casdatifan (AB521) / Arcus Biosci, Otsuka - LARVOL DELTA

HIF2α pathway aberrations across tumour types: A rare but actionable entity with high germline conversion (ESMO Asia 2025) - "Background: Knowledge of HIF2α pathway variants beyond VHL-associated RCC is limited, but emerging inhibitors like belzutifan and casdatifan highlight this rare, targetable group... HIF2α aberrations are rare (1–2%) outside VHL-RCC but span diverse cancer types. Excluding VHL ccRCC, high germline conversion rates on and off tumour, suggest germline assessment should be considered. Identifying this cohort of patients opens up therapeutics/trials options in addition to hereditary implications."

Clear Cell Renal Cell Carcinoma • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Sarcoma • Solid Tumor • EPAS1 • SDHA • VHL

Arcus’s R&D investment and resources will focus on casdatifan, a potential best-in-class HIF-2a inhibitor, and its emerging small molecule I&I programs. (Arcus Biosciences Press Release) - "The casdatifan program is expected to have multiple data readouts and cohort and study initiations in 2026 including: Early 2026: Additional analyses from the ARC-20 cohorts evaluating casdatifan monotherapy in late-line ccRCC, including updated PFS data for the 100mg once-daily (QD) cohort, which utilizes the selected Phase 3 dose and formulation; Mid-2026: More mature data from the ARC-20 cohort evaluating casdatifan plus cabozantinib in the IO-experienced setting....2H 2026: Initial data from one or more ARC-20 cohorts evaluating casdatifan in early-line settings, as well as a go-no-go decision on the Phase 3 portion of eVOLVE-RCC02; Late 2026: Potential initiation of a Phase 3 registrational study in an early-line or first-line ccRCC setting."

Clinical data • New P3 trial • Clear Cell Renal Cell Carcinoma • Renal Cell Carcinoma

Drug-Drug Interaction Study of Casdatifan in Healthy Adult Participants (ARC-29) (clinicaltrials.gov) - P1 | N=14 | Completed | Sponsor: Arcus Biosciences, Inc. | Active, not recruiting ➔ Completed

Trial completion

eVOLVE-RCC02: A Study to Investigate the Efficacy and Safety of Volrustomig ± Casdatifan vs Nivolumab + Ipilimumab as 1L Treatment for Advanced ccRCC (clinicaltrials.gov) - P3 | N=1116 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

Enrollment closed • Monotherapy • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

The company is pursuing a multi-pronged strategy for the development of casdatifan in early-line ccRCC, likely in combination with standard-of-care mechanisms, with the goal of initiating a Phase 3 study in early-line ccRCC in the second half of 2026 (Businesswire) - "This study will be informed by emerging data from eVOLVE-RCC02 and ARC-20."

New P3 trial • Clear Cell Renal Cell Carcinoma

Casdatifan (HIF-2a inhibitor):…Planned Data Readouts (Businesswire) - "(i) 1H 2026: Additional analyses from the ARC-20 cohorts evaluating casdatifan monotherapy in late-line ccRCC; (ii) Mid-2026: More mature data from the ARC-20 cohort evaluating casdatifan plus cabozantinib in the IO-experienced setting...; (iii) 2H 2026: Initial data from one or more ARC-20 cohorts evaluating casdatifan in early-line settings; (iv) 2H 2026: Data from the Phase 1b portion and a go-no-go decision on the Phase 3 portion of eVOLVE-RCC02."

P1 data • Trial status • Clear Cell Renal Cell Carcinoma

Taiho Pharmaceutical Exercises Option for an Exclusive License to Casdatifan in Japan and Certain Territories in Asia (Businesswire) - "This option exercise is based on a 2017 option and license agreement between Taiho and Arcus. This is the fifth option exercise by Taiho to an Arcus program....Arcus is currently conducting an ongoing global, registrational Phase 3 study, PEAK-1...in patients with clear cell renal cell carcinoma (ccRCC). Japan is also expected to participate in the study starting in the first half of 2026."

Licensing / partnership • Trial status • Clear Cell Renal Cell Carcinoma

Erythropoietin (EPO) is a Pharmacodynamic Biomarker for Systemic HIF-2α Inhibition that Correlates with the Clinical Activity of Casdatifan (AACR-NCI-EORTC 2025) - P1 | "sEPO may provide a window into systemic HIF-2α inhibition in ccRCC patients. Cas monotherapy resulted in deep and sustained reductions of sEPO, as well as a significant downregulation of tumor EPO and other HIF-2α target genes. Depth of sEPO reduction and tumor EPO expression were strongly associated with clinical benefit for Cas."

