Casdatifan Monotherapy Achieves Clinical Activity in Late-Line Kidney Cancer

The HIF-2α inhibitor casdatifan demonstrated positive efficacy in the treatment of patients with late-line metastatic clear cell renal cell carcinoma across all monotherapy cohorts in the phase 1/1b ARC-20 trial (NCT05536141), according to a press release from the developer, Arcus Biosciences.¹

There were 4 monotherapy cohorts included in the trial (n = 121). Cohort 1: patients received 50 mg of casdatifan twice daily; cohort 2: patients received 50 mg once daily; cohort 3: patients received 100 mg via tablet once daily; and cohort 4: patients received 150 mg once daily.

As of the data cut-off of August 15, 2025, disease control, defined as either a partial response or stable disease, had been achieved by 81% of patients; 74% of patients with confirmed responses (n = 28/38) across all 4 cohorts remained on treatment.

With a median follow-up of 15.2 months in the pooled analysis of patients across all 4 cohorts, the median progression-free survival (PFS) was 12.2 months (95% CI, 9.4-20.6); the 12- and 18-month PFS rates were 50% (95% CI, 41%-59%) and 43% (95% CI, 33%-53%), respectively.

The confirmed overall response rate (ORR) was 31% (95% CI, 23%-40%). Complete responses (CRs) were observed in 1%, partial responses (PRs) in 31%, stable disease in 50%, and progressive disease in 19%. The ORR, including responses pending confirmation, was 33%, as 2 responses are pending confirmation in the 100 mg cohort. The disease control rate (DCR) was 81% (95% CI, 63%-88%). The median time to response was 2.8 months.

Additionally, in the 100 mg via tablet once daily cohort (n = 31), which was determined to be the phase 3 dose, the median follow-up was 12.4 months. The median PFS was not estimable (NE; 95% CI, 5.7-NE), with 12- and 18-month PFS rates of 60% (95% CI, 40%-75%) and NE, respectively.

The confirmed ORR was 35% (95% CI, 19%-55%), with CRs achieved by 0%, PRs achieved by 35%, stable disease achieved by 48%, and progressive disease observed in 16%.The ORR, including responses pending confirmation, was 42%, as 2 patients had unconfirmed responses. The DCR was 84% (95% CI, 66%-95%), and the median time to response was 2.6 months.

“In the 100 mg tablet cohort, our phase 3 dose and formulation, casdatifan showed a 35% confirmed ORR, with two additional responses pending confirmation, and [median] PFS had not been reached, even with a median follow-up of 1 year,” Richard Markus, MD, PhD, chief medical officer at Arcus Biosciences, said in the press release.¹ “Even when we analyzed pooled data for the 121 patients treated with casdatifan monotherapy, casdatifan showed a confirmed ORR of 31% and a median PFS of 12.2 months, which is meaningfully longer than published data from studies with the only marketed HIF-2a inhibitor and for [tyrosine kinase inhibitors] alone in a similar patient population and setting.”

ARC-20 evaluated the safety, tolerability, and pharmacokinetic profile of casdatifan monotherapy and combination therapies in patients with clear cell renal cell carcinoma (RCC) and other solid tumors.

In the pooled analysis, 55% of patients had received at least 3 prior therapies, and 29% had received at least 4 prior lines of therapy; 71% of patients had an International Metastatic Renal Cell Carcinoma Database Consortium risk factor of intermediate or poor.

Eligible patients had at least 1 measurable lesion per RECIST and an ECOG performance status of 1 or less; in the dose escalation phase, patients had any pathologically confirmed solid tumor type where no other treatment options were available and a creatinine clearance of at least 40 mL/min.²

Exclusion criteria included use of any live vaccines against infectious diseases within 4 weeks of treatment initiation, history of trauma or major surgery within 28 days of initiation, and known psychiatric or substance abuse disorders that may interfere with cooperation with the trial requirements; in all expansion cohorts, prior treatment with any HIF-2α inhibitor was not permitted.

The primary end points of the trial were the number of patients with dose-limiting toxicities and adverse events (AEs). Secondary end points included the ORR per RECIST v1.1, the plasma concentration of casdatifan, the area under the plasma concentration time curve of casdatifan, and the maximum observed plasma concentration of casdatifan.

Regarding safety, in the pooled analysis (n = 127), any serious treatment-emergent AEs (TEAEs) were experienced by 31% of patients. Grade 3 or higher TEAEs related to casdatifan were anemia (41%) and hypoxia (11%). Treatment discontinuation occurred in 9% of patients, of which 1% and 3% were caused by anemia and hypoxia, respectively.

In the phase 3 dose cohort (n = 32), any serious TEAEs occurred in 31% of patients. Grade 3 or higher casdatifan-related TEAEs were anemia (25%) and hypoxia (9%); TEAEs led to treatment discontinuation in 9%, of which 0% and 3% were caused by anemia and hypoxia.

Previously, results from ARC-20, which showed that combining casdatifan with cabozantinib (Cabometyx) achieved meaningful clinical activity in patients with clear cell RCC, were shared at the 2025 Kidney Cancer Research Summit.³

References

1. Arcus Biosciences presents new data for its HIF-2a inhibitor casdatifan and discloses first inflammation programs at investor event. News release. Arcus Biosciences. October 6, 2025. Accessed October 6, 2025. https://tinyurl.com/y9ftysac
2. A phase 1 study of AB521 monotherapy and combination therapies in renal cell carcinoma and other solid tumors (ARC-20). ClincialTrials.gov. Updated September 29, 2025. Accessed October 6, 2025. https://tinyurl.com/mr3shb2r
3. Choueiri TK, Ornstein M, Barata P, et al. Combination casdatifan plus cabozantinib in previously treated patients with clear cell renal cell carcinoma: results from an expansion cohort of ARC-20 (NCT05536141). Presented at the 2025 Kidney Cancer Research Summit; July 17-18, 2025; Boston, MA.