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Clinical Trial
. 2023 Mar 13;14(1):1359.
doi: 10.1038/s41467-023-36976-1.

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

Victor Moreno  1 , Maria Vieito  2 , Juan Manuel Sepulveda  3 , Vladimir Galvao  2 , Tatiana Hernández-Guerrero  4 , Bernard Doger  4 , Omar Saavedra  2 , Carmelo Carlo-Stella  5   6 , Jean-Marie Michot  7 , Antoine Italiano  8 , Massimo Magagnoli  6 , Cecilia Carpio  2 , Antonio Pinto  9 , Rafael Sarmiento  10 , Barbara Amoroso  10 , Ida Aronchik  11 , Ellen Filvaroff  11 , Bishoy Hanna  11 , Xin Wei  11 , Zariana Nikolova  10 , Irene Braña  2
Affiliations
Clinical Trial

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

Victor Moreno et al. Nat Commun. .

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.

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Conflict of interest statement

V.M. has received consulting fees from Bristol Myers Squibb, Basilea, Bayer, Janssen, Nanobiotix, Pieris Pharmaceuticals, Regeneron/Sanofi, and Roche, and honoraria from Bristol Myers Squibb and Bayer. M.V. has received personal fees from Roche, EMD Serono, and TFS. J.M.S. has received personal fees and non-financial support from Celgene (a Bristol Myers Squibb Company), AbbVie, and Astellas, non-financial support from Ipsen, and research grants from Pfizer and IDP Pharma. J.-M.M. has received research grants from Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Novartis, Pfizer, Roche, and Sanofi, non-financial support from Bristol Myers Squibb, AstraZeneca, Bayer, Boehringer Ingelheim, GSK, MedImmune, Merck, NH TherAguix, Pfizer, and Roche, and other support from Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd, Merck, Merck Sharp & Dohme, Pfizer, and Regeneron. A.I. has received consulting fees from Epizyme, Lilly, Merck Sharp & Dohme, Novartis, Pharmamar, and Roche, and received research grants from Bristol Myers Squibb, AstraZeneca, Bayer, Chugai, Merck Sharp & Dohme, Novartis, Pharmamar, Pfizer, and Roche. M.M. has received honoraria from AstraZeneca and Sanofi. C.C. has received consulting fees for acting in an advisory role from Bristol Myers Squibb, Regeneron, Novartis, and Takeda. A.P. has received honoraria from Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, Helsinn Healthcare, Janssen, Celgene, Gilead Sciences, Incyte, Servier, Merck Sharp & Dohme, and Takeda. I.B. has received personal fees from Bristol Myers Squibb, AstraZeneca, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Rakuten Aspyrian, Roche, and research funding from Bristol Myers Squibb, AstraZeneca, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Rakuten Aspyrian, Roche, Celgene, GlaxoSmithKline, Incyte, Janssen, Kura, Novartis, Pfizer, Shattuck Labs, and VCN Biosciences. V.G., T.H.-G., B.D., O.S., and C.C.-S. have no conflicts of interest to disclose. R.S., B.A., and Z.N. are employed by the Centre for Innovation and Translational Research Europe, a Bristol Myers Squibb Company. E.F., B.H., and X.W. are employed by Bristol Myers Squibb. B.H., E.F., R.S., X.W., and Z.N. hold Bristol Myers Squibb stock. I.A. was employed by Bristol Myers Squibb at the time of the study.

