673P - A phase I dose-escalation and expansion study evaluating the safety and efficacy of the MDM2–p53 antagonist brigimadlin (BI 907828) in patients (pts) with solid tumours

Background

BI 907828, a highly potent mouse double minute-2 (MDM2)-p53 antagonist, has shown potent preclinical antitumour activity. This phase I study is evaluating BI 907828 in pts with advanced solid tumours. Here we report safety and efficacy for all pts who received BI 907828 once every 3 weeks (Q3W).

Methods

During dose escalation (phase Ia), pts received escalating doses of BI 907828 on day 1 of 21-day cycles (Q3W) or days 1 and 8 of 28-day cycles; recommended dose for expansion (RDE) was 45 mg Q3W (Gounder et al, ESMO 2021 ). During dose expansion (phase Ib), pts were enrolled in Cohort 1 (TP53wt, MDM2-amplified liposarcoma) or Cohort 2 (other TP53wt, MDM2-amplified solid tumours). Primary endpoint was progression-free survival (PFS); secondary endpoints included objective response and the number of pts with grade ≥3 treatment-related adverse events (TRAEs).

Results

At data cut off (April 2023), 140 pts had been enrolled to receive BI 907828 Q3W (29 in phase Ia; 111 in phase Ib); 78 (55.7%) were male, 77/62 (55.0%/44.3%) had ECOG PS 0/1, the median number of prior systemic therapies was 2. Of the 140 pts who received BI 907828 Q3W, 130 (92.9%) and 65 (46.4%) had any-grade and grade ≥3 TRAEs, respectively. The most common any-grade TRAEs were nausea (73.6%) and fatigue (57.9%). The most common grade ≥3 TRAEs were neutropenia (26.4%), thrombocytopenia (22.9%) and anemia (12.1%). Forty pts had serious AEs; the most common were thrombocytopenia (n=5), nausea, pulmonary embolism and neutropenia (n=4 each). At data cut off, 16/140 pts (11.4%) had a confirmed partial response (PR), and 89 pts had stable disease (SD), giving a disease control rate (DCR; at least SD) of 75.0%. Preliminary median PFS was 7.8 months; 36 pts (25.7%) had PFS >6 months. A total of 10 pts with advanced biliary tract cancer (BTC) received BI 907828 Q3W; of these, 3 (30%) had a confirmed PR and 5 had SD (DCR 80%). Two pts with BTC achieved PFS >12 months.

Conclusions

BI 907828 demonstrated antitumour activity and a manageable safety profile in pts with advanced solid tumours, including those with BTC; dose expansion is ongoing. BI 907828 is being further assessed in pts with BTC in the phase IIa/IIb open-label Brightline-2 trial (NCT05512377).

