Multinational phase 1 trial of tobemstomig for immune checkpoint inhibitor-experience melanoma

The IgG1-based bispecific antibody tobemstomig simultaneously targets and blocks PD-1 and LAG-3 expressed on T cells. A first-in-human multinational phase 1 trial evaluated tobemstomig in patients with advanced and or metastatic solid tumors in the dose escalation part, with expansion in three tumor-specific cohorts: checkpoint inhibitor (CPI)-experienced patients with melanoma and non-small cell lung cancer and CPI-naïve patients with esophageal squamous cell carcinoma. Thirty-five (escalation) and sixty-nine (expansion) patients were enrolled. Tobemstomig was well tolerated up to the highest tested dose of 2100 mg once every two weeks, which was established as the recommended dose for expansion. Tobemstomig exhibited linear pharmacokinetics across the studied dose range. During dose escalation, partial responses were achieved by 2 of 4 (dose 600 mg) and 4 of 13 (dose 2100 mg) patients. In the expansion part, partial responses were achieved by 6 of 41 patients with CPI-experienced melanoma (ORR 15%; 95% CI 6.6-26.9) and 1 of 8 patients with CPI-naïve ESCC (ORR 12.5%; 90% CI 0.6-47.1). Proof of mechanism was demonstrated in patients with CPI-experienced melanoma based on increases in the amounts of CD8⁺ T cells, expansion of stem-like CD8⁺ T cells, and the acquisition of cytotoxic effector functions, with limited changes in the regulatory T cell compartment. The authors conclude that tobemstomig had a tolerable and manageable safety profile across various advanced solid tumor indications, with encouraging antitumor activity in patients with CPI-experienced melanoma.