Siltuximab for the prevention of severe immune-related adverse events during immune checkpoint inhibitor rechallenge in advanced cancer: First interim analysis of the CIRES trial.

e24146 Background: Immune checkpoint inhibitors (ICI) predisposes patients to unpredictable irAEs. Many patients who had irAEs require ICI reinduction to control their cancer. The CIRES trial evaluates siltuximab, an anti-interleukin-6 (IL-6) antibody, to prevent severe irAEs during reinduction, because IL-6 signaling is central to irAE pathogenesis. We report the first pre-planned interim analysis for safety (NCT06470971). Methods: Adults (ECOG ≤2) with advanced cancers and prior severe irAEs [defined as ≥grade (G) 2 requiring ICI discontinuation and prednisone ≥0.5 mg/kg/day or equivalent] were eligible after recovery to ≤G1. Patients with ≥G3 myocarditis and encephalitis were excluded. The primary endpoint is the rate of recurrent or new severe irAE. Siltuximab (11 mg/kg q3w or 15 mg/kg q4w) was given up to 6 months with anti–PD-1 therapy. The protocol has a stopping criteria for severe irAEs in ≥3/10 patients. Results: Among the first 10 patients (Table 1), with a median follow-up of 14.7 months, no severe irAEs were observed. All irAEs were either G2 with fatigue (n = 1) and uveitis/scleritis (n = 1) or G1 with thyroid dysfunction being the most frequent (n = 4), hepatitis, fatigue, myalgia, arthralgia, and eosinophilia (1 each). Treatment-related adverse events (TRAEs) included G3 duodenal stenosis (n=1); G2 lymphopenia (n=4), mucositis, hypertension, thrombocytopenia, and hyperlipidemia (1 each); and non-clinically significant G1. At 6 months, best RECIST v1.1 responses were stable disease (n = 4) and progressive disease (n = 5); one had no measurable disease and remained without evidence of disease. Three patients continued ICI after completing the protocol without further irAEs. Conclusions: At this safety interim analysis, no recurrent or new severe irAEs were observed, indicating an encouraging signal for the efficacy of siltuximab to reduce the severity of irAE from anti–PD-1 therapy. Disease stabilization was observed in 40% of patients. Enrollment is ongoing. Clinical trial information: NCT06470971 . Patient characteristics. Demographics Histology n Prior Treatment n Prior IrAEs (Grade) n Median Age 66.2 Years RCC 3 ICI+TKI 3 Hepatitis (2&3) 3 Female 4 (40%) UC 2 ICI Monotherapy 2 Pneumonitis (2&3) 2 NSCLC 1 Dual ICI 2 Colitis (3) 1 Rechallenge ICI NET 1 ICI + Chemotherapy 2 Pancreatitis (3) 1 Nivolumab 6 PDAC 1 ICI + ADC 1 Myositis (2) 1 Pembrolizumab 4 Melanoma 1 Meningitis (3) 1 CIDP (3) 1 ADC, antibody drug conjugate; CIDP, chronic inflammatory demyelinating polyneuropathy; ICI, immune checkpoint inhibitor; NET, neuroendocrine tumor; NSCLC, non–small cell lung cancer; PDAC, pancreatic ductal adenocarcinoma. RCC, renal cell carcinoma; UC, urothelial carcinoma.