Biomarker • Clinical • PK/PD data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • EPAS1 • EPO • SERPINE1

Casdatifan data were better on every efficacy measure evaluated, across all four monotherapy cohorts (n=121) of the Phase 1/1b ARC-20 study in late-line metastatic kidney cancer, relative to published data from studies with the only marketed HIF-2a inhibitor (Arcus Biosciences Press Release) - "In the 100mg tablet cohort, our Phase 3 dose and formulation, casdatifan showed a 35% confirmed ORR, with two additional responses pending confirmation, and mPFS had not been reached, even with a median follow-up of one year...Even when we analyzed pooled data for the 121 patients treated with casdatifan monotherapy, casdatifan showed a confirmed ORR of 31% and a median PFS of 12.2 months...No unexpected safety signals were observed at the time of DCO, and casdatifan had an acceptable and manageable safety profile across all doses."

P1 data • Clear Cell Renal Cell Carcinoma

Study of Casdatifan and Cabozantinib Versus Placebo and Cabozantinib in Patients With Advanced Clear Cell Renal Cell Carcinoma (clinicaltrials.gov) - P3 | N=720 | Recruiting | Sponsor: Arcus Biosciences, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Drug-Drug Interaction Study of Casdatifan in Healthy Adult Participants (ARC-29) (clinicaltrials.gov) - P1 | N=14 | Active, not recruiting | Sponsor: Arcus Biosciences, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed

Casdatifan Plus Cabozantinib Shows Early-Phase Efficacy in Clear Cell RCC (OncLive) - "Rana R. McKay, MD, FASCO, discusses findings from the ARC-20 trial of casdatifan plus cabozantinib in pretreated clear cell renal cell carcinoma."

Media quote • Renal Cell Carcinoma

eVOLVE-RCC02: A Study to Investigate the Efficacy and Safety of Volrustomig ± Casdatifan vs Nivolumab + Ipilimumab as 1L Treatment for Advanced ccRCC (clinicaltrials.gov) - P3 | N=1116 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting

Enrollment open • Monotherapy • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Arcus Biosciences to Host Investor Event to Highlight its Late-Stage Casdatifan Program and Next Wave of Programs Focused on Inflammation (Arcus Biosciences Press Release) - "The event will highlight new data for Arcus’s HIF-2a inhibitor casdatifan from the monotherapy cohorts of the Phase 1b ARC-20 trial in late-line clear cell renal cell carcinoma (ccRCC)."

P1 data • Clear Cell Renal Cell Carcinoma • Von Hippel-Lindau Syndrome

Pharmacokinetics, pharmacodynamics and safety of casdatifan, a novel hypoxia-inducible factor-2α inhibitor, in healthy participants. (PubMed, Br J Clin Pharmacol) - P1 | "Casdatifan, after single and multiple dosing in healthy participants, was safe and tolerable. Linear PK was associated with a mean maximum erythropoietin reduction of 85% following a single dose and multiple doses of casdatifan, demonstrating a promising exposure-biological activity profile."

Journal • PK/PD data • Genito-urinary Cancer • Oncology • Solid Tumor • CYP3A4 • EPAS1

Welireg Plus Cabometyx Shows Tumor Control in Kidney Cancer Trial (Cure Today) - "'Treatment with Welireg showed meaningful clinical activity and disease control across doses,' wrote presenting study author, Dr. Toni K. Choueiri...said during the presentation."

Media quote

Dr McKay on the Role of Casdatifan Plus Cabozantinib in Clear Cell RCC (OncLive) - "Rana R. McKay, MD, FASCO, details the significance of casdatifan plus cabozantinib demonstrating better responses vs the respective agents alone in ccRCC."

Video • Renal Cell Carcinoma

Arcus Biosciences Reports Second-Quarter 2025 Financial Results and Provides a Pipeline Update (Businesswire) - "Pipeline Highlights: Casdatifan (HIF-2a inhibitor):...Planned Data Readouts: (i) Fall 2025: More mature data from the ARC-20 cohorts evaluating casdatifan monotherapy in patients who had progressed on both an anti-PD-1 and a TKI; (ii) 2026: More mature data from the casdatifan plus cabozantinib cohort and initial data from the new ARC-20 cohorts evaluating casdatifan in the 1L and IO-experienced settings."

