PurposeThe immunoglobulin G1-based bispecific antibody tobemstomig (RO7247669) simultaneously targets and blocks programmed cell death protein 1 and lymphocyte activation gene-3 expressed on activated T cells.Patients and methodsThis first-in-human, open-label, phase I clinical 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 checkpoint inhibitor (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, maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), pharmacokinetics (PK), drug receptor occupancy, and preliminary antitumor activity.ResultsThirty-five (dose-escalation) and sixty-nine patients (expansion) were enrolled. Tobemstomig was well tolerated up to the highest tested dose of 2,100 mg once every 2 weeks. The MTD was not reached, and 2,100 mg once every 2 weeks was established as the RDE. Tobemstomig exhibited linear PK across the studied dose range. Partial responses were achieved by 2 of 4 (600 mg) and 4 of 13 (2,100 mg) patients during dose escalation, 6 of 41 patients with CPI-experienced melanoma [objective response rate (ORR): 15%; 95% confidence interval (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.ConclusionsTobemstomig 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 patients with CPI-experienced melanoma indicates the therapeutic potential of tobemstomig and supports further investigation in earlier disease treatment settings.