Phase 1 Study Identifies Casdatifan Dose With Promising Responses in Pretreated Clear Cell RCC

Results from a phase 1 study presented Saturday showed that a 100 mg/day dose of casdatifan produced clinically meaningful responses in a third of patients previously treated for clear cell renal cell carcinoma (ccRCC).¹

Toni K. Choueiri, MD | Image credit: Dana-Farber

Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, presented data from the ARC-20 trial (NCT05536141) on casdatifan during the American Society of Clinical Oncology Genitourinary Cancers Symposium, held February 13-15, 2025, in San Francisco, California.

ARC-20 is an open-label dose escalation and expansion study that tested 3 doses of the small molecule in patients who were at least 18 years old and had been previously treated with PD-1 inhibitors and vascular endothelial growth factor receptor (VEGF)–tyrosine kinase inhibitor therapy for ccRCC. The phase 1 study end points included objective response rate (ORR) and treatment-emergent adverse events (TEAEs).

How Casdatifan Works

Under development by Arcus Biosciences, casdatifan targets hypoxia-inducible factor 2⍺ (HIF2⍺), described as a “transcription factor that induces target genes responsible for the hypoxic stress response.” Lacking oxygen, the immune system is less able to fight off cancer cell growth. HIF2α, in fact, binds with other proteins to switch off the body’s anti-inflammatory mechanisms, empowering genes that promote tumor growth in ccRCC, the most common type of kidney cancer.²

Casdatifan binds to HIF2⍺, disabling these mechanisms to cause cancer cell death. RCC is associated with von Hippel-Lindau (VHL) disease, a hereditary condition that causes HIF2α accumulation.

Previously, the HIF-2α inhibitor belzutifan (Welireg; Merck) was approved for treatment of adult patients with advanced RCC following treatment with an immune checkpoint inhibitor and a VEGF-tyrosine kinase inhibitor. Belzutifan is also approved to treat adult patients with VHL disease who develop RCC, central nervous system hemangioblastomas or pancreatic neuroendocrine tumors. Merck announced early today that belzutifan had received European Commission approval for these indications.³

Methods and Results

ARC-20 studied 3 doses of casdatifan: 50 mg twice daily, in 33 patients; 50 mg once daily, in 31 patients; and 100 mg once daily, in 29 patients.¹ Patients had no prior treatment with a HIF2α inhibitor. Median prior lines of therapy across the study arms was 3 (range, 1–7). Median age of the 50 mg twice daily group was 62 years; 50 mg once daily, 65 years; 100 mg once daily, 60 years.

Median follow-up with the 50 mg dose twice daily was 15 months; for 50 mg once daily, 12 months, and 100 mg once daily, 5 months. Results are as follows:

• Confirmed ORR for 50 mg twice daily dose, 8 patients, 25%; complete response (CR), 0; partial response (PR), 10 (31%); stable disease (SD), 16 (50%); progressive disease, 6 (19%).
• Confirmed ORR for 50 mg once daily dose, 8 patients, 29%; CR, 1 (4%); PR, 8 (29%); SD, 15 (54%); PD, 4 (14%).
• Confirmed ORR for 100 mg once daily dose, 9 patients, 33%; CR, 0; PR, 9 (33%); SD, 14 (52%); PD, 2 (7%).

“The 100 mg, once-a-day dose is the one that would go forward in combination strategies and in the phase 3 trial, despite only 5 months [of follow-up],” Choueiri said. “The majority of patients achieve tumor shrinkage, and many of the responses are ongoing, even the stable disease patients.”

Adverse events. TEAEs of grade 3 or higher were seen in 52% of the patients in both 50-mg dose levels—with longer follow-up—and in 41% of patients in the 100 mg/day group. TEAEs related to casdatifan were 49%, 32%, and 28% in the 3 groups, respectively. The most common TEAE, anemia, was seen in 88%, 90%, and 79% of the 3 groups across all grades; at grade 3 or higher, it was seen in 42%, 32%, and 17%, respectively. Three patients across all 3 groups had dose reductions and 1 stopped taking the drug due to anemia.

Hypoxia at all grades was 15%, 13%, and 14% in the 3 groups; at grade 3 or higher, it was 9%, 7%, and 10%, respectively. Across all groups, 2 patients stopped taking the drug due to hypoxia.

Choueiri announced that a phase 3 study, called PEAK-1, combining the 100 mg daily dose of casdatifan with 60 mg of the MET and VEGFR2 inhibitor cabozantinib (Cabometyx; Exelixis), will begin in the first half of this year. The trial is seeking to enroll patients with ccRCC whose cancer is not suitable for surgery or has spread, despite prior treatment with an immune checkpoint inhibitor.

Arcus Biosciences funded the study.

References

1. Choueiri TK, Lee JL, Merchan JR, 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):Abstract 441. doi:10.1200/JCO.2025.43.5_suppl.441

2. Clear cell renal cell carcinoma. National Cancer Institute. March 17, 2020. Accessed February 18, 2025. https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-kidney-tumors/clear-cell-renal-cell-carcinoma

3. Welireg (belzutifan) received first European Commission approval for two indications. News release. Merck. February 18, 2025. https://www.merck.com/news/welireg-belzutifan-receives-first-european-commission-approval-for-two-indications/