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 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, Personal, Speaker, Consultant, Advisor: Deciphera, Ellipses Pharma, Transgene, Exelixis, Boehringer Ingelheim, Studiecentrum voor Kernenergie, SQZ Biotechnology, Adcendo, PharmaMar, Merck Healthcare KGaA, Medpace, Cogent, Eisai, Curio Science, LLX Solutions, SERVIER, Genmab, Biolumina, Sanofi, Regeneron, Moleculin Biotech, Avacta Life Sciences, Amryt Pharma, UCB, Boxer Capital; Financial Interests, Institutional, Research Funding: CoBioRes NV, Eisai, G1 Therapeutics, PharmaMar, Genmab, Merck, Sartar Therapeutics, ONA Therapeutics, Adcendo. P. Lorusso: Financial Interests, Personal, Advisory Board: AbbVie, Genmab, Genentech, CytomX, Takeda, Cybrexa, Agenus, IQVIA, TRIGR, Pfizer, ImmunoMet, Black Diamond, GSK, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck, Astellas, Salarius, Silverback, MacroGenics, Kyowa Kirin, Kineta, Zentalis, Molecular Templates, ABL Bio, STCube, Bayer, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanist, Mersana, Roivant Sciences, BAKX Therapeutics, Scenic Biotech, Qualigen, NeuroTrials; Financial Interests, Personal, Other, Data Safety Monitoring Board: Agios, Five Prime, Halozyme; Financial Interests, Personal, Other, imCORE Alliance: Roche-Genentech; Financial Interests, Personal, Other, Consultant: SOTIO, SK Life; Financial Interests, Personal, Other, Data Safety Monitoring Committee: Tyme; Financial Interests, Personal, Advisory Board, Advisory Board & Consultant: I-Mab; Financial Interests, Personal, Stocks/Shares: BAXK; Financial Interests, Institutional, Local PI: AbbVie, ADC Therapeutics, ALX Oncology, Astellas Pharma, Black Diamond, Astex Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Calico Life Sciences, Corvus Pharmaceuticals, CytomX Therapeutics, Eisai Pharmaceuticals, Eli Lilly, EMD Sernono, Five Prime, FLX Bio, F-Star Delta Limited, Genentech, Genmab, Incyte, Linnaeus Therapeutics, MedImmune, Merck Sharp & Dohme, Moderna Therapeutics, NextCure, Pfizer, Ribon Therapeutics, SOTIO, Stemline Therapeutics, Takeda, Tesaro, Jounce; Non-Financial Interests, Other, AACI Clinical Research Innovation Steering Committee-Member: Association of American Cancer Institutes; Non-Financial Interests, Other, Molecular Cancer Therapeutics Editorial Board-Member: American Association for Cancer Research; Non-Financial Interests, Other, AACR Methods in Clinical Cancer Research Workshop-Co-Director: American Association for Cancer Research; Non-Financial Interests, Other, AACR Annual Report Committee-Member: American Association for Cancer Research; Non-Financial Interests, Other, Continuing Medical Education Committee-Member: American Association for Cancer Research; Non-Financial Interests, Other, ASCO Conquer Cancer Young Investigator Award Grand Selection Committee-Member: American Society of Clinical Oncology; Non-Financial Interests, Other, New Drugs in Oncology Seminar Planning Committee-Member: American Society of Clinical Oncology; Non-Financial Interests, Other, New Agents Committee: Translational Research Panel-Chair: Cancer Research Unite Kingdom; Non-Financial Interests, Other, Scientific Advisory Board-Member: Targeted Anti-Cancer Therapies; Non-Financial Interests, Other, Chair-Phase 0 Task Force: American Association of Cancer Research; Non-Financial Interests, Member: American Association for Cancer Research, ASCO; Other, Investigational Drug Steering Committee-Committee Member: National Cancer Institute; Other, Phase I Special Emphasis Panel-Grant Reviewer/Discussion Leader: National Cancer Institute; Other, NeXT Special Emphasis Panel-Grant Reviewer: National Cancer Institute/National Institute of Health; Other, Board of Scientific Counselors, Clinical Sciences & Epidemiology: National Cancer Institute; Other, Young Investigator Meeting, Cancer Therapy Evaluation Program-Professor: National Cancer Institute; Other, Academic Advisory Board SPORE GI Malignancies-Case Western Reserve University: Case Western Reserve University; Other, External Advisory Board-Member: University of Arizona; Other, External Scientific Advisory Board-Member: University of New Mexico; Other, Scientific External Advisory Board-Member: University of California at San Diego. N. Yamamoto: Financial Interests, Personal, Invited Speaker: ONO, Chugai, Daiichi Sankyo, Eisai; Financial Interests, Personal, Advisory Board: Eisai, Takeda, Boehringer Ingelheim, Cimic, Chugai, Healios; Financial Interests, Institutional, Local PI, Principal Investigator in industry sponsored trial: 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; Financial Interests, Institutional, Local PI, Principal investigator in industry sponsored trial: Carna Biosciences, Genmab, Shionogi, TORAY; Financial Interests, Institutional, Research Grant, Principal investigator in industry sponsored trial: Rakuten Medical, InventisBio Co., Ltd. I. Lugowska: Financial Interests, Personal, Writing Engagement: Roche, ESMO; Financial Interests, Institutional, Other, Research grants: Roche; Financial Interests, Institutional, Other, Research grant: Agenus; Financial Interests, Personal and Institutional, Coordinating PI: MSD, Roche, BMS, Janssen, Astra, Amgen, RyVu, Incyte, Siropa, Mennarini, Celon, Pfizer, Agenus, Rhizen; Non-Financial Interests, Project Lead: MSCI; Non-Financial Interests, Other, Board Member: OECI; Other, Robert Lugowski (my husband) co-ownership: Clininote. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer, AstraZeneca; Financial Interests, Personal, Full or part-time Employment: START; Financial Interests, Institutional, Local PI, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daiichi Sankyo, Debiopharm, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith: Multiple. C. Hu, G. Jayadeva, M. Lahmar: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. M. Gounder: Financial Interests, Personal, Other, Honoraria: Flatiron Health, PER, Medscape, Guidepoint Global, touchIME, Med Learning Group, More Health, Research to Practice, Great Debates and Updates, GLG; Financial Interests, Personal, Speaker, Consultant, Advisor: Daiichi Sankyo, Karyopharm Therapeutics, Epizyme, Bayer, Springworks Therapeutics, Boehringer Ingelheim, TYME, Ayala Pharmaceuticals, Rain Therapeutics, Regeneron; Financial Interests, Personal, Speaker’s Bureau: Amgen, Karyopharm Therapeutics, Boehringer Ingelheim; Financial Interests, Personal, Other, Patents, Royalties, Other Intellectual Property: UpToDate; Financial Interests, Institutional, Other, Patents, Royalties, Other Intellectual Property: GODDESS PRO Desmoid Tumor; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Epizyme; Non-Financial Interests, Personal, Other: Desmoid Tumor Research Foundation, Athenex. All other authors have declared no conflicts of interest.