Randomized, Double-Blind, Active-Control, Multicenter Phase 3 Trial of Casdatifan and Cabozantinib Versus Placebo and Cabozantinib in Patients With Advanced Clear Cell Renal Cell Carcinoma

The primary objective of this study is to compare progression-free survival (PFS) of casdatifan in combination with cabozantinib versus placebo in combination with cabozantinib in patients with advanced clear cell renal cell carcinoma. This endpoint is clinically relevant as it evaluates the efficacy of adding a HIF-2α inhibitor to a tyrosine kinase inhibitor in delaying disease progression in this patient population.

The secondary objectives include:

• Comparing overall survival (OS) of casdatifan plus cabozantinib versus placebo plus cabozantinib in all randomized patients.

• Assessing additional measures of clinical activity in all randomized patients.

• Evaluating the safety and tolerability of casdatifan or placebo in combination with cabozantinib in all treated patients.

• Evaluating disease-related symptoms based on patient-reported outcomes using the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy-Kidney Symptom Index – 19 Item Version (NFKSI-19) of casdatifan plus cabozantinib versus placebo plus cabozantinib in all randomized patients.

This clinical trial enrolled a total of **412 participants** diagnosed with **metastatic clear cell renal cell carcinoma** or **advanced clear cell renal cell carcinoma**. The study population included both **male and female subjects** comprising **adults** and **elderly patients**. Participants were selected based on specific clinical characteristics, including the presence of unresectable and measurable locally advanced or metastatic disease with a primary clear cell component. Eligible individuals were required to have a **Karnofsky Performance Status** score of at least 80%, indicating relatively preserved functional capacity. Additionally, participants needed to have at least one target lesion measurable by **computed tomography** or **magnetic resonance imaging** according to RECIST 1.1 criteria, located outside any previously irradiated field. Adequate organ and marrow function was confirmed within 72 hours prior to randomization. Women of childbearing potential were required to have a negative serum pregnancy test. The trial included a **vulnerable population**.

This is a randomized, double-blind, active-controlled, multicenter phase 3 clinical trial evaluating the efficacy and safety of casdatifan in combination with cabozantinib compared to placebo with cabozantinib in patients with advanced or metastatic clear cell renal cell carcinoma. The trial employs a randomized design where participants will be allocated to receive either the test combination of casdatifan plus cabozantinib or the control combination of placebo plus cabozantinib. Casdatifan is a small molecule inhibitor of HIF-2a administered as an oral tablet, while cabozantinib is a small molecule tyrosine-kinase inhibitor targeting c-Met, AXL, and VEGFR, also administered orally as a film-coated tablet. The maximum treatment period for all investigational products is 120 months. The trial is estimated to begin recruitment in January 2026 and conclude by June 2029, representing an overall trial duration of approximately 42 months.

The primary objective of the trial is to compare progression-free survival between the casdatifan plus cabozantinib arm and the placebo plus cabozantinib arm in all randomized patients. Progression-free survival is defined as the time from the date of randomization until progressive disease or death from any cause, whichever occurs first, as assessed by blinded independent central review according to RECIST 1.1 criteria. Secondary endpoints include overall survival, defined as the time from randomization until death from any cause; objective response rate, defined as the proportion of patients achieving confirmed complete response or confirmed partial response; duration of response, measured from the time of first response until progressive disease or death; and disease control rate, defined as the proportion of patients achieving confirmed complete response, confirmed partial response, or stable disease for at least 16 weeks from randomization. Additional secondary endpoints include assessment of the incidence and severity of treatment-emergent adverse events and treatment-emergent serious adverse events, evaluation of clinically meaningful trends in safety parameters, and time to first symptom deterioration using the NFKSI-DRS Items 1-9 sub-scale score.

Eligible participants must have unresectable and measurable locally advanced or metastatic renal cell carcinoma with a primary clear cell component. Additional inclusion criteria require a Karnofsky Performance Status score of 80% or higher, at least one target lesion measurable by computed tomography or magnetic resonance imaging per RECIST 1.1 that is not within a field of prior radiation therapy, adequate organ and marrow function within 72 hours prior to randomization, and for women of childbearing potential, a negative serum pregnancy test. The trial design incorporates systematic evaluation of tumor response and safety monitoring throughout the study period to comprehensively assess the therapeutic benefit and tolerability of the investigational combination.

Participants will undergo a screening visit to determine eligibility based on the specified inclusion and exclusion criteria, including assessment of disease characteristics, performance status, and baseline organ function. Following successful screening and randomization, participants will attend regular follow-up visits for administration of study treatment, tumor response assessment by imaging, safety monitoring, and collection of patient-reported outcomes. The frequency and content of these follow-up visits will be determined by the study protocol to ensure adequate monitoring of efficacy and safety parameters. An end-of-study visit will be conducted to perform final assessments and document the participant's status at study completion. Participant involvement in the trial may continue for up to 120 months or until study discontinuation. Conditions that may lead to early termination from the study include progressive disease, unacceptable toxicity, withdrawal of consent, investigator decision, loss to follow-up, or death.

The experimental medication **casdatifan** (AB521) is administered as a **tablet** via the **oral** route. Casdatifan is a small molecule inhibitor of **HIF-2α** (hypoxia-inducible factor 2-alpha). The maximum treatment period for casdatifan is 120 months.

The experimental medication **cabozantinib** is administered as a **film-coated tablet** via the **oral** route. Cabozantinib is a small molecule **tyrosine-kinase inhibitor** targeting c-Met, AXL, and **VEGFR** (vascular endothelial growth factor receptor). The maximum treatment period for cabozantinib is 120 months.

**Placebo** is administered as a tablet via the oral route. The placebo formulation is used as a comparator treatment in the control arm of the study. The maximum treatment period for placebo is 120 months.

The primary efficacy endpoint is progression-free survival, defined as the time from date of randomization until progressive disease or death from any cause, whichever comes first, as assessed by blinded independent central review according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary efficacy endpoints include overall survival, defined as the time from date of randomization until the date of death from any cause. Objective response rate is defined as the proportion of patients who have achieved confirmed complete response or confirmed partial response to study therapy, as assessed by blinded independent central review according to Response Evaluation Criteria in Solid Tumors version 1.1. Duration of response is measured from the time of first response (complete response or partial response) until the date of first documented progressive disease or death, whichever comes first, as assessed by blinded independent central review according to Response Evaluation Criteria in Solid Tumors version 1.1. Disease control rate is defined as the proportion of patients who have achieved confirmed complete response, confirmed partial response, or stable disease for at least 16 weeks from date of randomization, as assessed by blinded independent central review according to Response Evaluation Criteria in Solid Tumors version 1.1. Additional secondary endpoints include time to first symptom deterioration in National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy-Kidney Symptom Index – Disease Related Symptoms Items 1-9 sub-scale score. At least one target lesion measurable by computed tomography or magnetic resonance imaging per Response Evaluation Criteria in Solid Tumors version 1.1, not within a field of prior radiation therapy, is required for assessment.