Figures

Fig. 1
Fig. 1. Patient disposition as of June 16, 2022.
DLBCL diffuse large B-cell lymphoma, R/R relapsed/refractory.
Fig. 2
Fig. 2. Treatment-related adverse events reported in ≥10% of patients in the overall study population, or in ≥2 patients at grade ≥3 severity.
Grade 3 essential hypertension, hypokalemia, lipase increased, liver function test abnormal, presyncope, skin hemorrhage, and grade 4 blood creatinine phosphokinase increased, diabetes mellitus, and inappropriate antidiuretic hormone secretion were reported in one patient each in the overall part A population. Grade 3 abdominal infection, blood bilirubin increased, pneumonia and grade 4 blood creatinine increased, febrile neutropenia, leukopenia, and lymphopenia were reported in one patient each in the part B R/R DLBCL population. Grade 3 gamma-glutamyl transferase increased, hyperamylasemia, and syncope were reported in one patient each in the part C population. Source data are provided as a source data file. aNo grade 5 TRAEs were reported during the study. bNineteen patients received trotabresib 45 mg/day 4 days on/24 days off and four patients received trotabresib 30 mg/day 3 days on/11 days off. ALT alanine aminotransferase, DLBCL diffuse large B-cell lymphoma; R/R relapsed/refractory, TRAE treatment-related adverse event.
Fig. 3
Fig. 3. Summary of antitumoral activity.
Source data are provided as a source data file. aConfirmed best response is presented for part C, defined as a consecutive response of the same or better that is at least 4 weeks apart, regardless of tumor type. bORR = CR + PR. cCBR = CR + PR + SD ≥4 months. CBR clinical benefit rate, CR complete response, DLBCL diffuse large B-cell lymphoma, ORR objective response rate, PR partial response, R/R relapsed/refractory, SD stable disease.
Fig. 4
Fig. 4. Duration of treatment and best response.
a Patients with R/R DLBCL in part B (n = 23) and b part C (n = 41). A swim plot showing the duration of treatment for patients in part A is shown in Supplementary Fig. 1. Source data are provided as a source data file. CR complete response, DLBCL diffuse large B-cell lymphoma, NE not evaluable, R/R relapsed/refractory, SD stable disease, PD progressive disease, PR partial response.
Fig. 5
Fig. 5. Imaging results of representative responses to trotabresib.
a MRI evaluation of a patient with grade 2 astrocytoma. The patient had a complete response on trotabresib (red arrows), with the disappearance of both enhancing and non-enhancing areas compared with baseline. The patient discontinued after 19 cycles of treatment due to disease progression. b FDG-PET/CT evaluation of a patient with germinal center B-cell immunophenotype R/R DLBCL who had a 57% reduction in target lesion size after two cycles of trotabresib (blue arrow). This was accompanied by the appearance of a new metabolic lesion (red arrow), and treatment was discontinued after four cycles of trotabresib due to disease progression. c MRI evaluation of a patient with refractory high-grade astrocytoma. The patient had a minor response on trotabresib with a 38% reduction in tumor size (red arrows), and the patient remained on study treatment at cycle 34 with a continued response as of June 16, 2022. CT computed tomography, DLBCL diffuse large B-cell lymphoma, FDG fluorodeoxyglucose, MRI magnetic resonance imaging, PET positron emission tomography, R/R relapsed/refractory. The two left-most images in panel a are reprinted from Annals of Oncology 31(6), Moreno V, et al. Phase I study of CC-90010, a reversible, oral BET inhibitor in patients with advanced solid tumors and relapsed/refractory non-Hodgkin’s lymphoma, Page 780–788, Copyright 2020, with permission from Elsevier.
Fig. 6
Fig. 6. Blood CCR1 mRNA levels in part B.
a Four hours after the first (left) and last dose (right) in part B, and b from 0–192 h in patients receiving trotabresib 45 mg/day 4 days on/24 days off. For both figures, colored data points indicate individual patient values for the percentage of baseline CCR1 expression and black lines and error bars indicate mean ± SD. Source data are provided as a source data file. aData not shown for one patient with a percentage of baseline CCR1 expression of 1110.93; SD for this time point was 260.36. CCR1 C-C motif chemokine receptor 1, mRNA messenger RNA.
Fig. 7
Fig. 7. Study design.
BCC basal cell carcinoma, DLBCL diffuse large B-cell lymphoma, ECOG PS Eastern Cooperative Oncology Group performance status, RP2D recommended phase II dose.
See this image and copyright information in PMC

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