SAR443216 Engages HER2 With Manageable Toxicity in Advanced HER2+ Solid Tumors

Treatment with the HER2-targeted T-cell engager (TCE) SAR443216 is feasible with a manageable toxicity profile in patients with advanced HER2-positive solid tumors, according to findings from the intravenous (IV) dose-escalation portion of a first-in-human phase 1/1b trial (NCT05013554), which were presented at the 2025 ESMO Targeted Anticancer Therapies Congress.1

Three dose-limiting toxicities (DLTs) were reported across the 2-week lead-in dose levels of SAR443216: 1 case of grade 2 cardiac failure at 180 µg, and 2 cases of grade 4 alanine aminotransferase (ALT) level elevations at 720 µg. No DLTs were observed across the 3-week lead-in dose levels.

Across all treated patients (n = 40), 97.5% had any treatment-emergent adverse effects (TEAEs), 45% had grade 3 or higher TEAEs, 40% had any treatment-emergent serious AEs, and 2.5% had any TEAEs leading to permanent treatment discontinuation. Treatment-emergent AEs of special interest occurred in 30% of patients, and 87.5% of patients had any TEAEs related to SAR443216. The most common any-grade TRAEs included cytokine release syndrome (CRS; 17.5%) and infusion-related reactions (IRRs; 12.5%). Notably, all CRS effects were manageable and had quick recovery times with conventional treatment, according to the study investigators. The most common TEAEs of grade 3 or higher were increased ALT levels (15.0%) and increased aspartate aminotransferase (AST) levels (12.5%).

Investigators observed no severe or fatal TRAEs. Additionally, all reported CRS effects and TEAEs higher than grade 2 were related to disease progression.

Notably, this trial was terminated early because of the sponsor’s portfolio reprioritization; this termination was not related to the safety or efficacy of SAR443216. Due to the trial termination, the maximum tolerated dose of SAR443216 was not determined.

SAR443216 Mechanism of Action and Preclinical Data

SAR443216 is a novel tri-specific TCE that targets HER2-expressing cancer cells. The agent is composed of binding domains for HER2, CD3 (for T-cell activation), and CD28 (for co-stimulation), and can therefore activate T cells to kill HER2-expressing tumor cells.

A preclinical study of SAR443216 showed that the agent had T cell–dependent cellular cytotoxicity against various HER2-expressing cancer cell lines, including those with HER2-low expression.2 Of note, in a xenograft model of HER2-low breast cancer, SAR443216 had antitumor activity in immune-deficient NSG mice that were reconstituted with primary human T cells.Furthermore, the potency of in vitro T cell–dependent cellular cytotoxicity correlated with the surface expression of HER2 in the target cells.

Phase 1/1b Trial Design

The present multicenter, open-label, nonrandomized, dose-escalation phase 1/1b trial enrolled patients at least 18 years of age with HER2-positive (immunohistochemistry [IHC] 1+, 2+, or 3+) and/or -mutant advanced or metastatic solid tumors; an ECOG performance status of 0 or 1; at least 1 measurable lesion per RECIST 1.1 criteria; and a body weight of 45 kg to 150 kg.1 Patients were excluded if they had significant cardiac disease, a history of or current interstitial lung disease or pneumonitis, uncontrolled acute renal failure, or had received a prior solid organ or hematologic transplant.

After screening, as of May 21, 2024, 29 patients were treated with weekly IV SAR443216 at 2-week lead-in dose levels of 18 µg (n = 4), 60 µg (n = 3), 180 µg (n = 9), 240 µg (n = 4), 360 µg (n = 6), or 720 µg (n = 3); and 11 patients were treated at 3-week lead-in dose levels of 480 µg (n = 4), 720 µg (n = 4), or 900 µg (n = 3).

The primary end points included the incidence of DLTs, TEAEs, serious AEs, and laboratory abnormalities. Secondary end points included overall response rate, duration of response, progression-free survival, pharmacokinetics, and the incidence of antidrug antibodies (ADAs). Immunophenotyping with cytokine and soluble factor measurements was an exploratory end point.

Patient Characteristics

“Enrolled patients were highly heterogeneous in terms of tumor types, HER2 status, HER2 expression, or HER2 mutations/aberrations, and over 50% [of patients] had prior different HER2-targeted treatments,” lead study author Emiliano Calvo, MD, PhD, director of clinical research at START Madrid in Spain, stated in a presentation of the data.

