Sung-Bae Kim

Purpose:The bispecific antibodies lomvastomig and tobemstomig block the immune checkpoint receptor programmed cell death protein 1 (PD-1) and either TIM-3 or LAG-3, respectively. This phase II study assessed their efficacy compared with nivolumab in checkpoint inhibitor–naïve patients with unresectable advanced or recurrent esophageal squamous cell carcinoma (ESCC) who were refractory or intolerant to one prior line of chemotherapy. Patients and Methods:This active-controlled, blinded, multicenter study randomized patients (1:1:1) to treatment with lomvastomig (2,100 mg once every 2 weeks), tobemstomig (2,100 mg once every 2 weeks), or nivolumab (240 mg once every 2 weeks). The primary endpoint was overall survival (OS); secondary endpoints included objective response, progression-free survival, pharmacodynamic changes, safety/tolerability, immunogenicity, and pharmacokinetics. Results:A total of 190 patients were randomized: 27 to lomvastomig (this group was discontinued early), 82 to tobemstomig, and 81 to nivolumab. The median OS was lower in the lomvastomig [4.8 months; 80% confidence interval (CI), 2.8–5.8] and tobemstomig (6.7 months; 80% CI, 5.4–8.7) arms than in the nivolumab arm (8.1 months; 80% CI, 6.7–9). The objective response rates were 3.7%, 9.8%, and 8.6%, respectively. An exploratory biomarker analysis of tobemstomig-treated patients showed improved survival in the PD-L1–high [combined positive score (CPS) ≥ 10] versus the PD-L1–low (CPS < 10) subgroup, with the greatest benefit in patients with concurrent high expression of PD-L1 and LAG-3 (>median). Adverse events with lomvastomig and tobemstomig were manageable, and the safety profiles of all three compounds remained consistent with their known immune-mediated side effect profiles. Conclusions:Neither lomvastomig nor tobemstomig improved survival compared with nivolumab in the overall patient population. However, in the PD-L1–high (CPS ≥ 10) and PD-L1–high/LAG-3–high subgroups, tobemstomig was associated with prolonged survival, supporting PD-L1–guided treatment selection for tobemstomig in ESCC.

Baseline immune cell subset associations with objective response rate

Kaplan-Meier plots for baseline immunohistochemistry biomarker associations

Baseline prevalence and clinical response associations in immune cell subsets

Association between ctDNA and clinical response

Longitudinal analysis of regulatory T-cell dynamics following tobemstomig or nivolumab treatment

Baseline tissue gene expression and gene signature associations with clinical outcomes

Immunohistochemistry and immunofluorescent assay details