{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:58:56Z","timestamp":1790758736447,"version":"4.1.0"},"reference-count":35,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"unspecified","delay-in-days":6,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004339","name":"Sanofi","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100004339","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,8,3]]},"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this multicenter, open-label, non-randomized Phase 1 study (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05013554\">NCT05013554<\/jats:ext-link>\n                      ), SAR443216 was administered intravenously at dose levels (DLs) of 18\u2013900\u2009\u00b5g. 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>40 participants (n\u22653\u2009at each DL) were treated with SAR443216. The median treatment duration was ~8\u2009weeks 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 \u22653. 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\u2009weeks. Median follow-up time was 3.43\u2009weeks. 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05013554\">NCT05013554<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-014309","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:10:16Z","timestamp":1788786616000},"page":"e014309","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Phase 1\/1b open-label, first-in-human study of HER2\u00d7CD3\u00d7CD28 trispecific T-cell engager (SAR443216) in participants with R\/R HER2-expressing solid 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