452O - A phase I dose-escalation and expansion study evaluating the safety and efficacy of the MDM2–p53 antagonist BI 907828 in patients (pts) with solid tumours

Background

BI 907828, a highly potent mouse double minute-2 (MDM2)–p53 antagonist, has demonstrated preclinical antitumour activity, particularly in TP53 wild-type (wt), MDM2-amplified dedifferentiated liposarcoma (DDLPS) models. This phase I study is evaluating BI 907828 in pts with advanced solid tumours. During dose-escalation (phase Ia), the selected recommended dose for expansion (RDE) was 45 mg q3w (Gounder M, 2021).

Methods

During dose-expansion (phase Ib), pts were enrolled to Cohort 1 (TP53wt, MDM2-amplified sarcoma) or Cohort 2 (other TP53wt, MDM2-amplified solid tumours). Pts in Cohort 1 received BI 907828 45 mg q3w; pts in Cohort 2 received 30 or 40 mg on Days 1 and 3 of a 28-day cycle, with a safety run-in of the initial 6 pts per dose level, or 45 mg q3w (biliary tract cancer pts only). The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response and the number of pts with grade ≥3 treatment-related adverse events (AEs).

Results

As of March 2022, 94 pts were enrolled; 50 (53.2%) were male, 57/36 (60.6%/38.3%) had ECOG PS 0/1, respectively; the median number of prior systemic therapies was 2 (range: 0–11). At data cut off, 45/48 pts with advanced LPS were evaluable for tumour response. Disease control rate (complete + partial response (PR) + stable disease) was 93%/88% in pts with DDLPS/well-differentiated LPS (WDLPS), respectively. A confirmed PR was achieved in 5 pts (2 DDLPS, 3 WDLPS); 3 pts (2 DDLPS, 1 WDLPS) had an unconfirmed PR. Of the pts enrolled into phase Ia, 5/11 with DDLPS and 4/8 with WDLPS achieved a PFS >10.5 months. For pts with other solid tumours, 2/4 with MDM2-amplified biliary tract cancer and 1 with MDM2-amplified pancreatic adenocarcinoma had a confirmed PR. Of the 46 pts who received the RDE, 22 (47.8%) had grade ≥3 AEs; the most common were neutropenia (21.8%) and thrombocytopenia (19.6%). Serious AEs were experienced by 9 pts; the most common were nausea (n=3), pyrexia, abdominal pain, and thrombocytopenia (n=2 each).

Conclusions

BI 907828 demonstrated antitumour activity and a manageable safety profile in pts with advanced solid tumours, including LPS. The dose-expansion phase is ongoing.

Clinical trial identification

NCT03449381.

Editorial acknowledgement

Medical writing support for the development of this abstract, under the direction of the authors, was provided by Joanna Badawy, BSc, of Ashfield MedComms, an Ashfield Health company, and funded by Boehringer Ingelheim.

Legal entity responsible for the study

Boehringer Ingelheim.

Funding

Boehringer Ingelheim.

