A Randomized, Nivolumab-controlled, Phase 2 and Biomarker Study of Lomvastomig and Tobemstomig in Advanced or Metastatic Squamous Cell Carcinoma of the Esophagus.

Abstract

The bispecific antibodies lomvastomig and tobemstomig block the immune checkpoint receptor PD-1 and either TIM-3 or LAG-3, respectively. This phase 2 study assessed their efficacy compared with nivolumab in CPI-naïve patients with unresectable advanced or recurrent ESCC who were refractory or intolerant to one prior line of chemotherapy. This active-controlled, blinded, multicenter study randomized patients (1:1:1) to treatment with lomvastomig (2100 mg Q2W), tobemstomig (2100 mg Q2W), or nivolumab (240 mg Q2W). The primary endpoint was overall survival, secondary endpoints included objective response, progression-free survival, pharmacodynamic changes, safety/tolerability, immunogenicity, and pharmacokinetics. 190 patients were randomized, 27 to lomvastomig (this group was discontinued early), 82 to tobemstomig, and 81 to nivolumab. The median overall survival was lower in the lomvastomig (4.8 months; 80%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, 6.7-9.0). The objective response rate was 3.7%, 9.8%, and 8.6%, respectively. An exploratory biomarker analysis of tobemstomig-treated patients showed improved survival in the PD‑L1‑high (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 effects profiles. Neither lomvastomig nor tobemstomig improved survival compared to nivolumab in the overall patient population. However, in the PD-L1-high (CPS≥10) and PD-L1-high/LAG3-high subgroups, tobemstomig was associated with prolonged survival, supporting PD-L1-guided treatment selection for tobemstomig in ESCC.