Tobemstomig (PD-1×LAG-3) ± tiragolumab (anti-TIGIT) + axitinib adds toxicity without PFS/ORR gain in 1L ccRCC

Tobemstomig is a bispecific PD-1/LAG-3 checkpoint inhibitor evaluated with axitinib (VEGF-TKI), with or without tiragolumab (anti-TIGIT), versus pembrolizumab (anti–PD-1) + axitinib in this randomized, open-label Phase II trial in previously untreated unresectable/metastatic clear-cell RCC with IMDC intermediate/poor risk (NCT05805501; safety population n=198). After an interim futility analysis the study was terminated and the primary endpoint was amended to safety; descriptively, confirmed ORR was 51.5% (tobemstomig-axitinib; n=66) and 53.8% (tobemstomig-tiragolumab-axitinib; n=65) vs 51.5% (pembro-axitinib; n=67) with median PFS 12.4 vs 12.5 vs 12.5 months, respectively (i.e., no signal over the pembro-axitinib control and well below the ~15.4-month median PFS reported with pembro-axitinib in KEYNOTE-426). Grade 3–4 AEs were higher with tobemstomig-containing arms (62.1% and 67.7% vs 56.7%), as were treatment-related serious AEs (22.7% and 29.2% vs 13.4%). Take Home: If PD-1×LAG-3 (and even triplet PD-1×LAG-3 + TIGIT) can’t beat pembrolizumab-axitinib on PFS/ORR but clearly increases serious toxicity, it’s hard to justify further development in this crowded 1L ccRCC space without a biomarker-enriched strategy or a cleaner partner.