Disclosure

P. Schoeffski: Financial Interests, Institutional, Research Grant: CoBioRes NV, Eisai, G1 Therapeutics, PharamaMar, Genmab, Merck, Sartar Therapeutics, ONA Therapeutics; Financial Interests, Personal, Advisory Role: Deciphera, Ellipses Pharma, Blueprint Medicines, Transgene, Exelixis, Boehringer Ingelheim, Studiecentrum voor Kernenergie, SQZ Biotechnology, CRT Pioneer Fund LP, Acendar, PharmaMar, Merck Healthcare KGaA, Ysios Capital . N. Yamamoto: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Eli Lilly, ONO, Chugai, Sysmex, Daiichi-Sankyo, Eisai; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Takeda, ONO, Janssen Pharma, MSD, MERCK, GSK, Sumitomo Dainippon, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogi; Financial Interests, Personal, Advisory Role: Eisai, Takeda, Otsuka, Boehringer Ingelheim, Cimic, Chugai. T. Bauer: Financial Interests, Personal, Speaker’s Bureau: Bayer, Bristol-Myers Squibb, Lilly; Financial Interests, Personal, Advisory Board: Lilly, Pfizer; Financial Interests, Personal, Full or part-time Employment: Tennessee Oncology; Financial Interests, Institutional, Research Grant: Daiichi Sanyko, Incyte, Mirati Therapeutics, MedImmune, AbbVie, AstraZeneca, MabVax, Merck, Lilly, GlaxoSmithKline, Novartis, Pfizer, Genentech/Roche, ImmunoGen, Immuocore, Roche, Bristol-Myers Squibb, Amegen, Moderna Therapeutics, Sanofi, Boehringer Ingelheim, Astellas Pharma, Top Alliance BioScience, Loxo, Janssen, Takeda, Onyx, Foundation Medicine; Financial Interests, Personal, Advisory Role: Loxo, Pfizer, Bayer, AstraZeneca; Financial Interests, Institutional, Other, Travel, accommodation and expenses: Astellas Pharma, AstraZeneca, Celgene, Clovis Oncology, EMD Serono, Genentech, Lilly, Merck, Novartis, Pfizer. M. Patel: Financial Interests, Personal, Speaker’s Bureau: Exelis, Genentech/Roche, Taiho Pharmaceutical, Celgene; Financial Interests, Personal, Advisory Board: Mirati, Daiichi; Non-Financial Interests, Institutional, Funding: Acerta Pharma, ADC Therpeutics, Agenus, Aileron Therapeutics, AZ, Bicycle Therapeutics, BioNTech AG, Boehringer Ingelheim, Calithera Biosciences, Celgene, Checkpoint Therapeutics, CicloMed, Clovs Oncology, Curis, Cyteir, Daiichi Sankyo, eFFECTOR Therapeutics, Lilly, EMD Serono, Evelo Therapeutics, FORMA Therapeutics, Genentech/Roche, Gilead, GSK, H3 Biomedecine, Hengrui Therapeutics, Hutchinson MediPharma, Ignyta, Jacobio, Janssen, Jounce Therapeutics, Klus Pharma, Kymab, Loxo, LSK BioPharma, Lycera, Merck, Millenium, Mirato Therapeutics, Moderna Therapeutics, Pfizer, Phoenix Molecular Designs, Placon, Portola Pharmaceuticals, Prelude Therapeutics, QiLu Pharmaceuticals, PubGene, Revolution Medicines, Ribon Therapeutics, Seven and Eight Biopharmaceuticals, Syndax, Synthorx, Stemline Therapeutics, Taiho Pharmaceutical, Takeda, TopAlliance Biosciences Inc, Vedanta Biosciences, Verastem, Vigeo Therapeutics, xencor, ORIC pharmaceuticals, Artios, Treadwell Therapeutics, MadSpace Biosciences, IgM Biosciences, Puretech, Erasca Inc; Financial Interests, Personal, Advisory Role: Pharmacyclics, Janssen, Pfizer, EMD Serono; Financial Interests, Personal, Other, Travel, accommodation, expenses; Honoraria: Pfizer, Pharmacyclics, Bayer, Janssen Oncology, Genentech. M.M. Gounder: Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Royalties, Patents with MSKCC (GODDESS PRO) (consultant): MSKCC; Financial Interests, Personal, Other, (honorarium; speaker): Medscape, More Health, Physicians Education Resource, touchIME; Financial Interests, Personal, Other, (honorarium; consultant): Athenex, Ayala, Bayer, Boehringer Ingelheim, Daiichi, Epizyme, Karyopharm, Rain, Springworks, Tracon, TYME; Financial Interests, Personal, Other, (consulting fee; consultant): Guidepoint, GLG, Third Bridge, Flatiron Health. J. Geng: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. R. Sailer: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. G. Jayadeva: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. P. Lorusso: Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Personal, Sponsor/Funding: Five Prime Therapeutics; Financial Interests, Personal, Other, Travel, accommodation, expenses: Genentech; Financial Interests, Personal, Advisory Role: Genentech, CytomX Therapeutics, Roche/Genentech, Halozyme, Five Prime Therapeutics, Agenus, Agios, Cybrexa Therapeutics, Sotio, AbbVie, Genmab, Takeda, Tyme, IQvia, Trial to Reduce IDDUM in the Genetically at Risk (TRIGR), Pfizer, ImmunoMet, Black Diamond Therapeutics, GlaxoSmithKline, QED Therpeutics, AstraZenenca, EMD Seronon, Shattuck Labs, Astellas Pharma, Salarius Pharmaceuticals, Silverback Therapeutics, Macrogenics, Kyowa Kirin International, Kineta, Zentalis, Molecular Templates, ABL Boi, SK Life Sciences, ST Cuber, Bayer, I-Mab .