Casdatifan Demonstrates Clinical Activity and Tolerability in Metastatic ccRCC

3D rendering of kidney cancer with organs and tumors: © Matthieu - stock.adobe.com

Casdatifan, aHIF-2α inhibitor, demonstrated promising clinical activity and acceptable tolerability when used for the treatment of patients with metastatic clear cell renal cell carcinoma (ccRCC), according to findings from the phase 1/1b ARC-20 study (NCT05536141).¹

Findings from the dose-escalation portion of the study were presented at the 2024 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. In the 100-mg daily dose expansion cohort of ARC-20 (n = 32), casdatifan achieved an objective response rate (ORR) of 34%. The confirmed ORR was 25% among evaluable patients, with 2 additional responses pending confirmation at a median follow-up of 11 months (range, 3-15+).^1,2

Patients responded to casdatifan in a median time of 2.8 months (range, 1.2-5.5), and the disease control rate (DCR) was 81.3% (90% CI, 63.6%-92.8%). The median progression-free survival (PFS) has not been reached yet, with 18.8% of patients experiencing disease progression. Patients in this cohort were heavily pretreated, with all having progressed on at least 2 prior therapies, including anti–PD-1 agents and tyrosine kinase inhibitors (TKIs).

“Based on our experience in the ARC-20 study, we have seen casdatifan’s ability to quickly bring tumor growth under control and its high response and disease control rates,” said Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, the Jerome and Nancy Kohlberg Chair and professor of medicine at Harvard Medical School, and lead investigator of ARC-20, in a press release.1 “Based on these data, casdatifan has the potential to be a future treatment option for kidney cancer. I am particularly interested in planned research into novel combinations for casdatifan in both first- and second-line ccRCC.”

About the ARC-20 Trial

The ARC-20 trial is evaluating casdatifan in patients with ccRCC and other advanced solid tumors who meet RECIST 1.1 criteria and have acceptable organ and bone marrow function.³ The primary end points of the trial include safety, adverse effects (AEs), and dose-limiting toxicities (DLTs), and secondary endpoints consist of ORR and pharmacokinetics/pharmacodynamics.

Using a 3+3 design, the dose-escalation phase tested casdatifan alone at doses from 20 mg to 200 mg once daily, while the dose-expansion phase is focusing on patients with second-line or later ccRCC at doses of 50 mg (twice or once daily), 150 mg once daily, and 100 mg once daily. A cohort combining casdatifan at 100 mg daily with cabozantinib (Cabometyx) is also enrolling.

In dose escalation, 17 patients were treated with casdatifan across doses from 20 mg to 200 mg once daily. Of these, 6 patients had ccRCC and received casdatifan at doses of 20 mg QD (n = 3), 50 mg QD (n = 6), 50 mg BID (n = 4), and 150 mg QD (n = 4). No DLTs were observed, and the maximum tolerated dose was not reached, supporting dose expansion. The DCR in this cohort was 60%, and no grade 4/5 treatment-emergent AEs (TEAEs) were reported.

Safety and Tolerability

Casdatifan demonstrated a manageable safety profile across all cohorts. In the dose-escalation phase, no DLTs were observed across doses up to 200 mg daily. In the 50 mg twice-daily expansion cohort, 97% of patients experienced TEAEs, with 94% of these events considered drug related.^1,2

The most common TEAEs included anemia (85% of patients) and fatigue (50%). Grade 3 AEs were reported in 45% of patients, with serious AEs in 12% of patients. These included all-grade anemia and hypoxia, with grade 3 anemia reported in 36% of patients, leading to dose adjustments for some. Notably, no grade 4/5 adverse events were observed across the dose ranges.

Future Directions and Next Steps

Aside from the ARC-20 trial continuing with a 200-mg dose cohort underway, which plans to enroll patients who will be given casdatifan in combination with cabozantinib, findings from this study are expected to support the design of the upcoming phase 3 PEAK-1 trial.¹

PEAK-1 which will evaluate casdatifan plus cabozantinib against cabozantinib monotherapy in patients with metastatic ccRCC previously treated with anti–PD-1 therapies. The trial plans to enroll around 700 patients and will focus on PFS as a primary end point. Overall survival is the key secondary end point of the study.

Further, casdatifan is being investigated in combination with volrustomig, an experimental anti–PD-1/CTLA-4 bispecific antibody, aiming to expand its use in ccRCC subpopulations.

REFERENCES:

1. First clinical data for Arcus Biosciences’ HIF-2α inhibitor, casdatifan, showed promising clinical activity and tumor shrinkage in patients with metastatic kidney cancer. News release. Arcus Biosciences, Inc. October 24, 2024. Accessed November 4, 2024. https://tinyurl.com/rb3xwm2v

2. Choueiri TK, Garmezy B, Park SH, et al. Casdatifan in patients with previously treated clear cell renal cell carcinoma and other solid tumors: preliminary results from ARC-20, a phase 1, open-label, dose-escalation and expansion study. Presented at: 2024 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; October 23-25, 2024; Barcelona, Spain.

3. A phase 1 study of AB521 monotherapy and combination therapies in renal cell carcinoma and other solid tumors (ARC-20). ClinicalTrials.gov. Updated October 28, 2024. Accessed November 4, 2024. https://clinicaltrials.gov/study/NCT05536141