42O - A phase Ia/b, dose-escalation and expansion study evaluating the MDM2–p53 antagonist BI 907828 in patients with solid tumours: Safety and efficacy in patients with dedifferentiated liposarcoma (DDLPS)

Background

BI 907828, a highly potent, oral mouse double minute-2 (MDM2)–p53 antagonist, has demonstrated preclinical antitumour activity, particularly in TP53 wild-type (TP53wt), MDM2-amplified DDLPS models. This phase I study is evaluating BI 907828 in patients (pts) with advanced solid tumours, including DDLPS. During dose escalation, the selected recommended dose for expansion (RDE) was 45 mg q3w (Gounder et al, ASCO 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). Here we focus on Cohort 1 pts (all received BI 907828 45 mg q3w). The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response and grade ≥3 treatment-related adverse events (TRAEs). Here, we present preliminary safety and efficacy results in all pts with advanced DDLPS across dose escalation and expansion.

Results

As of July 2022, 107 pts were enrolled; 59 (55.1%) were male, 63/43 (58.9%/40.2%) had ECOG PS 0/1, respectively, and the median number of prior systemic therapies was 2 (range: 0–11). Of these, 39 pts had advanced DDLPS; 30 received the RDE of 45 mg q3w. Of the 39 DDLPS pts, 35 (89.7%) had a TRAE, including 14 (35.9%) with a grade ≥3 TRAE; the most common grade ≥3 TRAEs were thrombocytopenia (n=8), anaemia (n=4) and neutropenia (n=3). Six pts (15.4%) had an AE leading to dose reduction and 2 (5.1%) had an AE leading to discontinuation. At data cut off, 36 of the 39 DDLPS pts were evaluable for response. Five pts (13.9%) achieved a confirmed partial response (all had received BI 907828 45 mg q3w); a further 27 had stable disease, giving a disease control rate of 88.9%. Preliminary median PFS for all pts with DDLPS was 8.1 months (range: 0.8–21.0); 13 pts are ongoing on treatment.

Conclusions

BI 907828 demonstrated preliminary efficacy and a manageable safety profile in heavily pretreated pts with advanced DDLPS. BI 907828 is also being evaluated versus doxorubicin as first-line treatment for pts with advanced DDLPS in the ongoing phase II/III Brightline-1 study (NCT05218499).

Clinical trial identification

NCT03449381.

