Tocilizumab + Ipilimumab/Nivolumab Links Lower Early Grade ≥3 irAEs (43% vs ~60%) to Th17 Dampening in Front-Line Melanoma

In the phase I/II (NCT04940299) study, 35 treatment-naïve advanced melanoma patients received ipilimumab 3 mg/kg + nivolumab 1 mg/kg every 3 weeks plus weekly (162 mg, n = 16) or bi-weekly (n = 19) subcutaneous tocilizumab for up to 12 weeks. Within 12 weeks, grade ≥3 immune-related adverse events (irAEs) occurred 43% overall—lower than historical ipi/nivo which usually yields around ~55-60% of patients experiencing those irAEs. . The dose-dense (Q2W) cohort held toxicity at 40% through 90 days post-tocilizumab, whereas the regular weekly cohort climbed to 56%. Best-overall response rate was 66% (CR 17%, PR 49%), comparable to CheckMate-067 (58%). Tumor Nanostring showed 31 genes—led by RORC—up-regulated in high-grade irAEs; paired biopsies from patients without grade ≥3 irAEs displayed down-shifted IL-17/IL-1/TNF pathways after IL-6R blockade. Inflamed-tissue multiplex imaging and CyTOF blood profiling pinpointed expanded Th17 and γδ T-cell populations that persisted in toxicity-prone patients.