Casdatifan Monotherapy Shows Early Efficacy Signals and Tolerable Safety Profile in Pretreated ccRCC

Casdatifan, a HIF-2α inhibitor, demonstrated clinical activity and was associated with a manageable safety profile in patients with previously treated clear cell renal cell carcinoma (ccRCC), according to findings from the phase 1 ARC-20 trial (NCT05536141) presented at the 2025 Genitourinary Cancers Symposium.1

Data from the dose-escalation and -expansion portions of the study were presented by Toni K. Choueiri, MD, FASCO, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts. The median follow-up was 15 months (range, 7 to 19+ months), 12 months (range, 9 to 14+ months), and 5 months (range, 2 to 6+ months) in the 50 mg twice daily (n = 33), 50 mg per day (n = 31), and 100 mg per day (n = 29) casdatifan cohorts, respectively. The confirmed overall response rates (ORRs) were 25% (95% CI, 11.5%-43.4%), 29% (95% CI, 13.2%-48.7%), and 33% (95% CI, 16.5%-54.0%) in the 50 mg twice daily, 50 mg per day, and 100 mg per day cohorts, respectively. Best overall response was observed in 10 (31%), 9 (32%), and 9 (33%) patients, respectively.

The dose-escalation component included patients with advanced ccRCC and other solid tumors. Both the dose-escalation and -expansion components treated patients with casdatifan monotherapy. Primary outcomes included adverse effects (AEs) and dose-limiting toxicities; secondary outcomes included ORR and pharmacokinetics/pharmacodynamics; exploratory outcomes included progression-free survival (PFS), overall survival (OS), and biomarkers. Three dose-expansion cohorts incorporating 3 different dosages of casdatifan were evaluated: 50 mg twice daily, 50 mg once per day, and 100 mg once per day. Choueiri noted that the 100-mg regimen will be used in combination regimens and phase 3 trials.

Regarding baseline characteristics, Choueiri reported that all patients across the dosage cohorts had previously received both a VEGFR-TKI and PD-1/PD-L1 inhibitor, and most patients had intermediate International Metastatic RCC Database Consortium risk scores.

“Over 80% of patients…had at least 2 lines of therapy, so this is a heavily refractory population,” Choueiri said.

In addition, the median PFS was 9.7 months (95% CI, 5.5-not evaluable [NE]), NE (95% CI, 6.8-NE), and NE in the 50 mg twice daily, 50 mg per day, and 100 mg per day cohorts, respectively.2

Regarding the 100 mg per day cohort, Choueiri noted that, “the majority of patients achieved tumor shrinkage, and many of the responses are ongoing.”

Choueiri reported that casdatifan appeared to be well tolerated, with a comparable safety profile across the 3 dosage regimens. Any treatment-emergent AEs (TEAEs) were observed in 32 (97%), 30 (90%), and 28 (97%) patients in the 50 mg twice daily, 50 mg per day, and 100 mg per day regimens, respectively. TEAEs related to casdatifan were observed in 31 (94%), 28 (90%), and 27 (93%) patients in the 50 mg twice daily, 50 mg per day, and 100 mg per day regimens, respectively. Any grade 3 or higher TEAEs were reported in 17 (52%), 16 (52%), and 12 (41%) patients in the 50 mg twice daily, 50 mg per day, and 100 mg per day regimens, respectively. Grade 3 or higher TEAEs related to casdatifan were observed in 16 (49%), 10 (32%), and 8 (28%) patients in the 50 mg twice daily, 50 mg per day, and 100 mg per day regimens, respectively.

Choueiri highlighted that the rate of serious TEAEs related to casdatifan was 10% or lower in the 3 cohorts.

“Across doses, in the 93 enrolled patients, casdatifan showed clinical activity in [between 25% and 33% of patients with] previously treated ccRCC. Only 2…patients…had to discontinue therapy due to AEs,” Choueiri said.

“The newest data are from the 100 mg cohort using the tablet formulation [of casdatifan] and the expected go-forward dose for pivotal studies, which showed a 33% confirmed response rate despite the relatively short follow-up,” Richard Markus, MD, PhD, chief medical officer at Arcus Biosciences, said in a news release.2 “Casdatifan continues to be well tolerated, with a very low discontinuation rate, supporting its strong potential in combination therapy. We look forward to sharing initial results for the casdatifan-plus-cabozantinib cohort later [in 2025].”2

During his presentation, Choueiri also announced the planned phase 3 PEAK-1 trial, which will evaluate casdatifan plus cabozantinib (Cabometyx) in patients with advanced or metastatic ccRCC following prior PD-1 therapy. The trial, which is anticipated to open in the first half of 2025, will include patients with unresectable, locally advanced or metastatic ccRCC and measurable disease per RECIST 1.1 criteria who have received prior anti–PD-1/PD-L1 treatment, have not received cabozantinib, and who are HIF-2α inhibitor naive. Patients will be randomly assigned 2:1 to receive either casdatifan at 100 mg per day plus cabozantinib at 60 mg, or placebo plus cabozantinib at 60 mg. The primary end point will be PFS; OS, ORR, duration of response, and disease control rate will be secondary end points.

References

1. Choueiri T, Lee JL, Merchan J, et al. Casdatifan (cas) monotherapy in patients (pts) with previously treated clear cell renal cell carcinoma (ccRCC): safety, efficacy and subgroup analysis across multiple doses from ARC-20, a phase 1 open-label study. J Clin Oncol. 2025;43(suppl 5):441. doi:10.1200/JCO.2025.43.5_suppl.441
2. New data demonstrated best-in-class potential for casdatifan, a HIF-2a inhibitor, in patients with metastatic kidney cancer. News release. Arcus Biosciences. February 15, 2025. Accessed March 12, 2025. https://investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2025/New-Data-Demonstrated-Best-in-Class-Potential-for-Casdatifan-a-HIF-2a-Inhibitor-in-Patients-with-Metastatic-Kidney-Cancer/default.aspx