Phase 1/1b open-label, first-in-human study of HER2×CD3×CD28 trispecific T-cell engager (SAR443216) in participants with R/R HER2-expressing solid tumors.

Authors

Ecaterina E Dumbrava, Do-Youn Oh, Min-Hee Ryu, Emiliano Calvo, Elena Garralda, Wei-Pang Chung, Li-Yuan Bai, Katerin Rojas, Ozlem Yildirim, Serena Masciari, Gu Mi, Lei Wang, Federico Rotolo, Sarah Gailhac, Elham Attieh, Pinar Kanlikilicer, Barbara Buday, Raymond Perez, Faiza Rharbaoui, Giovanni Abbadessa, Victor Moreno

Published in

Journal for immunotherapy of cancer. Volume 14. Issue 9. Sep 07, 2026. Epub Sep 07, 2026.

Abstract

SAR443216 is an engineered human trispecific antibody that targets human epidermal growth factor receptor 2 (HER2)-positive (HER2+) cancer cells and activates T cells via co-engagement of cluster of differentiation (CD)3 and CD28. This first-in-human, dose-escalation study evaluated the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics of SAR443216 in participants with relapsed/refractory (R/R) HER2-expressing solid tumors.
In this multicenter, open-label, non-randomized Phase 1 study (NCT05013554), SAR443216 was administered intravenously at dose levels (DLs) of 18-900 µg. Dose escalation occurred within participants using intraparticipant lead-in dosing (2-week and 3-week lead-in cohorts). The primary objective was to determine the maximum tolerated dose (MTD); secondary objectives included PK, immunogenicity, and preliminary clinical activity.
40 participants (n≥3 at each DL) were treated with SAR443216. The median treatment duration was ~8 weeks in both 2-week and 3-week lead-in cohorts. Nearly all participants (97.5%) had at least one treatment-emergent adverse event (TEAE), of which 45% were grade ≥3. Most frequent TEAEs were cytokine release syndrome (CRS, 50%), fever (35%), alanine aminotransferase elevation (32.5%), aspartate aminotransferase elevation (27.5%), and infusion-related reactions (IRRs, 27.5%). No severe CRS, IRRs, fever, or pulmonary and cardiac toxicities were observed. Disease control rates were 34.5% in the 2-week and 36.4% in the 3-week lead-in cohorts. Average duration of disease stabilization was 10.48 weeks. Median follow-up time was 3.43 weeks. No objective responses were observed. The MTD was not reached. Dose-dependent PK showed overall consistent PK profiles across DLs. SAR443216 induced serum proinflammatory cytokines and increased multiple T-cell activation markers in peripheral blood mononuclear cells, indicating T-cell activation and target engagement. However, no clear trend in T-cell abundance or activation was observed among tumor-infiltrating T cells or other immune cells.
These findings indicate that SAR443216 treatment is feasible and well tolerated in participants with R/R HER2+solid tumors. Further evaluation is warranted to fully characterize the efficacy and safety of SAR443216.
NCT05013554.

PMID:
42705861
Bibliographic data and abstract were imported from PubMed on 08 Sep 2026.

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