Casdatifan demonstrates encouraging clinical activity in renal cell carcinoma

The HIF-2a inhibitor casdatifan (AB521) was well-tolerated and demonstrated promising durable clinical activity in heavily pretreated patients with clear cell renal cell carcinoma (ccRCC), according to initial data from the phase 1/1b ARC-20 trial (NCT05536141), which were presented at the 2024 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain.¹

The 200 mg cohort in the ARC-20 study remains ongoing.

“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 presenting author Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg chair and professor of medicine at Harvard Medical School, Boston, Massachusetts, in a news release on the findings.² “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.”

Data presented at the meeting included results from both the dose-escalation and dose-expansion phases of the ARC-20 trial.

At the time of data cutoff in April 2024, 17 patients were enrolled in the dose-escalation cohort of the study. Of these, 6 patients (35.3%) had ccRCC. Among all patients, 3 received 20 mg casdatifan QD, 6 received 50 mg casdatifan QD, 4 received 50 mg casdatifan BID, and 4 received 150 mg casdatifan QD.

No dose-limiting toxicities were reported across all cohorts, and the maximum tolerated dose was not reached. One patient discontinued treatment due to a grade 3 drug-related treatment-emergent adverse event (TEAE) of hypoxia in the 50 mg QD cohort. No grade 4/5 TEAEs were observed. The confirmed disease control rate was 60%.

The dose-expansion cohort was then initiated at the dose level of 50 mg BID. In total, 32 patients with ccRCC were included, of whom 29 were evaluable for efficacy. The median age was 62 years. Overall, 52% of patients had received at least 3 prior lines of therapy, and 26% had received at least 4 prior lines of therapy.

At a median follow-up of 11 months, the objective response rate (tumor shrinkage by at least 30%) was 34.4% (95% CI, 16-50).^2,3 Confirmed ORR was achieved in 25% (95% CI, 12-43) of patients. At the time of data cutoff, 2 patient responses were pending confirmation.

Primary progressive disease was noted in 18.8% of patients. The disease control rate (partial response or stable disease) was 81.3% (95% CI, 64-93). Five patients with stable disease experienced tumor reduction. Tumor shrinkage at any time was achieved in 69% (20/29) of patients. Over 50% of the patients enrolled in the study remained on treatment beyond 6 months.

The median progression-free survival (PFS) was not yet reached at the time of data cutoff.

Regarding safety, 42% of patients experienced at least 1 drug-related TEAE of grade 3 or higher. The most common TEAE was anemia (36%), which was managed mainly with dose interruptions. Further, 9% of patients experienced grade 3 hypoxia, which were also managed by dose interruptions. No grade 4/5 TEAEs nor any TEAEs that led to discontinuation were observed.

The 200 mg cohort in the ARC-20 study remains ongoing. Final completion of the trial is expected in January 2026.⁴

The study is also enrolling a cohort to evaluate casdatifan in combination with cabozantinib (Cabometyx), a VEGFR TKI, in patients with ccRCC. The data from the combination cohort are intended to support the phase 3 PEAK-1 trial, which will evaluate casdatifan plus cabozantinib vs cabozantinib monotherapy in patients with metastatic ccRCC who have previously received anti-PD-1 therapy.

PEAK-1 is expected to enroll approximately 700 patients. The primary end point for the phase 3 trial will be PFS, with a key secondary end point of overall survival.

Casdatifan is also currently being assessed in combination with volrustomig, an investigational anti-PD-1/CTLA-4 bispecific antibody, in patients with advanced ccRCC.

“In the 100mg daily dose-expansion cohort of ARC-20, casdatifan showed encouraging results, particularly a low primary progressive disease rate and very durable responses. This was accomplished with a manageable safety profile,” concluded Dimitry Nuyten, MD, PhD, chief medical officer of Arcus, in the news release.² “These data support the potential for casdatifan to be a best-in-class HIF-2a inhibitor for the treatment of ccRCC. We look forward to initiating our first phase 3 study for casdatifan, PEAK-1, in the first half of 2025, and expanding our development program into the first-line setting with a novel combination, as well as into other ccRCC subpopulations.”

References

1. Choueiri T, Garmezy B, Park SH, et al. Casdatifan in patients (pts) with previously treated clear cell renal cell cancer (ccRCC) and other solid tumors; preliminary results from ARC20: A phase 1, open-label dose-escalation and expansion study. Presented at: 2024 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. October 22-25, 2024. Barcelona, Spain. Abstract 4

2. First clinical data for Arcus Biosciences’ HIF-2a inhibitor, casdatifan, showed promising clinical activity and tumor shrinkage in patients with metastatic kidney cancer. News release. Arcus Biosciences. October 24, 2024. Accessed November 4, 2024. https://investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2024/First-Clinical-Data-for-Arcus-Biosciences-HIF-2a-Inhibitor-Casdatifan-Showed-Promising-Clinical-Activity-and-Tumor-Shrinkage-in-Patients-with-Metastatic-Kidney-Cancer/default.aspx

3. ARC-20 presentation: Phase 1b study of casdatifan in ccRCC. Arcus Biosciences. October 24, 2024. Accessed November 4, 2024. https://s202.q4cdn.com/599190870/files/doc_presentations/2024/Oct/24/ARC-20-Data_Investor-Deck_October-2024_FINAL-Updated-10-30-2024.pdf

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