Arcus Biosciences (NYSE:RCUS) presented updated clinical and translational data for casdatifan, its investigational HIF-2 alpha inhibitor, outlining development plans across first-line, second-line and later-line clear cell renal cell carcinoma (RCC).
Chief Executive Officer Terry Rosen said the company believes casdatifan has differentiated pharmacodynamic activity from belzutifan, another HIF-2 alpha inhibitor. Arcus attributed that distinction to deeper and more durable suppression of erythropoietin, or EPO, a biomarker of HIF-2 alpha inhibition.
Later-line data highlight survival signal
In a 120-patient later-line monotherapy cohort, Arcus reported a median overall survival of about three years for casdatifan. The patients had received a median of three prior treatment lines, and more than one-quarter had received four or more prior lines of therapy, according to the company.
Rosen said approximately 25% of patients remained on treatment after two years, with some patients experiencing deeper responses after remaining on therapy for more than two years. Arcus also reiterated that its earlier data showed a confirmed objective response rate about 50% higher and progression-free survival more than twice that reported for belzutifan in separate studies.
Chief Medical Officer Richard Markus said the safety profile observed with longer follow-up remained generally consistent with the known profile of HIF-2 alpha inhibition, including anemia and hypoxia.
Arcus plans a Phase III later-line study combining casdatifan with tivozanib. The company is currently enrolling a randomized ARC-20 cohort of casdatifan plus tivozanib versus tivozanib in patients previously exposed to HIF-2-directed therapy. The eventual Phase III program is expected to enroll patients regardless of prior HIF-2 inhibitor use.
Second-line PEAK-1 enrollment nearing completion
Arcus is evaluating casdatifan plus cabozantinib in the Phase III PEAK-1 trial against cabozantinib alone in the second-line setting. The company said enrollment is expected to be completed within the next few months.
In ARC-20 data, Rosen cited median progression-free survival of 14.5 months for the casdatifan-cabozantinib combination. He also pointed to an emerging overall-survival separation versus benchmarks from LITESPARK-011, a trial of belzutifan plus lenvatinib compared with cabozantinib.
Company executives emphasized that patient populations differed across studies, including prior exposure to tyrosine kinase inhibitors, or TKIs. Arcus said patients previously treated with lenvatinib or other TKIs performed similarly to patients without prior TKI treatment in its casdatifan-cabozantinib cohort. The company expects PEAK-1 to include meaningful numbers of patients previously treated with second-generation TKIs.
Markus said progression-free survival is the sole primary endpoint in PEAK-1. If the trial meets that endpoint, Arcus expects to test overall survival with statistical alpha transferred from the progression-free survival analysis.
First-line program targets lower primary progression
Arcus also presented first-line data for casdatifan combined with zimberelimab, an anti-PD-1 antibody, with or without ipilimumab. In the casdatifan-zimberelimab cohort, which had median follow-up of 11.5 months, the company reported a 7% rate of primary progression, a confirmed objective response rate of 50%, and a 69% progression-free survival rate at the 50% landmark.
Rosen compared those results with historical data from CheckMate 214 for nivolumab plus ipilimumab, while acknowledging that the studies were separate. Arcus said nivolumab-ipilimumab has historically been limited by primary progression in roughly one in five patients.
The company also reported that, among 25 patients in the casdatifan-zimberelimab-ipilimumab cohort who reached their first scan, one experienced primary progression. In the safety dataset, 50% of patients who had sufficient treatment duration received all four planned ipilimumab cycles, while another 28% received three cycles, Markus said.
Arcus plans to begin PEAK-20, a registrational first-line trial of casdatifan plus nivolumab and ipilimumab versus nivolumab and ipilimumab, by year-end. Progression-free survival will be the trial’s sole primary endpoint.
Translational findings link biomarker suppression to outcomes
President Juan Jaen presented analyses linking deeper reductions in EPO and plasminogen activator inhibitor-1, or PAI-1, with better response rates, progression-free survival and overall survival in 121 patients from later-line casdatifan monotherapy cohorts.
Jaen said patients whose tumors showed lower HIF-2 alpha activity appeared less likely to benefit, while the majority of patients with meaningful HIF-2 alpha activity had better outcomes. He also said Arcus believes prior anti-angiogenic TKI treatment can increase HIF-2 alpha activity, potentially explaining why casdatifan appeared to retain activity in previously TKI-treated patients while belzutifan performance declined in separate datasets.
Arcus said it expects to provide additional clinical updates as its studies mature, including data from combinations with axitinib and PD-(L)1xVEGF bispecific antibodies.
About Arcus Biosciences (NYSE:RCUS)
Arcus Biosciences, Inc is a clinical-stage biopharmaceutical company focused on developing therapies for cancer and other serious diseases. The company uses its research platform to discover and advance medicines designed to target immune suppression and other biological mechanisms involved in tumor growth.
Arcus’s oncology pipeline has included antibody-based and small-molecule therapies aimed at targets such as TIGIT, PD-1, CD73, and the adenosine A2A and A2B receptors. Its key development programs have included domvanalimab, zimberelimab, quemliclustat, and etrumadenant, which have been evaluated in clinical studies across several cancer types, including lung, gastrointestinal, and colorectal cancers.
Founded in 2015 and headquartered in Hayward, California, Arcus conducts research and clinical-development activities intended to support potential commercialization in international markets.
