1075TiP - A phase I/Ib open-label, first-in-human, single agent, dose escalation and expansion study of a HER2-targeted T cell engager (SAR443216) in patients with relapsed/refractory HER2-expressing solid tumors

Background

Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor overexpressed in multiple cancers and is a clinically validated target for cancer treatment with several approved HER2-targeted therapies. SAR443216 is a novel trispecific antibody T cell engager (TCE) that has shown preclinically to target HER2-expressing tumors by co-engaging tumor cells via HER2, and T cells via CD3 and CD28, resulting in T cell activation and tumor cytolysis. SAR443216 utilizes T cells of the adaptive immune system to eradicate HER2-expressing cancers, unlike other HER2 therapies.¹

Trial design

This is a first-in-human, open-label, multicenter, dose escalation and expansion phase 1/1b study evaluating safety, pharmacokinetics (PK), pharmacodynamics, and preliminary clinical efficacy of SAR443216 administered intravenously (IV) or subcutaneously (SC) as a single agent in patients with HER2-expressing solid tumors (EudraCT 2021-00008632/NCT05013554). The study is conducted in 2 parts: The dose escalation part (n=∼70 dose limiting toxicity [DLT] evaluable patients) will assess safety and dose findings of SAR443216 using Bayesian-CRM model, in patients with HER2-expressing solid tumors who have exhausted all standard of care therapies. Dose expansion part (n=∼130 in 4 cohorts) will assess the safety and efficacy of SAR443216 at the recommended dose for expansion in cohorts defined by HER2-expression (1+, 2+ or 3+ by IHC) and/or HER2-activating mutations. Adverse events (AEs) are assessed per NCI CTCAE v5 and tumor response as per RECIST 1.1. Primary endpoints are DLTs, treatment-emergent AEs, serious AEs, and laboratory abnormalities for dose escalation; objective response rate (ORR) and duration of response (DOR) for dose expansion. Key secondary endpoints include ORR, DOR, PK, and incidence of antidrug antibodies in all patients. Dose escalation recruitment is ongoing in South Korea, Spain, Taiwan, and USA. As of April 2023, 29 patients have been enrolled. 1. Seung E, et al. Nature. 2022;603:328-334.

Clinical trial identification

EudraCT 2021-00008632, NCT05013554.

Editorial acknowledgement

Padmanabham Salla, Sanofi Global Hub.

Legal entity responsible for the study

Sanofi.

Funding

Sanofi.

