61MO - Phase Ia/Ib study of the MDM2-p53 antagonist brigimadlin (BI 907828) in advanced solid tumours: Overall safety, and efficacy in patients (pts) with well-differentiated liposarcoma (WDLPS)

Background

Disruption of cell cycle arrest and apoptosis by inactivation of p53 is a key tumour survival and proliferation mechanism and can occur via MDM2 amplification. Thus, inhibiting MDM2 may restore p53 activity in TP53 wild-type tumours. Brigimadlin (BI 907828) is a highly potent, oral MDM2–p53 antagonist that has shown promising preclinical antitumour activity. This phase I study is assessing brigimadlin monotherapy in pts with advanced solid tumours, including WDLPS. Here we report safety data in all pts who received brigimadlin on Day 1 of 21-day cycles (q3w) and updated efficacy data in those with WDLPS.

Methods

In phase Ia, pts received escalating doses of brigimadlin and the recommended dose for expansion was defined as 45 mg q3w (LoRusso et al., Cancer Discovery, 2023). In phase Ib (dose expansion), pts were enrolled to Cohort 1 (TP53wt, MDM2-amplified sarcoma) or Cohort 2 (other TP53wt, MDM2-amplified solid tumours). The primary endpoint for phase Ib was progression-free survival (PFS); secondary endpoints included objective response, disease control rate, and grade ≥3 treatment-related adverse events (TRAEs).

Results

As of 7 Nov 2023, 217 pts had been enrolled. Of these, 190 pts received brigimadlin q3w: the median age was 61 years (19–83 years); 52.6% were male; and 55.8%/43.7% had an ECOG performance score of 0/1. Among these 190 pts, 169 (88.9%) had a TRAE, the most common being nausea (69.5%) and fatigue (54.2%). The most common grade ≥3 TRAEs were neutropenia (27.4%) and thrombocytopenia (23.7%). Seventy pts (36.8%) experienced an adverse event that led to dose reduction, and 11 pts (5.8%) discontinued treatment due to an adverse event. Of the 190 pts who received brigimadlin q3w, 31 had MDM2-amplified WDLPS, of whom 20 were response-evaluable: 3/20 pts (15%) had a confirmed partial response and 16/20 (80%) had stable disease, giving a disease control rate of 95% (19/20). The preliminary median PFS was 25.1 months.

Conclusions

Brigimadlin administered q3w demonstrated a manageable safety profile and encouraging preliminary efficacy in pts with advanced, MDM2-amplified WDLPS.

Clinical trial identification

NCT03449381.

Editorial acknowledgement

Medical writing support was provided by Lucy Lettin of Ashfield MedComms, an Inizio company, and funded by Boehringer Ingelheim.

Legal entity responsible for the study

Boehringer Ingelheim.

Funding

Boehringer Ingelheim.

Disclosure

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. 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, Genmab, Biolumina, 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, Takeda, Agenus, IQVIA, Pfizer, GSK, QED Therapeutics, 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, NeuroTrials, Actuate Therapeutics, Atreca Development, Cullinan, Quanta Therapeutics, Schrodinger, Boehringer Ingelheim; Financial Interests, Personal, Other: Roche-Genentech, SOTIO, Roivant Sciences, Amgen CodeBreak 202, DrenBio. N. Yamamoto: Financial Interests, Personal, Other: Chugai Pharma, ONO Pharmaceutical, Daiichi Sankyo/UCB Japan, Eisai; Financial Interests, Personal, Advisory Role: Eisai, Takeda, Boehringer Ingelheim, Cimic, Chugai Pharma, Healios, Merck; Financial Interests, Institutional, Funding: Chugai Pharma, Taiho Pharmaceuticals, Eisai, Astellas Pharma, Novartis, Daiichi Sankyo, Lilly Japan, Boehringer Ingelheim, Takeda, Kyowa Hakko Kirin, Bayer, Pfizer, ONO Pharmaceuticals, Janssen, MSD, AbbVie, Bristol Myers Squibb, Merck Serono, GSK, Sumitomo Dainippon, Carna iosciences, Genmad/Seattle Genetics, Shionogi, Toray Industries, Kaken Pharmaceutical, AstraZeneca, CMIC, InvestisBio, Rakuten Medical. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: AstraZeneca, Basilea, Bayer, Bristol Myers Squibb, Janssen; Financial Interests, Personal, Full or part-time Employment: START; Financial Interests, Institutional, Project Lead: Multiple; Financial Interests, Personal, Other: AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BioInvent International AB, Boehringer Ingelheim, Bristol Myers Squibb, Celegene, Daiichi Sankyo, Debiopharm, Eisai, e-Therapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchinson, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Therapeutics, Lilly, Loxo, MedSir, Menarini, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Tuming Point Therapeutics, Upshersmith. I. Lugowska: Financial Interests, Personal, Advisory Role: CLININOTR; Non-Financial Interests, Personal, Member of Board of Directors: OECI-EEIG; Financial Interests, Personal, Other: Roche, Boehringer Ingelheim, MSD, Janssen, Bristol Myers Squibb, RyVu, Incyte, Roche/Genetech, ESMO. U. Lauer: Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Research Grant: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Novartis, Asgard Therapeutics, Abalos Therapeutics; Financial Interests, Personal, Other: Boehringer Ingelheim. N. Somaiah: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim. 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, Research to Practice, 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, Boehringer Ingelheim, TYME, Rain Therapeutics, Regeneron; Financial Interests, Personal, Advisory Board: Ayala Pharmaceuticals; Financial Interests, Personal, Speaker’s Bureau: Amgen, Amgen, Boehringer Ingelheim; Financial Interests, Personal, Royalties: UpToDate, GODDESS PRO Desmoid Tumor; Non-Financial Interests, Personal, Other: Foundation Medicine, Athenex.