HIF-2a Inhibitor Casdatifan Shows Promise for Patients With Kidney Cancer

Results of the phase 1/1b ARC-20 (NCT05536141) study showed that single-agent casdatifan, an HIF-2a inhibitor with best-in-class potential, demonstrated superior efficacy in metrics such as median progression-free survival (mPFS) and overall response rate (ORR) in patients with late-line metastatic clear cell renal cell carcinoma (ccRCC).^1,2

In the pooled analysis (n = 121), the mPFS was 12.2 months (95% CI, 9.4–20.6), and the confirmed ORR was 31% (n = 38; 95% CI, 23%-40%).¹ This consisted of 1 complete response (CR), 27 partial responses (PRs), and 60 cases of stable disease (SD).

“Even when we analyzed pooled data for the 121 patients treated with casdatifan monotherapy, casdatifan showed a confirmed 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 TKIs alone in a similar patient population and setting,” said Richard Markus, MD, PhD, chief medical officer at Arcus Biosciences, in a press release. ¹

ARC-20 is a phase 1/1b dose-escalation study with 4 monotherapy cohorts. The cohorts consist of groups taking 50 mg twice daily, 50 mg once daily, 100 mg (tablet) once daily, and 150 mg once daily. The majority of the patients had progressed on at least 2 prior lines of therapy, consisting of both an anti–PD-1 and a VEGFR tyrosine kinase inhibitor (TKI).

In the 100-mg once-daily cohort, the mPFS was not evaluable (NE; 95% CI, 5.7-NE). The confirmed ORR was 35% (n = 11; 95% CI, 19%-55%), with 0 CRs, 11 PRs, and 15 cases of SD.

Of the 121 patients included in the pooled analysis, 31% experienced any-grade adverse events (AEs). Grade 3 or greater AEs included anemia (41%; n = 52) and hypoxia (11%; n = 14). Treatment-emergent AEs leading to discontinuation occurred in 9% of patients (n = 11), including 1 patient who discontinued due to anemia and 4 who discontinued due to hypoxia.

Casdatifan activates hundreds of genes in response to low oxygen levels, and when oxygen levels return to normal, HIF-2a is turned off. In patients with ccRCC, HIF-2a remains activated in the presence of oxygen because the shutoff mechanism is deficient. This can cause normal kidney cells to become cancerous.

Arcus Biosciences is investigating potential new drug candidates to advance into the clinic in 2026. These drug candidates include an MRGPRX2 small-molecule inhibitor, a potential treatment for atopic dermatitis and chronic spontaneous urticaria; a TNF-α (TNFR1) small-molecule inhibitor, a treatment for rheumatoid arthritis, psoriasis, and inflammatory bowel disease; and a CD40L small-molecule inhibitor, a potential treatment for multiple sclerosis and systemic lupus erythematosus.¹

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 7, 2025. https://tinyurl.com/mvtvu59n

2. A phase 1 study of AB521 monotherapy and combination therapies in renal cell carcinoma and other solid tumors (ARC-20). ClinicalTrials.gov. Updated September 29, 2025. Accessed October 7, 2025. https://clinicaltrials.gov/study/NCT05536141