BET Inhibitor Trotabresib Demonstrated Antitumor Activity Among Patients With Heavily Pretreated R/R DLBCL

According to findings from the phase 1 CC-90010-ST-001 trial recently published in Nature Communications, trotabresib, an oral bromodomain and extra-terminal motif (BET) protein inhibitor, demonstrated antitumor activity among patients with heavily pretreated relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), as well as advanced solid tumors. These findings demonstrate the potential value of trotabresib combined with other anticancer agents. 

Victor Moreno, MD, Hospital Universitario Fundación Jimenez Diaz, Madrid, Spain, and coauthors stated that BET inhibitors “play key roles in regulation of gene expression, and may play a role in cancer-cell proliferation, survival, and oncogenic progression.” 

The study authors aimed to assess the efficacy and safety of BET inhibitor trotabresib among patients with heavily pretreated R/R DLBCL or advanced solid tumors. Primary endpoints included safety, tolerability, maximum tolerated dose, and recommended phase 2 dose (RP2D). Secondary endpoints included an assessment of the clinical benefit rate, objective response rate, duration of response or stable disease, progression-free survival, overall survival, and pharmacokinetics. 

This trial included a dose-escalation phase (part A) and a dose-expansion phase (parts B and C). In part A, from July 31, 2017, to November 12, 2018, 69 patients with heavily-pretreated R/R DLBCL or advanced solid tumors were enrolled and treated with trotabresib. Results of part A indicated that trotabresib demonstrated promising tolerability and exhibited single-agent activity, and also determined the recommended phase 2 dose (RP2D) and schedule for the expansion study.

On June 18, 2019, 23 patients with R/R DLBCL were enrolled in part B, 19 of whom received trotabresib at 45 mg/day, 4 days on/24 days off, and 4 of whom received an alternate RP2D dose and schedule of trotabresib at 30 mg/day, 3 days on/11 days off. From October 21, 2019, to July 27, 2020, 41 patients with advanced solid tumors were enrolled in part to test the effects of food on the pharmacokinetics and safety of trotabresib administered at 45 mg/day, 4 days on/24 days off. 

Trotabresib monotherapy showed antitumor activity, with an ORR of 13.0% (95% CI, 2.8 to 33.6) in patients with R/R DLBCL (part B) and an ORR of 0.0% (95% CI, 0.0 to 8.6) and a clinical benefit rate of 31.7% (95% CI, 18.1 to 48.1) in patients with advanced solid tumors (part C). 

Treatment-related adverse events occurred in the majority of patients, and the most common severe events were hematological. However, these toxicities were generally manageable, with some patients remaining on treatment for 2 or more years, and 2 patients receiving 3 or more years of treatment.

These results demonstrate the potential of trotabresib as monotherapy for heavily-pretreated patients with R/R DLBCL or advanced solid tumors.

In conclusion, the study authors wrote, “These results support further investigation of trotabresib in combination with other anticancer agents.”

Source: 

Moreno V, Vieito M, Sepulveda JM, et al. BET inhibitor trotabresib in heavily pretreated patients with solid tumors and diffuse large B-cell lymphomas. Nat Commun. 2023;14(1):1359. Published 2023 Mar 13. doi:10.1038/s41467-023-36976-1