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BET inhibitor trotabresib in heavily pretreated patients with solid tumors and diffuse large B-cell lymphomas

Author

Listed:
  • Victor Moreno

    (Hospital Universitario Fundación Jimenez Diaz)

  • Maria Vieito

    (Vall d’Hebron Institute of Oncology (VHIO))

  • Juan Manuel Sepulveda

    (Hospital Universitario 12 de Octubre)

  • Vladimir Galvao

    (Vall d’Hebron Institute of Oncology (VHIO))

  • Tatiana Hernández-Guerrero

    (Hospital Universitario Fundación Jimenez Diaz)

  • Bernard Doger

    (Hospital Universitario Fundación Jimenez Diaz)

  • Omar Saavedra

    (Vall d’Hebron Institute of Oncology (VHIO))

  • Carmelo Carlo-Stella

    (Humanitas University, Rozzano
    Humanitas Research Hospital – IRCCS, Rozzano)

  • Jean-Marie Michot

    (Institut Gustave Roussy)

  • Antoine Italiano

    (Institut Bergonie Centre Regional de Lutte Contre Le Cancer de Bordeaux et Sud Ouest)

  • Massimo Magagnoli

    (Humanitas Research Hospital – IRCCS, Rozzano)

  • Cecilia Carpio

    (Vall d’Hebron Institute of Oncology (VHIO))

  • Antonio Pinto

    (Hematology-Oncology & Stem Cell Transplantation Unit, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS)

  • Rafael Sarmiento

    (Centre for Innovation and Translational Research Europe, a Bristol Myers Squibb Company)

  • Barbara Amoroso

    (Centre for Innovation and Translational Research Europe, a Bristol Myers Squibb Company)

  • Ida Aronchik

    (Bristol Myers Squibb)

  • Ellen Filvaroff

    (Bristol Myers Squibb)

  • Bishoy Hanna

    (Bristol Myers Squibb)

  • Xin Wei

    (Bristol Myers Squibb)

  • Zariana Nikolova

    (Centre for Innovation and Translational Research Europe, a Bristol Myers Squibb Company)

  • Irene Braña

    (Vall d’Hebron Institute of Oncology (VHIO))

Abstract

Bromodomain and extraterminal proteins (BET) play key roles in regulation of gene expression, and may play a role in cancer-cell proliferation, survival, and oncogenic progression. CC-90010-ST-001 (NCT03220347) is an open-label phase I study of trotabresib, an oral BET inhibitor, in heavily pretreated patients with advanced solid tumors and relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Primary endpoints were the safety, tolerability, maximum tolerated dose, and RP2D of trotabresib. Secondary endpoints were clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] of ≥4 months’ duration), objective response rate (CR + PR), duration of response or SD, progression-free survival, overall survival, and the pharmacokinetics (PK) of trotabresib. In addition, part C assessed the effects of food on the PK of trotabresib as a secondary endpoint. The dose escalation (part A) showed that trotabresib was well tolerated, had single-agent activity, and determined the recommended phase 2 dose (RP2D) and schedule for the expansion study. Here, we report long-term follow-up results from part A (N = 69) and data from patients treated with the RP2D of 45 mg/day 4 days on/24 days off or an alternate RP2D of 30 mg/day 3 days on/11 days off in the dose-expansion cohorts (parts B [N = 25] and C [N = 41]). Treatment-related adverse events (TRAEs) are reported in almost all patients. The most common severe TRAEs are hematological. Toxicities are generally manageable, allowing some patients to remain on treatment for ≥2 years, with two patients receiving ≥3 years of treatment. Trotabresib monotherapy shows antitumor activity, with an ORR of 13.0% (95% CI, 2.8–33.6) in patients with R/R DLBCL (part B) and an ORR of 0.0% (95% CI, 0.0–8.6) and a CBR of 31.7% (95% CI, 18.1–48.1) in patients with advanced solid tumors (part C). These results support further investigation of trotabresib in combination with other anticancer agents.

Suggested Citation

  • Victor Moreno & Maria Vieito & Juan Manuel Sepulveda & Vladimir Galvao & Tatiana Hernández-Guerrero & Bernard Doger & Omar Saavedra & Carmelo Carlo-Stella & Jean-Marie Michot & Antoine Italiano & Mass, 2023. "BET inhibitor trotabresib in heavily pretreated patients with solid tumors and diffuse large B-cell lymphomas," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36976-1
    DOI: 10.1038/s41467-023-36976-1
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    References listed on IDEAS

    as
    1. Panagis Filippakopoulos & Jun Qi & Sarah Picaud & Yao Shen & William B. Smith & Oleg Fedorov & Elizabeth M. Morse & Tracey Keates & Tyler T. Hickman & Ildiko Felletar & Martin Philpott & Shonagh Munro, 2010. "Selective inhibition of BET bromodomains," Nature, Nature, vol. 468(7327), pages 1067-1073, December.
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