P1 data • Clear Cell Renal Cell Carcinoma

Combination casdatifan plus cabozantinib in previously treated patients with clear cell renal cell carcinoma: results from an expansion cohort of ARC-20 (NCT05536141) (KCRS 2025) - P1 | "Conclusions In previously treated patients with ccRCC, casdatifan 100 mg plus cabozantinib 60 mg had a manageable AE profile with promising clinical activity. These data support continued evaluation of this combination in the phase 3 PEAK-1 clinical trial."

Clinical • IO biomarker • Anemia • Clear Cell Renal Cell Carcinoma • Fatigue • Genito-urinary Cancer • Heart Failure • Immunology • Oncology • Solid Tumor • EPAS1

Casdatifan +/- Cabozantinib Showed Early Efficacy, Safety in Pretreated RCC (Cancer Network) - P1 | N=302 | ARC-20 (NCT05536141) | Sponsor: Arcus Biosciences, Inc. | "Combining casdatifan plus cabozantinib (Cabometyx) led to meaningful clinical activity and was well tolerated as a therapy for patients who were pretreated with clear cell renal cell carcinoma (RCC), according to results from an expansion cohort of the phase 1 ARC-20 trial (NCT05536141) shared at the 2025 Kidney Cancer Research Summit. In the group of patients who received 50 mg of casdatifan twice daily (n = 32), at the median follow-up of 15 months (range, 7-19+), the confirmed overall response rate (ORR) was 25% (95% CI, 11.5%-43.4%). The best overall response rate (ORR) was 31%; 0 patients had a complete response (CR), 31% had a partial response (PR), 50% had stable disease (SD), and 19% had progressive disease (PD). In patients who received 50 mg once daily (n = 28), at the median follow-up of 12 months (range, 9-14+), the confirmed ORR was 29% (95% CI, 13.2%-48.7%)."

P1 data • Clear Cell Renal Cell Carcinoma • Renal Cell Carcinoma

Hypoxia Inducible Factor-2α (HIF-2α) Pathway Inhibitors. (PubMed, J Kidney Cancer VHL) - "We discuss the major key inhibitors, with focus on belzutifan and review the various trials investigating its efficacy in monotherapy as well as in combination therapies in RCC...We also highlight emerging HIF-2α inhibitors currently in clinical trials, namely casdatifan, NKT-2152, and DFF332. Finally, we address the major toxicities and management of these inhibitors."

Journal • Review • Endocrine Cancer • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • ARNT • CA9 • EPAS1 • POU5F1 • VHL

ARC-20: Casdatifan Plus Cabozantinib Expansion Cohort (YouTube) - "Brad McGregor, MD...opens up about the expansion cohort of the phase 1 ARC-20 study, which looked at combination casdatifan plus cabozantinib in previously treated patients with clear cell renal cell carcinoma."

Video

Study of Zanzalintinib (XL092) + AB521 and Zanzalintinib + AB521 + Nivolumab in Participants With Advanced Clear Cell Renal Cell Carcinoma (ccRCC) or Other Advanced Solid Tumors (STELLAR-009) (clinicaltrials.gov) - P1 | N=25 | Terminated | Sponsor: Exelixis | Phase classification: P1/2 ➔ P1 | Trial completion date: Jan 2027 ➔ May 2025 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jan 2026 ➔ May 2025; The study was terminated prior to starting the Phase 2 portion due to a business decision.

Phase classification • Trial completion date • Trial primary completion date • Trial termination • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

eVOLVE-RCC02: A Study to Investigate the Efficacy and Safety of Volrustomig ± Casdatifan vs Nivolumab + Ipilimumab as 1L Treatment for Advanced ccRCC (clinicaltrials.gov) - P3 | N=1116 | Not yet recruiting | Sponsor: AstraZeneca

Monotherapy • New P3 trial • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Combination casdatifan plus cabozantinib expansion cohort of phase 1 ARC-20 study in previously treated patients with clear cell renal cell carcinoma. (ASCO 2025) - P1 | "In previously treated patients with ccRCC, casdatifan 100 mg in combination with cabozantinib 60 mg had a manageable AE profile with promising clinical activity. These data support continued evaluation of this combination in the phase 3 PEAK-1 clinical trial."

Clinical • IO biomarker • P1 data • Anemia • Clear Cell Renal Cell Carcinoma • Fatigue • Genito-urinary Cancer • Oncology • Solid Tumor • EPAS1