Casdatifan is linked with promising safety, efficacy in clear cell RCC

The investigational HIF-2α inhibitor casdatifan has shown early promise in terms of clinical activity and was also found to be well tolerated in patients with previously treated clear cell renal cell carcinoma (RCC).¹

Data from the phase 1 ARC-20 trial (NCT05536141), a dose-escalation and dose-expansion study of casdatifan, were presented at the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium by Toni K. Choueiri, MD, FASCO, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts. The dose escalation component included patients with advanced solid tumors and who had clear cell RCC. The dose expansion component incorporated casdatifan monotherapy. Primary outcomes included adverse events (AEs) and dose-limiting toxicities; secondary outcomes included objective response rate (ORR) and pharmacokinetics-pharmacodynamics; exploratory outcomes included progression-free survival (PFS), overall survival, and biomarkers. Three cohorts incorporating 3 different dosages of casdatifan were evaluated: 50 mg twice daily (n = 33), 50 mg once per day (n = 31), and 100 mg once per day (n = 29). Choueiri noted that the 100 mg/day regimen will be used in combination regimens and phase 3 trials.

Toni K. Choueiri, MD, FASCO

Regarding baseline characteristics, Choueiri reported that all patients across the dosage cohorts had received both a VEGFR-TKI and PD-1/PD-L1 inhibitor, and that most patients had intermediate IMDC risk score.

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

Median follow-up was 15 months (range, 7-19+ months), 12 months (range, 9-14+ months), and 5 months (range, 2-6+ months) in the 50 mg twice daily, 50 mg/day, and 100 mg/day regimens, respectively. Confirmed ORR was 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/day, and 100 mg/day regimens, respectively. Best overall response was observed in 10 (31%) patients, 9 (32%) patients, and 9 (33%) patients in the 50 mg twice daily, 50 mg/day, and 100 mg/day regimens, respectively.

In addition, 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/day, and 100 mg/day regimens, respectively.²

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

In terms of AEs, Choueiri reported that casdatifan appeared to be well tolerated, with a comparable safety profile for the 3 dosage regimens. Any treatment-emergent AEs (TEAEs) were observed in 32 (97%) patients, 30 (90%) patients, and 28 (97%) patients in the 50 mg twice daily, 50 mg/day, and 100 mg/day regimens, respectively. TEAEs related to casdatifan were observed in 31 (94%) patients, 28 (90%) patients, and 27 (93%) patients in the 50 mg twice daily, 50 mg/day, and 100 mg/day regimens, respectively. Any grade 3 or higher TEAEs were reported in 17 (52%) patients, 16 (52%) patients, and 12 (41%) patients in the 50 mg twice daily, 50 mg/day, and 100 mg/day regimens, respectively. Grade 3 or higher TEAEs related to casdatifan were observed in 16 (49%) patients, 10 (32%) patients, and 8 (28%) patients in the 50 mg twice daily, 50 mg/day, and 100 mg/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 previously treated clear cell RCC between 25% and 33%. Only 2…patients…had to discontinue therapy due to adverse events,” Choueiri said.

During his presentation, Choueiri also announced the phase 3 trial PEAK-3, which will evaluate casdatifan plus cabozantinib (Cabometyx) in advanced or metastatic clear cell RCC 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 clear cell RCC, measurable disease per RECIST v1.1, who have received prior anti-PD-1/PD-L1 inhibitor treatment, have not received cabozantinib, and who are HIF-2α inhibitor naïve. Patients will be randomly assigned 2:1 to receive either casdatifan 100 mg/day plus cabozantinib 60 mg or placebo plus cabozantinib 60 mg. The primary end point will be PFS, with OS and ORR, duration of response, and disease control rate as secondary end points.

“The newest data are from the 100mg cohort using the tablet formulation and the expected go-forward dose for pivotal studies, which showed a 33% confirmed response rate despite the relatively short follow-up,” said Richard Markus, MD, PhD, chief medical officer at Arcus Biosciences in the 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 this year.”²

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 43, 2025 (suppl 5; abstr 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 February 16, 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