Ciforadent Disappoints in First-Line ccRCC Treatment

Interim results from a phase 1b/2 study demonstrated that the triplet combination of ipilimumab (Yervoy), nivolumab (Opdivo), and the A2AR antagonist ciforadent is feasible and well-tolerated, with a manageable safety profile, for the first-line treatment of clear cell renal cell carcinoma (ccRCC).¹

However, at a median follow-up of 9.4 months, this single-arm study did not show that the addition of ciforadenant significantly improved the objective response rate (ORR) or deep response rate compared to historical data for ipilimumab and nivolumab alone. Exploratory biomarker analyses revealed the complexity of adenosine biology, as a previously identified adenosine signature did not correlate with response in this trial. Conversely, an "OPTIC immune effector signature" was associated with a 100% ORR, highlighting potential avenues for future biomarker-driven trials. Longer follow-up is necessary to determine if blocking adenosine signaling impacts the durability of response.

Scientific Rationale and Core Hypothesis

The trial predicated on the hypothesis that blocking adenosine signaling within the RCC tumor microenvironment (TME) will decrease resistance to immunotherapy. This hypothesis is supported by several key observations:

• Role of Adenosine: Adenosine in the TME is known to block T-cell activation and promote myeloid suppression, thereby hindering antitumor immune responses.
• Ciforadenant Mechanism: Ciforadenant is an oral small molecule antagonist of A2AR. It has demonstrated efficacy in animal models and is associated with T-cell activation.
• Clinical Correlation: In a study of 60 patients with metastatic RCC, higher expression of A2AR was associated with worse overall survival (OS) for patients receiving PD-1/CTLA4 checkpoint inhibitors.

Clinical Trial Design

The study is a phase 1b/2, single-arm trial conducted by the Kidney Cancer Research Consortium to evaluate the safety and efficacy of adding ciforadenant to the standard ipilimumab and nivolumab combination in treatment-naïve patients with advanced ccRCC.^1,2 Patients were required to have an ECOG performance status of 0 or 1, measurable disease, and adequate organ function.

The treatment regimen consisted of:

• Ipilimumab: 1 mg/kg intravenously (IV) every 3 weeks (q3w)
• Nivolumab: 3 mg/kg IV every 3 weeks (q3w)
• Ciforadenant: 100 mg orally (PO) twice daily (BID)

The primary end point of phase 1b was safety, tolerability, and antitumor activity; the primary end point of phase 2 was tumor burden reduction >50%, with secondary end points of ORR, progression-free survival, and treatment-related adverse events.

Interim Clinical Outcomes

The primary conclusion from the interim analysis is that the addition of ciforadenant to ipilimumab and nivolumab did not significantly affect the deep response rate or the ORR.¹ With a median follow-up of 9.4 months, 2 patients achieved a complete response (4.0%), 21 achieved a partial response (42%), 16 had stable disease (32.0%), and 8 had progressive disease (16.0%). At the time of analysis, 19 patients remained on the trial. Longer follow-up is required to assess endpoints related to the durability of response.

The triplet therapy was determined to be feasible and generally well-tolerated. Five patients (10%) discontinued treatment due to toxicity. There were no treatment-related deaths reported in the study.

Translational and Biomarker Analysis

The trial placed a strong emphasis on translational research to understand the biological underpinnings of response and resistance. RNA sequencing analysis confirmed the existence of distinct RCC subtypes, including angiogenically driven, immune-inflamed, and high proliferative tumors.

An overlapping adenosine/myeloid signature has been previously associated with worse tumor biology and was hypothesized to predict response to ciforadenant. In this study, the adenosine signature did not correlate with response to the triplet therapy.

However, “prior adenosine signature was studied in the context of PD-1 monotherapy, not in combination with the CTLA-4 inhibitor ipilimumab,” Katy Beckermann, MD, Tennessee Oncology, said during a presentation of the data.

An exploratory analysis of the OPTIC immune effector signature yielded a strong positive correlation, with patients exhibiting this signature demonstrating a 100% ORR on the ipilimumab/nivolumab backbone.

The correlative analysis was constrained by missing data and the inability to derive RNA from historical bone metastases.

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: 2025 ESMO Congress; 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 November 18, 2025. https://www.clinicaltrials.gov/study/NCT05501054