Kidney cancer ranks among the ten most frequently diagnosed malignancies in both men and women in the United States. The predominant histologic subtype is clear cell renal cell carcinoma (ccRCC), which accounts for the majority of adult kidney cancer cases. Prognosis is highly stage-dependent: while early-stage RCC is associated with favorable outcomes and a high five-year survival rate, the prognosis significantly worsens in the setting of advanced or metastatic disease. Specifically, the five-year survival rate drops to approximately 18% for patients with metastatic RCC, underscoring the need for more effective systemic therapies and earlier detection strategies in this high-risk population.

A total of 27 patients were enrolled, with a median (range) follow-up of 2.9 (0.1–6.8) months. At the data cutoff, prior treatment settings included adjuvant-only therapy (n = 5/26) and metastatic disease—first-line (1L, n = 17/26) and second-line (2L, n = 4/26). Prior therapies consisted of immune-oncology (IO) alone (n = 15/26) or IO combined with a VEGFR‑TKI (n = 11/26). All-grade adverse events (AEs) occurred in 89% of patients, with the most common being anemia (n = 16 [59%]) and fatigue (n = 15 [56%]). The most frequent Grade ≥3 AEs (occurring in >10% of patients) were anemia (n = 7 [26%]) and hypoxia (n = 3 [11%]). No cardiac events were reported. Dose reductions due to AEs occurred in 3 patients (11%) for casdatifan only, 7 patients (26%) for cabozantinib only, and 2 patients (7%) for both casdatifan and cabozantinib. One patient (4%) discontinued treatment due to an AE—hypoxia related to casdatifan. As of January 27, 2025, responses were observed in the efficacy-evaluable population (n = 22), with an objective response rate (ORR) of 41%, including one complete response and eight partial responses. Antitumor activity was observed across all IMDC risk groups.

• Treatment with casdatifan, a HIF-2a inhibitor, plus cabozantinib showed a confirmed ORR of 46% in patients who reached a minimum of 12 weeks (two scans) of follow-up.

• The combination had a manageable safety profile, and there was no meaningful overlapping toxicity for the two drugs.

• These data support the initiation of PEAK-1, a Phase III study that will evaluate casdatifan plus cabozantinib in immunotherapy-experienced clear cell renal cell carcinoma patients, and eVOLVE-RCC02, a Phase Ib/III study in first-line ccRCC patients, both of which will begin shortly.

Arcus is pursuing a broad development program in both the immuno-oncology (IO)-naive and post-IO settings with differentiated combinations to maximize the opportunity for casdatifan in ccRCC. These studies include:

• Arcus’s planned Phase III study, PEAK-1, which will evaluate casdatifan plus cabozantinib versus cabozantinib monotherapy as a first- or second-line treatment in patients with metastatic ccRCC who have previously received anti-PD-1/PD-L1 therapy. The primary endpoint will be PFS with a key secondary endpoint of overall survival.

• ARC-20, which includes three cohorts evaluating casdatifan in earlier-line settings, including casdatifan plus zimberelimab in first-line ccRCC, casdatifan monotherapy in favorable risk ccRCC, and casdatifan monotherapy in immunotherapy-experienced, TKI-naive settings.

KOL insights: 

“The initial data for casdatifan plus cabozantinib in the ARC-20 study have already exceeded the historic benchmarks for either agent alone, as well as that of another HIF-2a inhibitor plus cabozantinib in the same second-line setting.” – Expert Opinion.

Conclusion:

The combination of casdatifan and cabozantinib demonstrated manageable safety and promising clinical activity in previously treated clear cell RCC — across all IMDC risk groups. Most patients had prior immunotherapy, either alone or combined with a VEGFR TKI. The most frequently reported AEs were anemia and fatigue, while severe events, such as anemia and hypoxia, were less frequently observed, and no cardiac events were reported. One patient discontinued due to hypoxia related to casdatifan. The objective response rate was favorable across diverse patient subsets, with nearly 3 months of follow-up. Casdatifan was well tolerated and delivered potent anti-cancer effects in advanced clear cell kidney cancer, strengthening its potential as a valuable option and supporting its ongoing evaluation in the Phase III PEAK-1 trial.