Abstract 371P
Background
BI 905711, a tetravalent bispecific antibody that cross-links TRAILR2 with CDH17, leads to CDH17-dependent TRAILR2 oligomerization, resulting in caspase activation, apoptosis and tumour growth inhibition in preclinical GI cancer models.
Methods
This phase Ia/b study of BI 905711 in pts with advanced GI cancers (NCT04137289) aimed to determine the maximum tolerated dose (MTD) based on the proportion of pts with dose-limiting toxicities (DLT), and assess pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumour activity. In phase Ia, pts received BI 905711 every 14 days at escalating doses guided by a Bayesian logistic regression model. One colorectal cancer (CRC) pt was enrolled at each of the 2 lowest dose levels (0.02/0.06 mg/kg) and 4 pts at each subsequent level (0.2/0.6/1.2/2.4/3.6/4.8 mg/kg). Up to 4 pts with non-CRC GI cancers were included at the dose level below the CRC cohort.
Results
As of 31 March 2022, 45 advanced GI cancer pts (26 CRC, 19 non-CRC) had received BI 905711 (dose range 0.02–4.8 mg/kg); pts had received a median of 3 (range 1–11) prior lines of treatment. No DLTs were observed and the MTD was not reached. 15 pts (7 CRC, 8 non-CRC) had treatment-related AEs (TRAEs); most TRAEs were grade 1/2, but 5 TRAEs were grade 3: AST increased (2 pts], fatigue, ALT increased and blood bilirubin increased (1 pt each]. 3 pts had grade 1/2 infusion-related reactions that resolved and did not prevent retreatment. Cmax and AUC0–336 of BI 905711 increased dose proportionally with no accumulation after repeated dosing; terminal geometric mean T1/2 was ∼2–3 days (0.6–3.6 mg/kg dose). PD biomarker modulation on the level of plasma caspase-3/7 activity occurred most commonly at 0.6 mg/kg (4/7 pts) or 1.2 mg/kg (2/6 pts). 6 CRC and 6 non-CRC pts achieved stable disease; of these, 4 and 4 pts were progression-free ≥4 months (PFS4). In the 0.6 mg/kg dose group, 3/8 pts achieved PFS4.
Conclusions
BI 905711 showed a tolerable safety profile with favourable PK properties. Early signs of disease control in these heavily pretreated pts was observed and will be further assessed in phase Ib in 4 dose groups: 0.6/1.2/2.4 mg/kg every 14 days, and 0.6 mg/kg weekly.
Clinical trial identification
NCT04137289.
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 Ashfield Health company, and funded by Boehringer Ingelheim.
Legal entity responsible for the study
Boehringer Ingelheim.
Funding
Boehringer Ingelheim.
Disclosure
J.J. Harding: Non-Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb, Pfizer, Lilly , Novartis, Incyte, Calithera Biosciences, Polaris , Yiviva , Debiopharm Group, Zymeworks, Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb, CytomX Therapeutics, Lilly, Eisai, Imvax, Merck , Exelixis , Zymeworks, Adaptimmune. R.D. Hofheinz: Financial Interests, Institutional, Funding: Deutsche, Krebshilfe, Sanofi, Amgen, Merck; Financial Interests, Personal, Advisory Role: Amgen, AstraZeneca, Bayer, BMS, Boehringer, Lilly, Merck, MSD, Piere Fabre, Roche, Sanofi, Servier; Financial Interests, Personal, Other, Honoraria: Amgen, AstraZeneca, Bayer, BMS, Boehringer, Lilly, Medac, Merck, MSD, Piere Fabre , Roche , Saladax , Sanofi , Servier; Financial Interests, Personal, Other, Travel, accommodation and expenses: Amgen , Astra Zeneca, Bayer, BMS, Boehringer, Lilly, Merck, MSD, Piere Fabre, Roche, Sanofi , Servier. M.E. Elez Fernandez: Financial Interests, Personal, Advisory Board: Hoffman La - Roche, Bristol Myers Squibb, Servier, Amgen, Merck, Serono, Array, Biopharma, Sanofi, Bayer; Financial Interests, Institutional, Funding: Array Biopharma, MSD, Abbvie, Amgen, GlaxoSmithKline, Astrazeneca, Merck, Sharp & Dohme Corp., Bristol Myers Squibb, Novartis, Boehringer Ingelheim, Hoffman, La-Roche, Medimmune, Pierre-Fabre, Sanofi, Aventis. Y. Kuboki: Financial Interests, Personal, Advisory Board: Takeda , Boehringer Ingelheim , Amgen ; Financial Interests, Institutional, Funding: Taiho Pharmaceutical , Takeda, Incyte, Daiichi Sankyo , Ono Pharmaceutical , Boehringer Ingelheim, Amgen, Chugai Pharma, GlaxoSmithKline , Astellas Pharma , Genmab, Janssen Oncology , AbbVie , Lilly ; Financial Interests, Personal, Other, Honoraria: Taiho Pharmaceutical , Bayer, Lilly Japan , Ono Pharmaceutical , Bristol-Myers Squibb Japan , Merck Serono. D. Rasco: Financial Interests, Institutional, Funding: Celgene, Asana Biosciences, Eisai, Merck, Ascentage Pharma, Macrogenics, AbbVie, Constellation Pharmaceuticals, Astex Pharmaceuticals, Compugen , Coordination Therapeutics, GlaxoSmithKline, Incyte, Gossamer Bio, Seven and Eight Biopharmaceuticals, Bolt Biotherapeutics, Boehringer Ingelheim, PureTech, Takeda. M. Cecchini: Financial Interests, Personal, Stocks/Shares: Parthenon Therapeutics ; Financial Interests, Personal, Other, Travel, accommodations, expenses: AstraZeneca , Eisai , Agios , Genentech/Roche; Financial Interests, Personal, Other, Honoraria: AstraZeneca , Eisai , Agios , GRAIL , Aptitude Health, Dava Oncology. L. Shen: Financial Interests, Personal, Speaker’s Bureau: Hutchison Whampoa, MSD; Financial Interests, Institutional, Funding: Yaojie Ankang (Nanjing), Baiji Senzhou (Beijing), Beijing Xiantong, Biomedical Technology Co. Ltd, QiLu Pharmaceutical, Zaiding Pharmaceutical; Financial Interests, Personal, Advisory Board: MSD, Bristol-Myers Squibb, AstraZeneca, Daiichi Sankyo, Roche, Mingji, Biopharmaceutical, Harbour BioMed, Merck. S. Archuadze: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. J. Geng: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. F. Haderk: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. S. Pant: Financial Interests, Personal, Advisory Role: Xencor, 4D Pharma, Zymeworks, Ipsen, Novartis, Janssen ; Financial Interests, Personal, Advisory Board: Xencor, Zymeworks, Ipsen ; Financial Interests, Personal, Other, Honoraria: 4D Pharma; Financial Interests, Institutional, Funding: Mirati Therapeutics, Pfizer, Lilly, Xencor, Novartis, Bristol-Myers Squibb, Ipsen, Astellas Pharma, Purple Biotech, 4D Pharma , Boehringer Ingelheim, NGM Biopharmaceuticals, Janssen, Arcus Biosciences, Elicio Therapeutics, Zymeworks, BioNtech.