A First-in-Human Phase I Clinical Trial Evaluating Clinical Activity and Proof of Mechanism of Tobemstomig, a PD-1–LAG-3 Bispecific Antibody, in Patients with CPI-Experienced Melanoma

PURPOSE: The IgG1-based bispecific antibody tobemstomig (RO7247669) simultaneously targets and blocks PD-1 and LAG-3 expressed on activated T cells. PATIENTS AND METHODS: This first-in-human, open-label, phase 1 trial of tobemstomig included a dose-escalation part in patients with advanced and/or metastatic solid tumors and an expansion part with three tumor-specific cohorts, enrolling CPI‑experienced patients with melanoma and non-small-cell lung cancer (NSCLC) and CPI‑naïve patients with esophageal squamous cell carcinoma (ESCC). Primary and secondary objectives included safety/tolerability, MTD and/or recommended dose for expansion (RDE), pharmacokinetics, drug receptor occupancy, and preliminary antitumor activity. RESULTS: Thirty-five (dose-escalation) and 69 patients (expansion) were enrolled. Tobemstomig was well-tolerated up to the highest tested dose of 2100 mg Q2W. The MTD was not reached, and 2100 mg Q2W was established as the RDE. Tobemstomig exhibited linear pharmacokinetics across the studied dose range. Partial responses were achieved by 2/4 (600 mg) and 4/13 (2100 mg) patients during dose-escalation, 6/41 CPI‑experienced melanoma patients (ORR: 15%; 95%CI: 6.6, 26.9) and 1/8 CPI-naïve ESCC patients (ORR: 12.5%; 90%CI: 0.6, 47.1). Proof-of-mechanism was demonstrated in CPI-experienced melanoma patients 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 Treg compartment. CONCLUSIONS: Tobemstomig had a tolerable and manageable safety profile across various advanced solid tumor indications. The encouraging antitumor activity associated with pharmacodynamic activity, and proof-of-mechanism in CPI-experienced melanoma patients, indicates the therapeutic potential of tobemstomig and supports further investigation in earlier disease treatment settings.