Abstract CT025: Dabrafenib plus trametinib in BRAF V600E-mutant high-grade (HGG) and low-grade glioma (LGG)

  • Vivek Subbiah
    1Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX;
  • Alexander Stein
    2Department of Internal Medicine II (Oncology Center), University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
  • Martin van den Bent
    3Erasmus MC Cancer Institute, Rotterdam, Netherlands;
  • Antje Wick
    4Department of Neurology, University of Heidelberg, Heidelberg, Germany;
  • Filip Y. de Vos
    5Department of Medical Oncology, University Medical Center Utrecht, University Utrecht, Utrecht, Netherlands;
  • Nikolas von Bubnoff
    6a) University Medical Center Freiburg; b) Department of Hematology and Oncology, Medical Center, University of Schleswig-Holstein, Campus Lübeck, Freiburg; Lübeck, Germany;
  • Myra E. van Linde
    7Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, De Boelelaan 1117, Amsterdam, Netherlands;
  • Albert Lai
    8Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA;
  • Gerald W. Prager
    9Department of Medicine I, AKH Wien, Vienna, Austria;
  • Mario Campone
    10Institut de Cancérologie de l'Ouest, Saint-Herblain, France;
  • Angelica Fasolo
    11Department of Medical Oncology, Ospedale San Raffaele IRCCS, Milano, Italy;
  • Jose A. Lopez-Martin
    1212 de Octubre University Hospital & Research Institute (i+12), Madrid, Spain;
  • Tae Min Kim
    13Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea;
  • Ralf-Dieter Hofheinz
    14University Hospital of Mannheim, Mannheim, Germany;
  • Jean-Yves Blay
    15Center Leon Berard & University Claude Bernard Lyon I, Lyon, France;
  • Daniel C. Cho
    16Perlmutter Cancer Center at NYU Langone Medical Center, New York, NY;
  • Anas Gazzah
    17Gustave Roussy Cancer Institute, Villejuif, France;
  • Damien Pouessel
    18Department of Medical Oncology & Clinical Research Unit, Institut Claudius Regaud/Institut Universitaire du Cancer de Toulouse (IUCT-Oncopole), Toulouse, France;
  • Jeffrey Yachnin
    19Karolinska University Hospital, Solna, Sweden;
  • Aislyn Boran
    20Global Drug Development, Oncology Development Unit, Novartis Pharmaceuticals Corporation, East Hanover, NJ;
  • Paul Burgess
    21Global Drug Development, Oncology Development Unit, Novartis Pharma AG, Basel, Switzerland;
  • Palanichamy Ilankumaran
    20Global Drug Development, Oncology Development Unit, Novartis Pharmaceuticals Corporation, East Hanover, NJ;
  • Eduard Gasal
    20Global Drug Development, Oncology Development Unit, Novartis Pharmaceuticals Corporation, East Hanover, NJ;
  • Patrick Y. Wen
    22Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA.

抄録

<jats:title>Abstract</jats:title> <jats:p>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.</jats:p> <jats:p>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.</jats:p>

収録刊行物

  • Cancer Research

    Cancer Research 81 (13_Supplement), CT025-CT025, 2021-07-01

    American Association for Cancer Research (AACR)

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