Abstract CT083: Tumor-agnostic efficacy and safety of dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: ROAR basket study
Authors: Subbiah Vivek , Kreitman Robert J. , Wainberg Zev A. , Gazzah Anas , Lassen Ulrik , Stein Alexander , Wen Patrick Y. , Dietrich Sascha , Jonge Maja JA , Blay Jean-Yves , Italiano Antoine , Yonemori Kan , Cho Daniel C. , de Vos Filip YFL , Moreau Philippe , Fernandez Elena Elez , Schellens Jan H. , Zielinski Christoph C. , Redhu Suman , Passos Vanessa Q. , Ilankumaran Palanichamy , Bang Yung-Jue 
Published: April 2023

Abstract
Beyond melanoma, BRAFV600E alterations are prevalent across multiple tumors. We conducted a basket trial (NCT02034110) to assess efficacy and safety of oral BRAF inhibitor dabrafenib (150 mg BD) plus MEK inhibitor trametinib (2 mg OD) in 206 patients (eight cohorts) with BRAFV600E-mutated advanced rare cancers. Patients with anaplastic carcinoma thyroid, biliary tract cancer, gastrointestinal stromal tumor, adenocarcinoma of small intestine, low-grade (eight histologies)/high-grade (seven histologies) glioma, hairy cell leukemia, and multiple myeloma were treated until unacceptable toxicity, disease progression, or death. Overall, median duration of exposure to dabrafenib and trametinib was 12.5 (1–82) and 12.0 (1–84) months, respectively. Primary endpoint was tumor response; secondary endpoints were duration of response, progression free and overall survival, and safety (investigator-assessed). Overall response rate was 56% (38.1%, 72.1%), 53% (37.7%, 68.8%), 0%, 67% (9.4%, 99.2%), 54% (25.1%, 80.8%), 33% (20.0%, 49.0%), 89% (77.8%, 95.9%), and 50% (18.7%, 81.3%), respectively. Median (95% confidence interval) duration of response was 14.4 (7.4, not reached), 8.9 (5.6, 13.7), not reached, 7.7 (not reached, not reached), not reached (5.5, not reached), 31.2 (7.4, 44.2), not reached, and 11.1 (5.6, not reached) months, respectively. Durable and clinically meaningful responses were observed in solid and hematological malignancies (21 histologies). Safety profile was acceptable; most frequent (≥20% 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 is a promising approach in patients with BRAFV600E-mutated advanced rare cancers. These results supported the accelerated FDA approval for a tumor-agnostic BRAF+MEK inhibitor combination representing a precision medicine milestone.
Median progression free and overall survival in BRAFV600E-mutated advanced rare cancer patients ATC(N=36) BTC(N=43) LGG(N=13) HGG(N=45) ASI (N=3) HCL(N=55) MM(N=10) PFS 6.7 (4.7, 13.8) 9.0 (5.5, 9.4) NE 5.5 (1.8, 13.7) 9.5 NE 6.3 (2.3, 12.9) OS 14.5 (6.8, 23.2) 13.5 (10.4, 17.6) 17.6 (9.5, 32.2) NE 21.8 (3.4, NR) NE 33.9 (2.9, 44.6) Patient in the GIST cohort (n=1) did not attain a complete or partial response. ASI, adenocarcinoma of small intestine; ATC, anaplastic thyroid cancer; BTC, biliary tract cancer; GIST, gastrointestinal stromal tumor; HCL, hairy cell leukemia; HGG, high grade (WHO G3/G4) glioma; LGG, low (WHO G1/G2) grade glioma; MM, multiple myeloma; NE, not evaluable; NR, not reached; OS, overall survival; PFS, progression free survival; WHO, World Health Organization.
Citation Format: Vivek Subbiah, Robert J. Kreitman, Zev A. Wainberg, Anas Gazzah, Ulrik Lassen, Alexander Stein, Patrick Y. Wen, Sascha Dietrich, Maja JA Jonge, Jean-Yves Blay, Antoine Italiano, Kan Yonemori, Daniel C. Cho, Filip YFL de Vos, Philippe Moreau, Elena Elez Fernandez, Jan H. Schellens, Christoph C. Zielinski, Suman Redhu, Vanessa Q. Passos, Palanichamy Ilankumaran, Yung-Jue Bang. Tumor-agnostic efficacy and safety of dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: ROAR basket study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT083.