Phase III Study of Savolitinib Plus Durvalumab Versus Sunitinib and Durvalumab Monotherapy in MET-Driven Unresectable or Metastatic Papillary Renal Cell Carcinoma

The primary objective of this study is to demonstrate the effectiveness of **savolitinib** plus **durvalumab** relative to **sunitinib** by assessing progression-free survival (PFS) in participants with **MET-driven**, unresectable, and locally advanced or metastatic **Papillary Renal Cell Carcinoma** (PRCC). This is clinically relevant as PFS is a critical endpoint in evaluating the efficacy of cancer therapies, providing insights into the treatment's ability to delay disease progression.

Secondary objectives include:

• Demonstrating the effectiveness of savolitinib plus durvalumab relative to sunitinib by assessing overall survival (OS), objective response rate (ORR), duration of response (DoR), disease control rate (DCR) at 24 and 48 weeks, and time from randomization to second progression or death (PFS2).
• Demonstrating the effectiveness of savolitinib plus durvalumab relative to durvalumab monotherapy by assessing ORR, DoR, and PFS.
• Assessing patient-reported symptoms, functioning, and health-related quality of life (HRQoL) in participants treated with savolitinib plus durvalumab relative to sunitinib.
• Evaluating the pharmacokinetics (PK) of savolitinib and durvalumab in participants with MET-driven, unresectable, and locally advanced or metastatic PRCC.

The clinical trial involves a total of **82 participants** diagnosed with **MET-driven, unresectable and locally advanced or metastatic Papillary Renal Cell Carcinoma** (PRCC). The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of unresectable and locally advanced or metastatic PRCC, with the condition being centrally confirmed as MET-driven. The trial population is characterized by a **Karnofsky Score** of 70 or higher, indicating a general good health status, and participants must have adequate organ and bone marrow function. Lifestyle considerations such as diet and physical activity are not specified. The trial includes a vulnerable population, and participants must have a life expectancy of at least 12 weeks. The selection process ensures that participants have not received prior systemic anti-cancer treatment in the metastatic setting, nor prior exposure to MET inhibitors, Durvalumab, or Sunitinib. The study aims to assess the effectiveness of savolitinib plus durvalumab compared to sunitinib by evaluating progression-free survival in this specific patient group.

The clinical trial is designed as a **randomized**, open-label, multi-center study to evaluate the efficacy of **savolitinib** plus **durvalumab** compared to **sunitinib** and durvalumab monotherapy in participants with MET-driven, unresectable, and locally advanced or metastatic papillary renal cell carcinoma (PRCC). The trial aims to assess progression-free survival (PFS) as the primary endpoint, with secondary endpoints including overall survival (OS), objective response rate (ORR), duration of response (DoR), disease control rate (DCR), and PFS2. The trial is expected to conclude by June 29, 2026, with recruitment having commenced on October 23, 2021.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as histologically confirmed PRCC, MET-driven status, and adequate organ function. The inclusion criteria also require a Karnofsky Score of at least 70 and a life expectancy of at least 12 weeks. Following randomization, participants will receive treatment according to their assigned group, with regular follow-up visits to monitor treatment response and safety. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected duration of participant involvement is contingent on the treatment arm and individual response, with a maximum treatment period of 28 days for **durvalumab** and **savolitinib**, and 6 days for **sunitinib**. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The trial will adhere to rigorous standards to ensure the integrity of data collection and analysis, with assessments conducted by a blinded independent central review (BICR) to minimize bias.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Savolitinib** is provided in the form of film-coated tablets, with a maximum daily dose of 600 mg and a total dose of 16,800 mg over a 28-day period. The route of administration is oral. **Savolitinib** is a chemical-origin compound, and participant compliance is monitored through regular assessments.

**Durvalumab** is administered as a solution for infusion, with a maximum daily dose of 1500 mg. The administration is conducted intravenously over a 28-day period. **Durvalumab** is a human IgG1κ monoclonal antibody that blocks the interaction of PD-L1 with PD-1 on T-cells and CD80 on immune cells, engineered to reduce antibody-dependent cellular cytotoxicity (ADCC).

**Sunitinib** is available in hard capsule form, with a maximum daily dose of 50 mg and a total dose of 1400 mg over a 6-day period. The administration route is oral. **Sunitinib** is a chemical-origin compound, and its administration is monitored to ensure adherence to the dosing schedule.

**Flixabi** (infliximab) is provided as a powder for concentrate for solution for infusion, with a maximum daily dose of 5 mg/kg and a total dose of 210 mg/kg over a 6-day period. The administration is intravenous. **Flixabi** is a protein-origin compound, and its administration is closely monitored to ensure participant safety and compliance.

**Myfenax** (mycophenolate mofetil) is administered in the form of film-coated tablets, with a maximum daily dose of 2 g and a total dose of 28 g over a 14-day period. The route of administration is oral. **Myfenax** is a chemical-origin compound, and participant adherence to the dosing schedule is monitored throughout the trial.

The efficacy of the clinical trial will be assessed primarily through the measurement of **progression-free survival (PFS)**. PFS is defined as the time from randomization until disease progression, as determined by RECIST 1.1 criteria, or death due to any cause. This assessment will be conducted by a blinded independent central review (BICR). Secondary endpoints include overall survival (OS), objective response rate (ORR), duration of response (DoR), disease control rate (DCR) at 24 or 48 weeks, and PFS2. These secondary endpoints will also be evaluated using RECIST 1.1 criteria and assessed by BICR.

Additional secondary endpoints involve the time to deterioration and change from baseline in symptoms, functioning, and health-related quality of life (HRQoL). Pharmacokinetic parameters will be measured for participants receiving savolitinib plus durvalumab, including plasma concentration of savolitinib and its metabolites, and serum concentration of durvalumab. For participants receiving durvalumab monotherapy, serum concentration of durvalumab will be measured. These measurements will be taken pre-dose and at specified time points post-dose.