Triplet Therapy Proves Feasibility, Lacks Enhanced Efficacy in Advanced ccRCC

The triplet therapy of ciforadenant, nivolumab (Opdivo), and ipilimumab (Yervoy) showed acceptable safety but failed to improve efficacy in patients with untreated, advanced clear cell kidney cancer (ccRCC), according to findings presented at the 2025 European Society for Medical Oncology (ESMO) Congress, October 17-20 in Berlin, Germany.¹

The results of the phase 1b/2 study (NCT05501054)² were presented by Kathryn Beckermann, MD, PhD, co-investigator of the study and director of Genitourinary Cancer Research at Tennessee Oncology. This was a single-arm cohort study with a total enrollment of 50 patients.

Phase 1b consisted of 1 mg of ipilimumab administered intravenously (IV) every 3 weeks, 3 mg of nivolumab IV every 3 weeks, and 100 mg of ciforadenant. The primary end point was safety, tolerability, and antitumor response. Phase 2 consisted of the same doses at the same intervals. Here, the primary end point was a tumor burden reduction of >50%; H0 32% to 48%. The secondary end points of phase 2 were overall response rate (ORR), progression-free survival (PFS), and treatment-related adverse events (TRAEs).

The depth of response was > 50% tumor reduction, which 17 patients (34%) achieved. The median follow-up was 9.4 months. Additionally, 16% of patients had progressive disease (PD) as best response. The median progression-free survival (PFS) was 11 months. Majority of patients had 3 or more sites of metastatic disease.

Treatment discontinuation due to toxicity occurred in 5 patients (10%), and no treatment-related deaths were reported. Majority of patients, 96%, reported experiencing TRAEs of any grade, and 68% experienced TRAEs grade >3. Some of the most reported TRAEs included but are not limited to AST increase, hyponatremia, troponin T increase, colitis, fatigue, anemia, adrenal insufficiency, diarrhea, and rash.

Patient eligibility included having advanced ccRCC, having received no prior systemic therapy, having an ECOG score of 0 or 1, having measurable disease, giving a tumor sample for histologic confirmation and biomarker assessment, and having adequate organ function.

Fewer patients were able to undergo nephrectomy compared with the CheckMate 214 phase 3 study (NCT02231749).³ The purpose of the CheckMate 214 study was to compare the ORR, PFS, and overall survival (OS) of nivolumab combined with ipilimumab to sunitinib monotherapy in patients with previously untreated RCC.

“In this first kidney cancer research consortium trial, this triplet therapy was feasible and well-tolerated in this early analysis, and the deep response rate and [ORR] was not significantly affected by the addition of ciforadenant,” concluded Beckermann during the presentation.

DISCLOSURES: Beckermann is a consultant to Alpine Bioscience, Aveo, Aravive, Arcus, Adicept, BMS, Exelixis, Eisai, J&J, Merck, Nimbus, Novartis, and Xencor.

REFERENCES:

1. Beckermann K, Haas N, George D, et al. Phase 1b/2 Trial of Ipi + Nivo + Ciforadenant in 1L ccRCC: Safety, Efficacy, and Translational Correlates: a Kidney Cancer Research Consortium Trial. Presented at the European Society for Medical Oncology (ESMO) Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract 2596MO.

2. Phase 1b/2 Trial of Ipilimumab, Nivolumab, and Ciforadenant (Adenosine A2a Receptor Antagonist in First-line Advanced Renal Cell Carcinoma. ClinicalTrials.gov. Updated August 1, 2025. Accessed October 21, 2025. https://clinicaltrials.gov/study/NCT05501054

3. Nivolumab Combined With Ipilimumab Versus Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 214). ClinicalTrials.gov. Updated June 26, 2025. Accessed October 21, 2025. https://clinicaltrials.gov/study/NCT02231749