Editorial acknowledgement

Medical writing support for the development of this abstract, under the direction of the authors, was provided by Jane Saunders, PhD, of Ashfield MedComms, an Inizio 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, PharmaMar, Genmab, Merck, Sartar Therapeutics, ONA Therapeutics, Roche, Adcendo; Financial Interests, Personal, Other, Honoraria/advisory role: Blueprint Medicines, Deciphera, Ellipses Pharma, Transgene, Exelixis, Boehringer Ingelheim, SQZ Biotechnology, Adcendo, PharmaMar, Merck Healthcare KGaA, Cogent Biosciences, Servier, Sanofi, Moleculin, Avacta, Amryt, UCB. N. Yamamoto: Financial Interests, Personal, Speaker’s Bureau: Ono, Chugai, Daiichi Sankyo, Eisai; Financial Interests, Institutional, Research Grant: Astellas, 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, Toray, Kaken, AstraZeneca, Cmic; Financial Interests, Personal, Advisory Role: Eisai, Takeda, Otsuka, Boehringer Ingelheim, Cimic, Chugai, Merck, Healios. T. Bauer: Financial Interests, Personal, Speaker’s Bureau: Bayer, Lilly; Financial Interests, Personal, Full or part-time Employment: Tennessee Oncology; Financial Interests, Institutional, Research Grant: Daiichi Sankyo, Incyte, Mirati Therapeutics, MedImmune, AbbVie, AstraZeneca, MabVax, Merck, Lilly, GlaxoSmithKline, Novartis, Pfizer, Genentech/Roche, Immunogen, Immunocore, Roche, Bristol Myers Squibb, Amgen, Moderna Therapeutics, Sanofi, Boehringer Ingelheim, Astellas Pharma, Top Alliance BioScience, Loxo, Janssen, Takeda, Onyx, Foundation Medicine; Financial Interests, Personal, Advisory Role: Pfizer, Bayer, Lilly, Sanofi; Financial Interests, Personal, Other, travel, accommodation, expenses: Pfizer. M. Patel: Financial Interests, Institutional, Research Grant: Acerta Pharma, ADC Therapeutics, Agenus, Aileron Therapeutics, AstraZeneca, BioNTech, Boehringer Ingelheim, Celgene, CicloMed, Clovis Oncology, Cyteir, Daiichi Sankyo, Lilly, Evelo Therapeutics, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, H3 Biomedicine, Hengrui Therapeutics, Hutchison MediPharma, Jacobio, Janssen, KLUS Pharma, Kymab, Loxo, LSK BioPharma, Lycera, Macrogenics, Merck, Millennium, Mirati Therapeutics, Moderna Therapeutics, Pfizer, Prelude Therapeutics, Ribon Therapeutics, Seven, Eight Biopharmaceuticals, Syndax, Taiho Pharmaceutical, Tesaro, TopAlliance BioSciences Inc., Vigeo Therapeutics, ORIC Pharmaceuticals, Artios, Treadwell Therapeutics, MabSpace Biosciences, IgM Biosciences, Puretech, Artios, BioTheryX, Black Diamond Therapeutics, IgM Biosciences, NGM Biopharmaceuticals, Novartis, PureTech, Relay Therapeutics, Samumed, Silicon Therapeutics, TeneoBio, Treadwell Therapeutics, Zymeworks, Olema Oncology, Adagene, Astellas Pharma, NGM Biopharmaceuticals, Accutar Biotech, TeneoBio, Nurix, Novartis, Compugen, Artios, Blueprint Medicines, Bayer, Bicycle Therapeutics, BioTheryX, Cullinan Oncology, Erasca, Inc., Immune-Onc Therapeutics, Immunitas, Jazz Pharmaceuticals, NGM Biopharmaceuticals, ORIC Pharmaceuticals, Pionyr, Revolution Medicines, Ribon Therapeutics, Step Pharma, Syndax, Synthorx; Financial Interests, Personal, Advisory Role: Olema Pharmaceuticals; Financial Interests, Personal, Leadership Role: ION Pharma; Financial Interests, Personal, Other, honoraria: Janssen Oncology; Financial Interests, Personal, Research Grant: Xencor. P. Lorusso: Financial Interests, Personal, Stocks/Shares: BAKX Therapeutics; Financial Interests, Institutional, Research Grant: 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 IDDM in the Genetically at Risk (TRIGR), Pfizer, ImmunoMet, Black Diamond Therapeutics, GlaxoSmithKline, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck Labs, Astellas Pharma, Salarius Pharmaceutical, Silverback Therapeutics, Macrogenics, Kyowa Kirin International, Kineta, Zentalis, Molecular Templates, ABL Bio, SK Life Sciences, ST Cube, Bayer, I-Mab, Seattle Genetics, ImCheck therapeutics, Relay Therapeutics, Stemline Therapeutics, Mekanistic Therapeutics, Compass Therapeutics, BAKX Therapeutics, Scenic Biotech, Qualigen Therapeutics, Roivant, Neurotrials Research; Financial Interests, Personal, Other, travel, accommodations, expenses: Genentech; Financial Interests, Personal, Other, honoraria: Five Prime Therapeutics. M. Lahmar: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. S. Durland-Busbice: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. J. Geng: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. M. Gounder: Financial Interests, Personal, Speaker’s Bureau: Amgen, Karyopharm Therapeutics, Boehringer Ingelheim; Financial Interests, Personal, Proprietary Information: UpToDate; Financial Interests, Institutional, Proprietary Information: GODDESS PRO Desmoid Tumor; Financial Interests, Personal, Advisory Role: Daiichi Sankyo, Karyopharm Therapeutics, Epizyme, Bayer, Springworks Therapeutics, Boehringer Ingelheim, Tyme, Ayala Pharmaceuticals, Rain Therapeutics, Regeneron; Financial Interests, Personal, Other, travel, accommodation, expenses: Epizyme; Financial Interests, Personal, Other, other: Desmoid Tumor Research Foundation; Financial Interests, Personal, Other, honoraria: Flatiron Health, PER, Medscape, Guidepoint Global, touchIME, Med Learning Group, MORE Health; Non-Financial Interests, Personal, Other, Uncompensated Relationships: Foundation Medicine, Athenex; Financial Interests, Personal, Other, Open Payments Link: https://openpaymentsdata.cms.gov/physician/459583.