology Agnostic Research (ROAR) and National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH, NCT02465060 ) studies in adults and a study ( NCT02124772 ) in pediatric patients with refractory or recurrent solid tumors. This was the first approval for a tumor-agnostic BRAF and MEK inhibitor combination approach and was a considerable advance in precision medicine.
Funding Information:
The ROAR study was designed and data were analyzed by the sponsor (Novartis) in collaboration with the trial steering committee. Study funding was provided by Novartis. Writing and editorial assistance was provided by T. Jandoo, Novartis Healthcare Pvt. Ltd., India. The authors thank G. Gao for supporting data analysis for the manuscript. V.S., an Andrew Sabin Family Foundation Fellow at The University of Texas MD Anderson Cancer Center, acknowledges support from the Jacquelyn A. Brady Fund and is supported by National Institutes of Health grants R01CA242845 and R01CA273168. The MD Anderson Cancer Center Department of Investigational Cancer Therapeutics is supported by the Cancer Prevention and Research Institute of Texas (RP1100584), the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (1U01 CA180964), National Center for Clinical and Translational Sciences grant UL1 TR000371 and the MD Anderson Cancer Center Support Grant (P30 CA016672). This trial was originally designed and sponsored by GlaxoSmithKline. Novartis Pharmaceuticals Corporation is the current sponsor of the trial.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/5
Y1 - 2023/5
N2 - BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (≥20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: NCT02034110 .
AB - BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (≥20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: NCT02034110 .
UR - https://www.scopus.com/pages/publications/85152683237
U2 - 10.1038/s41591-023-02321-8
DO - 10.1038/s41591-023-02321-8
M3 - Article
C2 - 37059834
SN - 1078-8956
VL - 29
SP - 1103
EP - 1112
JO - Nature Medicine
JF - Nature Medicine
IS - 5
ER -