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

Victor Moreno (), Maria Vieito, Juan Manuel Sepulveda, Vladimir Galvao, Tatiana Hernández-Guerrero, Bernard Doger, Omar Saavedra, Carmelo Carlo-Stella, Jean-Marie Michot, Antoine Italiano, Massimo Magagnoli, Cecilia Carpio, Antonio Pinto, Rafael Sarmiento, Barbara Amoroso, Ida Aronchik, Ellen Filvaroff, Bishoy Hanna, Xin Wei, Zariana Nikolova and Irene Braña
Additional contact information
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
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)

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36976-1

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