Among all treated patients, the median age was 67.9 years, 62.5% were female, and 52.5% had an ECOG performance status of 1. Primary tumor locations included the breast (17.5%), stomach (12.5%), lung (7.5%), rectum (7.5%), and other locations (55.0%). In total, 75% of patients had received at least 3 prior regimens. Tumor histologies included IHC 3+ (42.5%), 2+ (25.0%), and 1+ (10.0%). HER2 abnormalities or alterations were detected in 55.0% of patients.

Cohort-Specific Safety Findings: 2-Week Lead-In Dose Levels

Among patients in the 2-week lead-in dose level group who received SAR443216 at 18 µg, any TEAEs, grade 3 or higher TEAEs, any treatment-emergent serious AEs, any treatment-emergent AEs of special interest, and any TEAEs related to SAR443216 occurred in 3 (75.0%), 3 (75.0%), 3 (75.0%), 1 (25.0%), and 2 (50.0%) patients, respectively. No TEAEs led to permanent treatment discontinuation. One patient had any-grade CRS. No IRRs were reported. No grade 3 or higher increases in ALT or AST levels were reported.

Of those who received SAR443216 at 60 µg, any TEAEs, grade 3 or higher TEAEs, any treatment-emergent serious AEs, and any TEAEs related to SAR443216 occurred in 3 (100%), 1 (33.3%), 2 (66.7%), and 1 (33.3%) patients, respectively. No TEAEs led to permanent treatment discontinuation, and no treatment-emergent AEs of special interest were reported. No CRS or IRRs were observed. No grade 3 or higher increases in ALT or AST levels were reported.

Among those who received SAR443216 at 180 µg, any TEAEs, grade 3 or higher TEAEs, any treatment-emergent serious AEs, any TEAEs leading to permanent discontinuation, any treatment-emergent AEs of special interest, and any TEAEs related to SAR443216 occurred in 9 (100%), 4 (44.4%), 3 (33.3%), 1 (11.1%), 2 (22.2%), and 8 (88.9%) patients, respectively. Two patients had any-grade CRS. No IRRs were reported. Grade 3 or higher increases in ALT or AST levels were reported in 2 patients and 1 patient, respectively.

Of those who received SAR443216 at 240 µg, any TEAEs, grade 3 or higher TEAEs, any treatment-emergent serious AEs, any treatment-emergent AEs of special interest, and any TEAEs related to SAR443216 occurred in 4 (100%), 2 (50.0%), 2 (50.0%), 2 (50.0%), and 4 (100%) patients, respectively. No patients had TEAEs leading to permanent discontinuation. Two patients had any-grade IRRs. No CRS was reported. Grade 3 or higher increases in ALT or AST levels were reported in 1 patient each.

Among those who received SAR443216 at 360 µg, any TEAEs, grade 3 or higher TEAEs, any treatment-emergent serious AEs, any treatment-emergent AEs of special interest, and any TEAEs related to SAR443216 occurred in 6 (100%), 2 (33.3%), 1 (16.7%), 1 (16.7%), and 6 (100%) patients, respectively. No patients had TEAEs leading to permanent discontinuation. No CRS or IRRs were reported. Grade 3 or higher increased AST levels occurred in 1 patient. No grade 3 or higher increased ALT levels were observed.

Of those who received SAR443216 at 720 µg, any TEAEs, grade 3 or higher TEAEs, any treatment-emergent serious AEs, any treatment-emergent AEs of special interest, and any TEAEs related to SAR443216 occurred in all 3 patients (100%). No patients had TEAEs leading to permanent discontinuation. Any-grade CRS and IRRs occurred in 1 patient each. Grade 3 or higher increased ALT levels and AST levels occurred in 2 and 1 patients, respectively.

Cohort-Specific Safety Findings: 3-Week Lead-In Dose Levels

Among patients in the 3-week lead-in dose level group who received SAR443216 at 480 µg, any TEAEs, grade 3 or higher TEAEs, any treatment-emergent AEs of special interest, and any TEAEs related to SAR443216 occurred in 4 (100%), 1 (25.0%), 2 (50.0%), and 4 (100%) patients, respectively. No treatment-emergent serious AEs were observed, and no TEAEs led to permanent treatment discontinuation. Any-grade CRS and IRRs were observed in 1 patient each. Grade 3 or higher increases in ALT or AST levels were reported in 1 patient each.

