Multinational randomized phase 2 study of lomvastomib versus tobemstomig versus nivolumab for advanced ESCC

The bispecific antibodies lomvastomig and tobemstomig block the immune checkpoint receptor PD-1 and either TIM-3 or LAG-3, respectively. A multinational randomized phase 2 trial assessed their efficacy compared with nivolumab in ICI-naïve patients with unresectable advanced or metastatic or recurrent squamous cell carcinoma of the esophagus (ESCC). The study randomized 190 patients to lomvastomig 2100 mg every two weeks (Q2W; n=27; this group was discontinued early), tobemstomig 2100 mg Q2W (n=82), or nivolumab 240 mg Q2W (n=81). The primary endpoint was overall survival (OS). The median OS was lower in the lomvastomig (4.8 months; 80% CI 2.8-5.8) and tobemstomig (6.7; 5.4-8.7) arms than in the nivolumab arm (8.1; 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 (higher than median). Adverse events with lomvastomig and tobemstomig were manageable. The author conclude that neither lomvastomig nor tobemstomig improved survival compared to nivolumab in the overall patient population. However, in the PD-L1-high and PD-L1-high/LAG3-high subgroups, tobemstomig was associated with prolonged survival, supporting PD-L1-guided treatment selection for tobemstomig in ESCC.