656P - 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 (+) cancer cells by binding to CD3, CD28, and HER2. Here, we present safety, pharmacokinetics (PK), and biomarker data for 9 dose levels (DLs) of SAR443216 investigated 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 increasing doses with a 2-week lead-in (DL 18–720 μg) or a 3-week lead-in (DL 480–900 μg) in 9 DLs in adult pts with HER2+ (HER2-expression [1+, 2+, or 3+ by immunohistochemistry] and/or HER2-activating mutations) metastatic solid tumors. The primary endpoints were dose-limiting toxicities (DLTs), treatment emergent adverse events (TEAEs), serious adverse events and lab abnormalities. Secondary endpoints were efficacy, PK and antidrug antibodies (ADA) against SAR443216.

Results

As of 6 March 2024, 40 pts received IV SAR443216, with at least 3 pts in each DL. All pts were heavily pre-treated for HER2+ and/or HER2 mutant metastatic solid tumours, including breast, ovarian and gastric cancer. Three DLTs were observed, all in the 2-week lead-in DLs (1 cardiac failure at 180 μg and 2 increased transaminases at 720 μg). Most frequent TEAEs in all DLs 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). Only 1 pt discontinued treatment due to AE (pt with DLT of grade 2 cardiac failure). Other than disease progression, no grade 5 TEAEs were observed. The maximum tolerated dose of SAR443216 was not reached. No objective responses were observed, disease control rate was 35% (14/40 pts). PK was mostly dose-proportional in the explored dose range, with terminal T_1/2 of 1–2 days. Moderate immunogenicity (ADA in ∼20%, 6/28) was observed after IV. Transient increase of serum pro-inflammatory cytokines (INFγ and IL2) were noted after each infusion.

Conclusions

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

Clinical trial identification

NCT05013554.

Editorial acknowledgement

Medical writing support for this abstract was provided by Padmanabham Salla of Sanofi.

Legal entity responsible for the study

Sanofi.

Funding

Sanofi.

Disclosure

V. Moreno Garcia: Financial Interests, Personal, Stocks/Shares, Employment: START; Other, Personal, Consulting or advisory role: Merck, Bristol Myers Squibb, Janssen Oncology, Roche, Basilea, Affimed Therapeutics, AstraZeneca; Other, Personal, Speaker’s Bureau: Bayer, Pierre Fabre; Other, Personal, Travel, accommodation, expenses: Sanofi, Regeneron; Other, Personal, Expert testimony: Medscape, Bayer, Nanobiotix; Other, Personal, Relationship: Bristol Myers Squibb; Financial Interests, Institutional, Research funding: AbbVie; Financial Interests, Institutional, Research funding: 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, 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. M.H. Ryu: Other, Personal, Honoraria: Daehwa Pharmaceutical, Ono, BMS, MSD, Lilly, Novartis, AstraZeneca, Daiichi Sankyo; Other, Personal, Consulting or advisory role: Daehwa Pharmaceutical, Ono, BMS, MSD, Lilly, Taiho Pharmaceutical, Novartis, AstraZeneca, Daiichi Sankyo. E. Calvo: Financial Interests, Personal, Stocks/Shares, Employment: START; Financial Interests, Personal, Stocks/Shares, Employment: HM Hospitales; Other, Personal, Advisory Role, Consulting or Advisory Role: Nanobiotix; Other, Personal, Advisory Role, Consulting or Advisory Role: Janssen-Cilag; Other, Personal, Advisory Role, Consulting or Advisory Role: Roche, Genentech, TargImmune Therapeutics, Servier, Bristol Myers 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, Advisory Board, Leadership role: START; Financial Interests, Personal, Advisory Board, Leadership role: PharmaMar; Financial Interests, Personal, Advisory Board, Leadership role in European Organisation for Research and Treatment of Cancer (EORTC): European Organisation for Research and Treatment of Cancer (EORTC); Financial Interests, Personal, Advisory Board, Leadership role: Sanofi; Financial Interests, Personal, Advisory Board, Leadership role: BeiGene; Financial Interests, Personal, Advisory Board, Leadership role: Novartis; Financial Interests, Personal, Advisory Board, Leadership role: Merus NV. E. Garralda: Other, Personal, Consulting or advisory role: Roche, Ellipses Pharma, NeoMed, Janssen, Boehringer Ingelheim, Alkermes, Thermo Fisher Scientific, Bristol Myers Squibb, Discovery, Anaveon, F-Star, Hengrui Therapeutics, Sanofi; Other, Personal, Speaker’s Bureau, Consulting or advisory role: MSD, Roche, Thermo Fisher Scientific, Lilly, Novartis; Other, Personal, Relationship: Affimed Therapeutics, Amgen, Anaveon, AstraZeneca, BioNTech, Catalym, CytomX Therapeutics, F. Hoffmann-La Roche, 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 Funding: Novartis, Roche, Thermo Fisher Scientific, AstraZeneca, MedImmune, Taiho Oncology, BeiGene. W. Chung: Other, Personal, Honoraria: Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Everest Medicine, Kirin, MSD, Pfizer, Roche, Viatris; Other, Personal, Consulting or advisory role: AstraZeneca, Daiichi Sankyo, Everest Medicine, Eli Lilly, Gilead, MSD, Pfizer. L. Bai: Other, Personal, Honoraria: Pfizer, Eli Lilly, Cstone Pharmaceuticals, Ono Pharmaceuticals, Ipsen; Other, Personal, Consulting or advisory role: Zai Lab, Cstone Pharmaceuticals; Financial Interests, Personal, Research funding: Eisai. O. Yildirim, S. Masciari, G. Mi, L. Wang, P. Kanlikilicer, B. Buday, F. Rharbaoui, G. Abbadessa: Financial Interests, Personal, Stocks/Shares, Sanofi employee may hold company stock/stock options: Sanofi. E.E. Dumbrava: Other, Personal, Consulting or advisory role: Bolt Therapeutics; Financial Interests, Personal, Research funding for institution: Bayer, Immunocore, Amgen, 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.