Of those who received SAR443216 at 720 µg, any TEAEs, grade 3 or higher TEAEs, any treatment-emergent serious AEs, any treatment-emergent AEs of special interest, and any TEAEs related to SAR443216 occurred in 4 (100%), 1 (25.0%), 1, (25.0%), 1 (25.0%), and 4 (100%) patients, respectively. Any-grade CRS and IRRs were observed in 1 patient each. No grade 3 or higher increases in ALT or AST levels were reported.

Among those who received SAR443216 at 900 µg, any TEAEs, grade 3 or higher TEAEs, any treatment-emergent serious AEs, and any TEAEs related to SAR443216 occurred in 3 (100%), 1, (33.3%), 1 (33.3%), and 3 (100%) patients, respectively. No TEAEs leading to permanent discontinuation or treatment-emergent AEs of special interest were reported. No CRS or IRRs were observed. No grade 3 or higher increases in ALT or AST levels were reported.

Efficacy Findings

No patients achieved objective response with SAR443216. However, the disease control rate was 35%.

Among patients treated at the 2-week lead-in dose level, best responses included progressive disease (PD; n = 19) and stable disease (SD; n = 10). Of note, 2 patients with best responses of PD had no relative change from baseline following treatment.

Among patients treated at the 3-week lead-in dose level, best responses included PD (n = 6), SD (n = 4), and not evaluable (NE; n = 1). Of note, 1 patient with a best response of PD and the patient who was NE for had no relative change from baseline following treatment.

Additional Findings and Next Steps

SAR443216 was associated with generally dose-proportional pharmacokinetics. The mean maximum concentrations of SAR443216 increased as dose levels increased. For instance, the mean maximum concentration of the agent was 1.9 ng/mL at the 18-µg dose and 96 ng/mL at the 720-µg dose. Exposure to the agent was associated with moderate-to-high variability, with coefficients of variation ranging from 30% to greater than 100%. Additionally, SAR443216 had a half-life between 1 and 2 days (between 20 and 50 hours).

Regarding the modulation of serum cytokines with SAR443216 treatment, levels of interleukin 2 and INF-γ increased at 10 hours post-infusion and returned to baseline at 24 hours post-infusion starting at cycle 1 day 4. Investigators explained that this finding suggests that SAR443216 activates T cells and displays target engagement.

Furthermore, SAR443216 infusion led to increases in levels of T-cell activation markers, including CD57, PD1, HLA-DR, the cytotoxicity biomarker granzyme B, and the proliferation biomarker Ki-67; as well as decreases in regulatory T-cell levels. After each infusion, investigators also noted rapid decreases in peripheral lymphocyte counts.

Investigators saw moderate immunogenicity post- SAR443216 infusion. Treatment-emergent ADAs were reported in 27.6% of patients in the 2-week lead-in group and 9.1% of those in the 3-week lead-in group. Some patients with ADAs had reduced pharmacokinetic exposure. The median time to ADA onset was 60.0 days (range from quartile 1-quartile 3, 34-106) in the 2-week lead-in group and 108 days in the 3-week lead-in group.

Taken together, these findings are consistent with proof of mechanism. Further evaluation in patients with high expression of HER2 would be reasonable,” Calvo concluded.

Disclosures: Calvo reported being an employee of START, HM Hospitales; serving in consulting or advisory roles with Adcendo, Amunix, Anaveon, AstraZeneca/MedImmune, Bristol-Meyers Squibb, Chugai Pharma, Diaccurate, Elevation Oncology, Ellipses Pharma, Genmab, Janssen-Cilag, MonTa Biosciences, MSD Oncology, Nanobiotix, Nouscom, Novartis, OncoDNA, PharmaMar, Roche/Genentech, Servier, TargImmune Therapeutics, T-Knife, and Syneos Health; serving in leadership roles with BeiGene, European Organisation for Research and Treatment of Cancer (EORTC), Merus NV, Novartis, PharmaMar, Sanofi, and START; having other relationships with CRIS Cancer Foundation, Foundation PharmaMar, and Investigational Therapeutics in Oncological Sciences; and having stock and other ownership interests in HM Hospitales, Oncoart Associated, and START.

References

1. Calvo E, Moreno Garcia V, Oh D-Y, et al. 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. ESMO Open. 2025;10(suppl 2):104199. doi:10.1016/j.esmoop.2024.104199
2. Sha W, Vadde S, Song Z, et al. Abstract 1825: SAR443216, a novel trispecific T cell engager with potent T cell-dependent cytotoxicity for HER2-low tumors. Cancer Res. 2021;81(suppl 13):1825. doi:10.1158/1538-7445.AM2021-1825