56O - A phase Ia/Ib study of the MDM2-p53 antagonist brigimadlin (BI 907828): Safety and efficacy in patients with dedifferentiated liposarcoma

Background

Targeting the MDM2–p53 interaction represents a potential therapeutic option in liposarcoma. In an earlier analysis of this phase Ia/Ib study (NCT03449381), brigimadlin, a highly potent, orally available MDM2–p53 antagonist showed promising safety and efficacy in patients (pts) with advanced solid tumours including DDLPS. Here we focus on safety and efficacy in pts with DDLPS.

Methods

In the phase Ia dose escalation, the recommended dose for expansion was defined as 45 mg on Day 1 of 21-day cycles (q3w; LoRusso et al., Cancer Discovery, 2023). Phase Ib included two cohorts: Cohort 1 (TP53wt, MDM2-amplified advanced sarcoma) and Cohort 2 (other TP53wt, MDM2-amplified advanced solid tumours); both cohorts received brigimadlin q3w. In phase Ib, the primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) and grade ≥3 treatment-related adverse events (TRAEs).

Results

As of 7 November 2023, 190 pts have been enrolled across phase Ia/Ib to receive brigimadlin q3w (52.6% male; 80.0% white; 55.8%/43.7% ECOG PS 0/1; median 2 prior lines of therapy). In 90 pts with DDLPS who received brigimadlin q3w, median PFS was 8.1 months. In 86 response-evaluable pts, one complete response and 15 partial responses were observed (ORR: 18.6%), and a best response of stable disease was observed in 60 pts (disease control rate: 88.4%). In pts with DDLPS treated in phase Ib (n=84), any-grade TRAEs were reported in 78 (92.9%) pts, most commonly nausea (n=63, 75.0%), fatigue (n=52, 61.9%) and neutropenia (n=45, 53.6%). Grade ≥3 TRAEs were reported in 36 (42.9%) pts, most commonly thrombocytopenia (n=19, 22.6%), neutropenia (n=19, 22.6%) and anaemia (n=8, 9.5%). Adverse events leading to treatment discontinuation occurred in 4 (4.8%) pts. An analysis of radiomic features of tumours will be presented.

Conclusions

Brigimadlin q3w demonstrated manageable toxicity and encouraging efficacy with a high rate of disease control in DDLPS pts. Brigimadlin is being evaluated versus doxorubicin as first-line treatment for pts with advanced DDLPS in the phase II/III Brightline-1 study (NCT05218499), for which the FDA has granted a Fast Track Designation.

Clinical trial identification

NCT03449381.

Editorial acknowledgement

Medical writing support for the development of this abstract under the direction of the authors was provided by Jim Sinclair, PhD, of Ashfield MedComms, an Inizio company, and was funded by Boehringer Ingelheim.

Legal entity responsible for the study

Boehringer Ingelheim.

Funding

Boehringer Ingelheim.

Disclosure

P. Schöffski: Financial Interests, Personal, Advisory Role: Deciphera, Ellipses Pharma, Transgene, Exelixis, Boehringer Ingelheim, Studiecentrum voor Kernenergie (SCK CEN), SQZ Biotechnology, Adcendo, PharmaMar, Merck, Medpace, Cogent Biosciences, Eisai, Curio Science, LLX Solutions, Servier, Biolumina, Genmab, Sanofi, Regeneron, Moleculin Biotech, Avacta Life Sciences, Amryt Pharma, UCB, Boxer Capital; Financial Interests, Institutional, Funding: CoBioRes NV, Eisai, G1 Therapeutics, PharmaMar, Genmab, Merck, Sartar Therapeutics, ONA therapeutics, Adcendo. P. Lorusso: Financial Interests, Personal, Advisory Board: AbbVie, Roche-Genentech, Takeda, Agenus, IQVIA, Pfizer, GSK, QED Therapeutics, AstraZeneca, AstraZeneca, EMD Serono, Kyowa Kirin Pharmaceutical Development, Kineta, Inc., Zentalis Pharmaceuticals, Molecular Templates, ABL Bio, STCube Pharmaceuticals, I-Mab, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanistic, Mersana Therapeutics, BAKX Therapeutics, Scenic Biotech, Qualigen, Roivant Sciences, NeuroTrials, Actuate Therapeutics, Atreca Development, Cullinan, Quanta Therapeutics, Schrodinger; Financial Interests, Personal, Other: SOTIO, Amgen CodeBreak 202, DrenBio, Boehringer Ingelheim. N. Yamamoto: Financial Interests, Personal, Other: Chugai Pharma, ONO Pharmaceuticals, Daiichi Sankyo/UCB Japan, Eisai; Financial Interests, Personal, Advisory Role: Eisai, Takeda, Boehringer Ingelheim, Cimic, Healios, Merck; Financial Interests, Institutional, Funding: Chiome Bioscience, Otsuka, Chugai Pharmaceuticals, Taiho Pharmaceuticals, Eisai, Astellas Pharma, Novartis, Daiichi Sankyo, Lilly Japan, Boehringer Ingelheim, Takeda, Kyowa Hakko Kirinn, Bayer, Pfizer, ONO Pharmaceutical, Janssen, MSD, AbbVie, Bristol Myers Squibb, Merck Serono, GSK, Sumitomo Dainippon, Carna Biosciences, Genmab/Seattle Genetics, Shionogi, Kaken Pharmaceutical, AstraZeneca, CMIC, Rakuten Medical. P. Reichardt: Financial Interests, Personal, Full or part-time Employment: Helios Klinikum Berlin-Buch GmbH; Financial Interests, Personal, Advisory Role: Bayer, Novartis, Roche, Deciphera, Mundibiopharma, PharmaMar, Blueprint Medicines, GSK, Boehringer Ingelheim; Financial Interests, Personal, Other: Clinigen, Deciphera, PharmaMar, Boehringer Ingelheim; Non-Financial Interests, Personal, Other: Chairman of the German Sarcoma Foundation. L. Schwartz: Financial Interests, Personal, Advisory Role: DSMB Member Regeneron, BMS, Merck. C. Hu, H.T. Landsteiner, G. Jayadeva: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. M. Gounder: Financial Interests, Personal, Other: Flatiron Health, PER, Medscape, Guidepoint Global, touchIME, Med Learning Group, More Health, More Health, Great Debates and Updates, GLG, OncLive/MJH Life Sciences, Epizyme, Desmoid Tumor Research Foundation; Financial Interests, Personal, Advisory Role: Daiichi Sankyo, Karyopharm Therapeutics, Epizyme, Bayer, Springworks Therapeutics, TYME, Boehringer Ingelheim, Ayala Pharmaceuticals, Rain Therapeutics, Regeneron; Financial Interests, Personal, Speaker’s Bureau: Amgen, Karyopharm Therapeutics, Boehringer Ingelheim; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Royalties: GODDESS PRO Desmoid Tumor; Non-Financial Interests, Personal, Other: Foundation Medicine, Athenex. All other authors have declared no conflicts of interest.