Casdatifan Plus Cabozantinib Shows Early-Phase Efficacy in Clear Cell RCC

The novel HIF-2α inhibitor casdatifan in combination with cabozantinib (Cabometyx) led to encouraging responses with a manageable safety profile in patients with pretreated clear cell renal cell carcinoma (RCC), spurring investigators to further pursue the development of this regimen for this patient population, according to Rana R. McKay, MD, FASCO.

“Casdatifan targets the fundamental HIF-2α pathway that drives RCC biology and cabozantinib provides multikinase inhibition affecting [tumor] angiogenesis, invasion, and metastasis,” McKay, a professor in the Departments of Medicine and Urology at the University of California San Diego Health, said in an interview with OncLive®. “This dual approach appears to be synergistic, and it’s going to be tested in a large phase 3 trial.”

At a median follow-up of 5.3 months (range, 2.8-9.1) findings from the expansion cohort of the phase 1 ARC-20 trial (NCT05536141) presented during the 2025 ASCO Annual Meeting demonstrated that efficacy-evaluable patients who received casdatifan plus cabozantinib (n = 24) achieved a confirmed overall response rate (ORR) of 46% (95% CI, 25.6%-67.2%), including a complete response (CR) rate of 4%.1 On June 1, 2025, Arcus Biosciences announced that, based on the findings from ARC-20, the phase 3 PEAK-1 (NCT07011719) and phase 1b/3 eVOLVE-RCC02 (NCT07000149) trials will be initiated to further evaluate casdatifan in patients with clear cell RCC.2 PEAK-1 will examine casdatifan plus cabozantinib vs cabozantinib monotherapy as a first- or second-line treatment in patients with metastatic disease who received a prior anti–PD-1/PD-L1 therapy. eVOLVE-RCC02 will evaluate frontline casdatifan plus volrustomig.

In the interview, McKay discussed the significance of the data from ARC-20, the future of HIF-2α for the treatment of patients with clear cell RCC, as well as PEAK-1 and eVOLVE-RCC02.

OncLive: What were the key efficacy data from ARC-20?

McKay: The results of the ARC-20 expansion cohort were quite impressive and represent a meaningful advancement in the treatment of [patients with] second-line clear cell RCC. The 46% confirmed ORR with a 4% CR rate and low primary progressive disease rates are impressive to think about in the context of this phase 1 trial, considering that 79% of patients had intermediate- or poor-risk disease. The clinical benefit rate of this combination was over 90%.

The depth of responses is equally encouraging, with the waterfall plot showing that nearly all evaluable patients experienced some degree of [tumor] shrinkage. This suggests that the combination is not just achieving responses but meaningful tumor regression across the majority of patients. The safety profile, while showing expected toxicities such as anemia and fatigue, appears to be manageable, and most adverse effects did not require dose modifications.

What are the potential clinical implications of these data?

This represents the validation of the HIF-2α inhibition strategy in combination therapy in [patients with] RCC. The mechanistic rationale for targeting the HIF/VHL pathway, which is fundamentally disrupted in clear cell RCC, combined with an antiangiogenic such as cabozantinib, appears to be delivering on its therapeutic promise.

In terms of pharmacokinetic profile, casdatifan has a half-life of less than 24 hours and dose-proportional exposure seems to offer practical advantages for the combination. The erythropoietin suppression that’s seen with casdatifan is more dramatic and sustained which suggests improved potency and better tolerability. There are currently several HIF-2α inhibitors that are approved or being evaluated in [patients with] kidney cancer.

What is the significance of the combination showing better efficacy vs casdatifan or cabozantinib monotherapy in the second-line setting?

This finding underscores the value of rational combination therapy in RCC. Although we don’t have direct head-to-head comparisons in this study, historical data suggest that single-agent cabozantinib typically has an ORR of approximately 25% to 30% depending on the context. The 46% ORR seen here with the combination is a numeric improvement. I believe the significance lies in the complementary mechanisms of action.

What do these results indicate about the future of HIF-2α inhibition in patients with clear cell RCC?

These results strongly suggest that HIF-2α inhibition will continue to play an increasingly central role in clear cell RCC treatment. The success of this combination validates the biological rationale for targeting this pathway and suggests we’re moving towards a more sophisticated mechanism-based treatment approach.

The future likely involves several key developments. We’ll see HIF-2α inhibitors tested in earlier lines. Multiple clinical trials are already looking at [HIF-2α inhibitors] in the frontline and adjuvant settings.

Potentially, the improved pharmacokinetic profile of casdatifan compared with existing HIF-2α inhibitors suggests that we may see better tolerance and improved efficacy, although that still needs to be tested. We haven’t yet delved into biomarker development strategies, but those could open the door to understanding [how] VHL status, HIF-2α levels, and other molecular markers could [help us] optimize treatment selection.

How could results from the ongoing PEAK-1 and eVOLVE-RCC02 trials affect the treatment landscape?

These trials represent the critical next steps in validating the clinical utility of this combination. eVOLVE-RCC02, which was recently unveiled at the 2025 Kidney Cancer Research Summit, is looking at adding casdatifan to the backbone of volrustomig, which is a PD-1/CTLA-4 inhibitor.

These data are going to be critically important. They’re going to provide larger patient cohorts and randomized data to confirm the promising results that have been seen in some of these early studies. I believe these trials are going to provide important information regarding next-generation treatments for patients with advanced RCC and I’m excited about their ongoing enrollment.

References

1. Choueiri TK, Ornstein MC, Barata PC, et al. Combination casdatifan plus cabozantinib expansion cohort of phase 1 ARC-20 study in previously treated patients with clear cell renal cell carcinoma. J Clin Oncol. 2025;43(suppl 16):4506. doi:10.1200/JCO.2025.43.16_suppl.4506
2. Initial data from the ARC-20 study of casdatifan plus cabozantinib showed nearly half of patients with metastatic kidney cancer had a confirmed response. News release. June 1, 2025. Accessed July 31, 2025. https://investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2025/Initial-Data-from-the-ARC-20-Study-of-Casdatifan-Plus-Cabozantinib-Showed-Nearly-Half-of-Patients-with-Metastatic-Kidney-Cancer-Had-a-Confirmed-Response/default.aspx