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Ciforadenant in combination with ipilimumab and nivolumab was safe and feasible but did not enhance activity in frontline ccRCC.
The addition of the adenosine A2a receptor antagonist ciforadenantto ipilimumab (Yervoy) and nivolumab (Opdivo) displayed acceptable safety but failed to improve responses as a first-line treatment for patients with clear cell renal cell carcinoma (ccRCC), according to data from a phase 1b/2 Kidney Cancer Research Consortium study (NCT05501054) presented during the 2025 ESMO Congress.1
At a median follow-up of 9.4 months, patients who received the triplet (n = 50) experienced a partial response rate of 42% and a complete response rate of 4.0%. Stable disease was achieved by 32.0% of patients and 16.0% experienced disease progression. The mean depth of response was –24.3%; 66.0% of patients did not experience a depth of response above 50%.
“Triplet therapy [with ipilimumab, nivolumab, and ciforadenant] is feasible and well tolerated [in this study],” Katy Beckermann, MD, PhD, the director of genitourinary cancer research at Tennessee Oncology in Franklin, and her coauthors wrote in their presentation. “In this interim analysis of a single-arm study, the deep response rate/overall response rate [ORR] was not significantly affected by the addition of ciforadenant to ipilimumab/nivolumab.”
The trial enrolled adult patients with patients with ccRCC who received no prior systemic therapy.1,2 Patients were also required to have an ECOG performance status of 0 or 1, measurable disease, and adequate organ function.
After the safety lead-in, patients in phase 1b of the study received intravenous (IV) ipilimumab at 1 mg/kg every 3 weeks plus IV nivolumab at 3 mg/kg every 3 weeks, and oral ciforadenant at 100 mg twice daily. The same dosing schedule was followed during the phase 2 portion of the study.
The primary end points were safety, tolerability, and antitumor activity in phase 1b. In phase 2, the primary end points were the rate of tumor burden reduction of at least 50%. Secondary end points included ORR, progression-free survival (PFS), and the rate of treatment-related adverse effects (TRAEs). Gene expression signatures were also assessed as an exploratory end point in phase 2.
At baseline, the median age was 61.5 years (IQR, 53-70).1 Most patients were male (88.0%), had an ECOG performance status of 1 (58.0%), had IMDC intermediate-risk disease (71.4%), and underwent prior nephrectomy (54.0%). Patients had 1 (16.0%), 2 (34.0%), 3 (36.0%), 4 (12.0%), or 4 or more (2.0%) metastatic sites.
Additional findings from the study revealed that the median time on treatment was 9.2 months. The median duration of response was 8.51 months (95% CI, 2.66-not evaluable). The median PFS was 11.04 months (95% CI, 7.1-13.8). Nineteen patients remained on the trial at the data cutoff.
In terms of safety, treatment discontinuation due to toxicity occurred in 5 patients and there were no treatment-related deaths. The most common any-grade TRAEs included fatigue (44%), rash (44%), anemia (28%), and hyponatremia (32%). The most common grade 3 or higher TRAEs included increased aspartate aminotransferase levels (8%), hyponatremia (6%), and increased troponin T levels (6%). Overall, any-grade and grade 3 or higher TRAEs occurred at respective rates of 96% and 68%.
“Comprehensive correlative analyses highlight the complexity of adenosine biology and provide support for biomarker trials,” Beckermann and her coauthors wrote in their conclusion. “Key questions remain, and longer follow-up is needed to determine whether adenosine signaling blockade influences durability of response.”
Disclosures: Beckermann is a consultant for Alpine Bioscience, Aveo, Aravive, Arcus, Adicept, BMS, Exelixis, Eisai, J&J, Merck, Nimbus, Novartis, and Xencor.