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
Mené sur 104 patients atteints d'une tumeur solide de stade avancé ou métastatique (mélanome, cancer du poumon non à petites cellules, carcinome épidermoïde de l'oesophage), cet essai de phase I détermine la dose maximale tolérée du tobemstomig (un anticorps bispécifique ciblant PD-1 et LAG-3), puis évalue ses caractéristiques pharmacocinétiques et son efficacité du point de vue du taux de réponse et en fonction de l'administration antérieure d'un traitement par inhibiteur de point de contrôle immunitaire
Purpose: The 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 Methods: This 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.
Results: Thirty-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.
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 patients with CPI-experienced melanoma indicates the therapeutic potential of tobemstomig and supports further investigation in earlier disease treatment settings.
Clinical Cancer Research , résumé, 2026