Disclosure

E.E. Dumbrava: Financial Interests, Institutional, Research Funding: Bayer, Immunocare, Amgen, Aileron Therapeutics, Compugen, TRACON Pharma, Unum Therapeutics, Bolt Therapeutics, Aprea Therapeutics, Bellicum Pharmaceuticals, PMV Pharma, Triumvira Immunolgics, Inc, Seagen, Mereo BioPharma 5, Sanofi, Astex Pharmaceuticals, Immunomedics/Gliead, Rain Therapeutics, Gateway Foundation; Financial Interests, Personal, Advisory Role, Consulting and Advisory Role: Bolt Therapeutics. E. Calvo: Financial Interests, Personal, Full or part-time Employment: START, HM Hospitales; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Nanobiotix, Janssen-Cilag, Roche/Genentech, TargImmune Therapeutics; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: Servier, Bristol Myers Squibb, Amunix, Adcendo, Annaveon, AstraZeneca/MedImmune, Chugai Pharma, MonTa Biosciences, MSD Oncology, Nouscom, Novartis, OncoDNA, T-Knife, Elevation Oncology, PharmaMar, Ellipses Pharma, Syneos Health, Genmab, Diaccurate; Other, Personal, Leadership Role: START, PharmaMar, European Organisation for Research and Treatment of Cancer (EORTC), Sanofi, BeiGene, Novartis, Merus NV; Other, Personal, Other, Other relationship: Investigational Therapeutics in Oncological Sciences, Foundation PharmaMar, CRIS Cancer Foundation; Financial Interests, Personal, Stocks or ownership: START, Oncoart Associated; Financial Interests, Personal, Other, Honoraria: HM Hospitales; Financial Interests, Personal, Research Funding: START. E. Garralda: Financial Interests, Personal, Full or part-time Employment: Next Oncology; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Roche; Financial Interests, Personal, Advisory Role, Consulting or Advisory role: Ellipses Pharma, Janssen, Boehringer Ingelheim, Seagen; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: Alkermes, Thermo Fisher Scientific, MAB Discovery, Anaveon, F-Star, Hengrui Therapeutics, Sanofi, Incyte; Financial Interests, Personal, Speaker’s Bureau: MSD, Roche, Thermo Fisher Scientific, Lilly, Novartis, Seagen; Other, Institutional, Other, Other relationship: Affimed Therapeutics, Amgen, Anaveon, AstraZeneca, BioNTech, Catalym, CytomX Therapeutics, F. Hoffmann LaRoche, F-Star, Genentech, Genmab, Hutchinson MediPharma, Imcheck Therapeutics, Immunocore, Janssen-Cilag, MedImmune, Merck KGaA, Novartis, Peptomyc, Ribon Therapeutics, Roche, Seagen, Symphogen, Taiho Pharmaceutical, Sotio, Adaptimmune, Bicycle Therapeutics, Bioinvent, Boehringer Ingelheim, Cyclacel, Cytovation, HiFiBio Therapeutics, Incyte, SERVIER, Pfizer, Relay Therapeutics, Replimune, Ryvu Therapeutics, SQZ Biotech, T Knife; Financial Interests, Institutional, Research Funding: Novartis, Roche, Thermo Fisher Scientific, AstraZeneca/MedImmune, Taiho Oncology, BeiGene, Janssen. M.H. Ryu: Financial Interests, Personal, Advisory Role, Consulting or advisory role: Daehwa Pharmaceutical, Bristol Myers Squibb, Lilly, Ono Pharmaceutical, MSD, Taiho Pharmaceutical, Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: AstraZeneca; Financial Interests, Personal, Other, Honoraria: Daehwa Pharmaceutical, Bristol Myers Squibb, Lilly, Ono Pharmaceutical, MSD, Taiho Pharmaceutical, Novartis, Daiichi Sankyo, AstraZeneca. D. Oh: Financial Interests, Personal, Advisory Role, Consulting or advisory role: AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho Pharmaceutical, ASLAN Pharmaceuticals, Halozyme, Zymeworks, Celgene, Basilea, BeiGene, Turning Point Therapeutics, Yuhan, Arcus Biosciences, IQVIA; Financial Interests, Personal, Research Funding: AstraZeneca, Novartis, Array BioPharma, Lilly, SERVIER, BeiGene, MSD, Handok. L. Bai: Financial Interests, Personal, Advisory Role, Consulting or advisory role: Zai Lab, CStone Pharmaceuticals; Financial Interests, Personal, Other, Honoraria: Pfizer, Lilly, CStone Pharmaceuticals, Ono Pharmaceuticals, Ipsen; Financial Interests, Personal, Research Funding: Eisai. W. Chung: Financial Interests, Personal, Other, Honoraria: Amgen, Everest Medicine, Kyowa Kirin, MSD, Pfizer, Roche, Viatris, Daiichi Sankyo Pharmaceutical, AstraZeneca Co., Lilli O.; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: Everest Medicine, Gilead Sciences, MSD, Pfizer, Daiichi Sankyo Pharmaceutical, AstraZeneca Co., Lilli O.. O. Yildirim: Financial Interests, Personal, Full or part-time Employment, Sanofi employee may hold company stock/stock options: Sanofi. S. Masciari: Financial Interests, Personal, Full or part-time Employment, Sanofi employee may hold company stock/stock options: Sanofi. K. Kang: Financial Interests, Personal, Full or part-time Employment, Sanofi employee may hold company stock/stock options: Sanofi. B. Buday: Financial Interests, Personal, Full or part-time Employment, Sanofi employee may hold company stock/stock options: Sanofi. F. Rharbaoui: Financial Interests, Personal, Full or part-time Employment, Sanofi employee may hold company stock/stock options: Sanofi. G. Abbadessa: Financial Interests, Personal, Full or part-time Employment, Sanofi employee may hold company stock/stock options: Sanofi. V. Moreno Garcia: Financial Interests, Personal, Full or part-time Employment: START; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Merck, Bristol Myers Squibb, Bayer, Janssen Oncology, Roche, Basilea, Affimed Therapeutics, AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Bayer, Pierre fabre; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Sanofi/Regeneron; Other, Personal, Other, Expert testimony: Medscape/Bayer, Nanobiotix, Bristol Myers Squibb; Other, Personal, Other, Other relationship: Bristol Myers Squibb; Financial Interests, Institutional, Research Funding: AbbVie, ACEA Biosciences, Adaptimmune, Amgen, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Eisai, E-therapeutics, GSK, Janssen, Menarini, Merck, Nanobiotix, Novartis, Pfizer, PharmaMar, PsiOxus Therapeutics, Puma Biotechnology, Regeneron, RigonTEC, Roche, Sanofi, Sierra Oncology, Synthon, Taiho Pharmaceutical, Takedo, Tesaro, Transgene. All other authors have declared no conflicts of interest.