40O - Phase I/Ib open-label study of an HER2-targeted T cell engager (TCE)‒SAR443216 in patients (pts) with advanced solid tumors: Intravenous (IV) dose-escalation results

Background

SAR443216 is a novel trispecific antibody targeting HER2-expressing tumors. It activates T cells for cytolysis of HER2-positive (HER2+) cancer cells by binding to CD3, CD28, and HER2. Here, we present safety, PK, and biomarker data for 9 dose levels (DLs) of SAR443216 in pts with advanced solid tumors in the IV dose-escalation cohort of a first-in-human open-label phase 1/1b trial (NCT05013554).

Methods

SAR443216 was administered IV weekly at 9 DLs with a 2-week lead-in (DL 18–720 μg) or a 3-week lead-in (DL 480–900 μg) in adults with HER2+ (HER2-expression [1+, 2+, or 3+ by immunohistochemistry] and/or HER2-activating mutations) metastatic solid tumors. Primary endpoints were dose-limiting toxicities (DLT)s, TEAEs, SAEs, and lab abnormalities. Secondary endpoints were efficacy, PK, and antidrug antibodies (ADA) against SAR443216. Exploratory endpoints were immunophenotyping by flow cytometry, along with measurements of cytokines and soluble factors.

Results

By 6 March 2024, 40 heavily pre-treated pts received IV administration of SAR443216, with at least 3 pts in each DL. Three DLTs were observed, all in the 2-week lead-in DLs: one Grade 2 cardiac failure (180 μg), two Grade 4 increased transaminases (720 μg). Most frequent TEAEs were cytokine release syndrome (50% all Grade 1–2), ALT and AST increase (32.5% and 27.5% all Grades; 15% and 12.5% Grade 3–4, respectively), and pyrexia (35% all Grade 1–2). One patient discontinued treatment due to Grade 2 cardiac failure (also DLT). Grade 5 TEAEs were not observed. MTD was not reached, and objective responses were not observed. Disease control rate was 35% (14/40 pts). PK was mostly dose-proportional with terminal T_1/2 of 1–2 days. Moderate immunogenicity (ADA in ∼20% pts, 6/28) was observed. Transient increase of serum pro-inflammatory cytokines (INFγ and IL2) was noted after each SAR443216 infusion. In addition, after each infusion, a rapid decrease in peripheral lymphocyte counts was observed. This lymphocyte distribution was accompanied by an increase in the T cell activation markers.

Conclusions

Treatment with TCE SAR443216 in advanced HER2+ solid tumors is feasible with manageable toxicities.

Clinical trial identification

Legal entity responsible for the study

Sanofi.

Funding

Sanofi.

Disclosure

E. Calvo: Financial Interests, Personal, Full or part-time Employment: START, HM Hospitales; Financial Interests, Personal, Advisory Role: Nanobiotix, Janssen-Cilag, Roche/Genentech, TargImmune Therapeutics, Servier, Bristol-Meyers Squibb, Amunix, Adcendo, Anaveon, AstraZeneca/MedImmune, Chugai Pharma, MonTa Biosciences, MSD Oncology, Nouscom, Novartis, OncoDNA, T-Knife, Elevation Oncology, PharmaMar, Ellipses Pharma, Syneos Health, Genmab, Diaccurate; Financial Interests, Personal, Leadership Role: START, PharmaMar, European Organisation for Research and Treatment of Cancer (EORTC), Sanofi, BeiGene, Novartis, Merus NV; Financial Interests, Personal, Other: Investigational Therapeutics in Oncological Sciences, Foundation PharmaMar, CRIS Cancer Foundation; Financial Interests, Personal, Stocks/Shares: START, Oncoart Associated, HM Hospitales. V. Moreno Garcia: Financial Interests, Personal, Full or part-time Employment: START; Other, Personal, Advisory Role: Merck, Bristol Myers Squibb, Janssen Oncology, Roche, Basilea, Affimed Therapeutics, AstraZeneca; Other, Personal, Speaker’s Bureau: Bayer, Pierre Fabre; Financial Interests, Personal, Other, Travel, accommodations, expenses: Sanofi, Regeneron; Other, Personal, Expert Testimony: Medscape, Bayer, Nanobiotix; Other, Personal, Other: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: 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, Rigon TEC, Roche, Sanofi, Sierra Oncology, Synthon, Taiho Pharmaceutical, Takeda, Tesaro, Transgene. D. Oh: Other, Personal, 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 Grant: AstraZeneca, Novartis, Array BioPharma, Lilly, Servier, BeiGene, MSD, Handok. M.H. Ryu: Financial Interests, Personal, Other, Honoraria: Daehwa Pharmaceutical, Ono, BMS, MSD, Lilly, Novartis, AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Other: Daehwa Pharmaceutical, Ono; Financial Interests, Personal, Advisory Role: BMS, MSD, Lilly, Taiho Pharmaceutical, Novartis, AstraZeneca, Daiichi Sankyo. E. Garralda: Other, Personal, Advisory Role: Roche, Ellipses Pharma, NeoMed, Janssen, Boehringer Ingelheim, Alkermes, Thermo Fisher Scientific, Bristol Myers Squibb, MAB Discovery, Anaveon, F-Star, Hengrui Therapeutics, Sanofi; Other, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Invited Speaker: Roche, Thermo Fisher Scientific, Lilly, Novartis; Other, Personal, Other: Affimed therapeutics, Amgen, Anaveon, AstraZeneca, BioNTech, Catalym, CytomX Therapeutics, F. Hoffmann laRoche, F-star, Genentech, Genmab, Hutchinson MediPharma, Imcheck Therapeutics, Immunocore, Janssen-Cilag, MedImmune, Merch KGaA, Novartis, Peptomyc, Ribon Therapeutics, Roche, Symphogen, Taiho Pharmaceuticals, 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 Grant: Novartis, Roche, Thermo Fisher Scientific, AstraZeneca/MedImmune, Taiho oncology, BeiGene. W. Chung: Other, Personal, Other, Honoraria: Amgen, AstraZeneca, Daiichi-Sankyo, Eli Lilly, Everest Medicine, Kyowa Kirin, MSD, Pfizer, Roche, Viatris; Financial Interests, Personal, Advisory Role: AstraZeneca, Daiichi-Sankyo, Everest Medicine, Eli Lilly, Gilead, MSD, Pfizer. L. Bai: Other, Personal, Other, Honoraria: Pfizer, Eli Lilly, Cstone Pharmaceuticals, Ono Pharmaceuticlas, Ipsen; Other, Personal, Advisory Role: Zai Lab, Cstone Pharmaceuticals; Financial Interests, Personal, Research Grant: Eisai. O. Yildirim, S. Masciari, G. Mi, L. Wang, D. Carene, S. Gailhac, R. Perez, P. Kanlikilicer, F. Rharbaoui, G. Abbadessa: Financial Interests, Personal, Full or part-time Employment, Sanofi employees may hold company stock/stock options: Sanofi. E.E. Dumbrava: Other, Personal, Advisory Role: Bolt Therapeutics; Financial Interests, Institutional, Research Grant: Bayer, Immunocore, Amge, Aileron Therapeutics, Compugen, Tracon Pharma, Unum Therapeutics, Bolt Therapeutics, Aprea Therapeutics, Bellicum Pharmaceuticals, PMV Pharma, Triunvira Immunologics Inc, Seagen, Mereo BioPharma, Sanofi, Astex Pharmaceuticals, Immunomedics/Gilead, Rain Therapeutics, Gateway Foundation. All other authors have declared no conflicts of interest.