First Clinical Data for Arcus Biosciences' HIF-2a Inhibitor Casdatifan Demonstrates Promising Activity and Tumor Shrinkage in Metastatic Kidney Cancer

Arcus Biosciences, Inc., a clinical-stage biopharmaceutical company, has unveiled promising early clinical data for casdatifan, a potential best-in-class HIF-2a inhibitor, during the 2024 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain. The data was presented by Dr. Toni K. Choueiri of the Dana-Farber Cancer Institute.

Dr. Choueiri highlighted the impressive performance of casdatifan in the ARC-20 study, a Phase 1/1b trial targeting metastatic clear cell renal cell carcinoma (ccRCC). Casdatifan demonstrated an objective response rate (ORR) of 34% (with 2 responses pending confirmation) and 25% (confirmed) in the 100mg daily dose expansion cohort comprising 32 patients. The study observed a low primary progression rate of 19% and a high disease control rate of 81%, with a significant number of patients continuing treatment.

Dr. Dimitry Nuyten, Chief Medical Officer of Arcus, expressed his optimism about casdatifan's potential, noting its low rate of primary progressive disease and durable responses with a manageable safety profile. Nuyten emphasized that these results support the prospect of casdatifan becoming a best-in-class HIF-2a inhibitor for ccRCC treatment. Arcus plans to initiate its first Phase 3 study for casdatifan, PEAK-1, in the first half of 2025, which will explore its use in combination with other therapies and target different ccRCC subpopulations.

The ARC-20 study, comprising dose-escalation and dose-expansion phases, evaluated casdatifan across doses ranging from 20mg to 200mg. No dose-limiting toxicities were observed, with the maximum tolerated dose not reached at up to 150mg daily. For the expansion phase, a 100mg daily dose (50mg BID) was chosen and tested in patients with metastatic ccRCC who had progressed after at least two prior lines of therapy, including anti-PD-1 and tyrosine kinase inhibitor (TKI) treatments.

Most patients in the study had been heavily pre-treated, with 52% having undergone at least three prior lines of therapy and 26% having received four or more. Additionally, 61% of patients had an intermediate risk factor according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). After a median follow-up of 11 months, casdatifan showed rapid time to response with a primary progressive disease rate of 19%. Disease control was achieved by 81% of patients, and the median progression-free survival had not been reached at the data cut-off date.

The initial results of the 100mg dose expansion cohort are as follows:
- Objective Response Rate (ORR): 34% (11 patients) with 2 responses pending confirmation, and 25% (8 patients) confirmed
- Progressive Disease: 19% (6 patients)
- Disease Control Rate: 81%
- Median Progression-Free Survival: Not reached

Casdatifan's safety profile was acceptable and manageable, with no unexpected safety signals observed. Grade 3 treatment-emergent adverse events (TEAEs) related to casdatifan included anemia (36%) and hypoxia (9%). None of the patients discontinued treatment due to anemia, and no TEAEs were life-threatening or led to death.

Arcus is expanding its development program for casdatifan to maximize its potential in ccRCC, both as monotherapy and in combination with other treatments. The ARC-20 study also includes a cohort evaluating casdatifan in combination with cabozantinib, a VEGFR TKI, aimed at supporting the planned Phase 3 PEAK-1 study. This upcoming trial will compare casdatifan plus cabozantinib against cabozantinib alone in patients with metastatic ccRCC previously treated with anti-PD-1 therapy, with progression-free survival as the primary endpoint and overall survival as a key secondary endpoint.

Overall, these promising results underscore casdatifan's potential as an effective treatment for metastatic ccRCC, paving the way for further research and development in this area.