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  • 1
    Online Resource
    Online Resource
    Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial
    Springer Science and Business Media LLC ; 2023
    In:  Nature Medicine Vol. 29, No. 5 ( 2023-05), p. 1103-1112
    Details
    In: Nature Medicine, Springer Science and Business Media LLC, Vol. 29, No. 5 ( 2023-05), p. 1103-1112
    Abstract: 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 .
    Type of Medium: Online Resource
    ISSN: 1078-8956 , 1546-170X
    URL: Article
    DOI: 10.1038/s41591-023-02321-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 2
    Online Resource
    Online Resource
    Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial
    Elsevier BV ; 2022
    In:  The Lancet Oncology Vol. 23, No. 1 ( 2022-01), p. 53-64
    Details
    In: The Lancet Oncology, Elsevier BV, Vol. 23, No. 1 ( 2022-01), p. 53-64
    Type of Medium: Online Resource
    ISSN: 1470-2045
    URL: Article
    DOI: 10.1016/S1470-2045(21)00578-7
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
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  • 3
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    Online Resource
    Abstract CT025: Dabrafenib plus trametinib in BRAF V600E-mutant high-grade (HGG) and low-grade glioma (LGG)
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. CT025-CT025
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. CT025-CT025
    Abstract: Background: More effective treatments are needed to improve outcomes in HGG and LGG. Activating BRAF mutations occur in ~3% of glioblastomas and 15% of LGGs. BRAF inhibitor dabrafenib + MEK inhibitor trametinib combination is FDA-approved in BRAF V600-positive melanoma, NSCLC, and anaplastic thyroid cancer. Methods: We conducted a nonrandomized, open-label, phase 2 basket study (NCT02034110) of dabrafenib + trametinib in pts with BRAF V600E mutation-positive rare cancers; here we report results for the HGG and LGG cohorts. Adult pts with histologically confirmed recurrent/progressive HGG (Grade III, IV) or LGG (Grade I, II) per WHO 2007 classification received oral dabrafenib, 150 mg twice daily, and oral trametinib, 2 mg once daily, until unacceptable toxicity, disease progression, or death. The primary endpoint was investigator-assessed objective response rate (ORR) using RANO criteria. Secondary endpoints included progression-free survival (PFS), duration of response (DOR), overall survival (OS), and safety; molecular characterization of baseline tumor samples was an exploratory endpoint. Results: As of Sept 14, 2020, 45 pts (23 male) were enrolled in the HGG cohort; 35 discontinued, 6 remained on treatment, 4 were in follow up. The majority had glioblastoma (69%), followed by anaplastic pleomorphic xanthoastrocytoma and anaplastic astrocytoma (each 11%); of pts with known IDH/MGMT status, 3/29 pts had IDH1 mutations and 8/17 had MGMT promoter methylation. Prior therapies included radiotherapy (98%), surgery, and chemotherapy (93% each). Median (range) follow-up was 12.7 (1.1-56.1) months (mo); ORR was 33% (3 CR, 12 PR); median DOR was 36.9 mo (95% CI, 7.4-44.2). Median PFS and OS were 3.8 mo (95% CI, 1.8-9.2) and 17.6 mo (95% CI, 9.5-45.2), respectively. The LGG cohort enrolled 13 pts (4 male); 7 discontinued, 5 remained on treatment, 1 was in follow up. Most common histologies were ganglioglioma (31%), diffuse astrocytoma, and pleomorphic xanthoastrocytoma (each 15%); of pts with known IDH/MGMT status, 1/8 pts had IDH1 mutation and 0/2 had MGMT promoter methylation. Prior therapies included surgery (92%), radiotherapy (62%), and chemotherapy (38%). Median (range) follow-up was 32.2 (0.8-71.8) mo; ORR was 69% (1 CR, 6 PR, 2 MR); median DOR, PFS, and OS were not reached. Overall, 54/58 pts (93%) experienced adverse events (AEs) across cohorts, most commonly (≥30%) fatigue (50%), headache (43%), nausea (34%), and pyrexia (33%); 31 pts (53%) had grade ≥3 AEs, most commonly (≥5%) fatigue, decreased neutrophil count (9% each), headache, and neutropenia (5% each). Next-generation sequencing showed a heterogenous landscape and low tumor mutation burden. Conclusions: Dabrafenib + trametinib demonstrated promising efficacy in pts with BRAF V600E mutation-positive recurrent/refractory HGG and LGG. The safety profile was consistent with the known safety profile for other indications. Citation Format: Vivek Subbiah, Alexander Stein, Martin van den Bent, Antje Wick, Filip Y. de Vos, Nikolas von Bubnoff, Myra E. van Linde, Albert Lai, Gerald W. Prager, Mario Campone, Angelica Fasolo, Jose A. Lopez-Martin, Tae Min Kim, Ralf-Dieter Hofheinz, Jean-Yves Blay, Daniel C. Cho, Anas Gazzah, Damien Pouessel, Jeffrey Yachnin, Aislyn Boran, Paul Burgess, Palanichamy Ilankumaran, Eduard Gasal, Patrick Y. Wen. Dabrafenib plus trametinib in BRAF V600E-mutant high-grade (HGG) and low-grade glioma (LGG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT025.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-CT025
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 4
    Online Resource
    Online Resource
    Abstract CT083: Tumor-agnostic efficacy and safety of dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: ROAR basket study
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT083-CT083
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT083-CT083
    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.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-CT083
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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