Non-Inferiority Phase III Study of Treatment Interruption vs. Continuation with Pembrolizumab and Axitinib in Intermediate-Risk Metastatic Renal Cell Carcinoma

The primary objective of this study is to assess the **non-inferiority** of a treatment pause compared to treatment continuation with PD-1/PD-L1 immune checkpoint inhibitors (ICIs) combined with VEGFR-Tyrosine Kinase Inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC) who are classified as having a good risk or only one adverse prognostic factor intermediate risk according to the IMDC score. These patients must have achieved an objective response between the end of the 11th month and the end of the 13th month of treatment with the combination regimens. This objective is clinically relevant as it explores the potential for reducing treatment burden and associated toxicities without compromising efficacy in a specific patient population.

Secondary objectives include:

• Comparing the overall safety profile between treatment pause and continuation.
• Evaluating health-related quality of life differences between the two treatment strategies.
• Assessing anxiety and depression levels in patients undergoing treatment pause versus continuation.
• Comparing 2-year overall survival and progression-free survival between the two groups.
• Describing the modalities of progression, such as site and lesion characteristics, for patients in the experimental arm.
• Describing therapeutic modalities at progression for patients in the experimental arm.
• Evaluating oncological outcomes upon restarting PD-1/PD-L1 ICI + VEGFR-TKI in the event of progression for patients in the experimental arm.
• In France only, comparing healthcare resource utilization and costs at 12 months between treatment pause and continuation, with costs estimated from the perspective of the French Healthcare System.

The clinical trial involves participants diagnosed with **metastatic renal cell carcinoma** (mRCC) who are classified as having a good or only one adverse prognostic factor intermediate risk according to the International Metastatic RCC Database Consortium (IMDC) criteria. The study population includes both male and female subjects aged 18 years and older, with a **Karnofsky Performance Status** grade of 70% or higher, indicating a generally good health status. Participants must have measurable disease as per RECIST v1.1 criteria and adequate organ function. The trial includes individuals who have achieved an objective response between the end of the 11th month and the end of the 13th month of treatment with a combination of PD-1/PD-L1 immune checkpoint inhibitors and VEGFR-Tyrosine Kinase inhibitors. The trial population was selected based on their prior first-line therapy with these combination treatments, and they must have ongoing treatment without significant discontinuation. Lifestyle considerations such as the use of effective contraception for females of childbearing potential and condom use for sexually active males are required. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the **non-inferiority** of a treatment pause compared to treatment continuation in patients with **metastatic renal cell carcinoma** (mRCC) who have achieved an objective response after 12 months of treatment with PD-1/PD-L1 immune checkpoint inhibitors (ICIs) and VEGFR-Tyrosine Kinase Inhibitors (TKIs). This is a randomized, non-inferiority, phase III study. The trial will involve a double-blind methodology to ensure unbiased results, with participants randomly assigned to either the treatment pause or continuation group. The trial is expected to last until January 2027, with recruitment having commenced in January 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and disease characteristics. Follow-up visits will occur regularly to monitor disease progression, adverse events, and quality of life, using standardized assessments like RECIST v1.1 and the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19). The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any long-term effects of the treatment strategy.

The expected length of participant involvement is up to 24 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. Participants must adhere to study procedures and maintain adequate organ function throughout the trial. The primary endpoint is the percentage of participants without progression at 12 months post-randomization, while secondary endpoints include adverse event rates, quality of life changes, and overall survival metrics. The trial aims to provide valuable insights into the management of mRCC, potentially influencing future treatment protocols.

The clinical trial involves the administration of **Inlyta** (axitinib) as an experimental medication. Inlyta is provided in the form of 5 mg **film-coated tablets**. The active substance, axitinib, is of chemical origin. The medication is administered orally with a maximum daily dose of 10 mg, and the total dose should not exceed 3650 mg over the course of the treatment. The maximum treatment period is 24 months. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

Another experimental medication used in the trial is **KEYTRUDA** (pembrolizumab), which is supplied as a 25 mg/mL **concentrate for solution for infusion**. Pembrolizumab is a protein-based substance. The administration route is intravenous, with a maximum daily dose of 200 mg and a total dose limit of 4800 mg over the treatment period. The maximum duration for treatment with KEYTRUDA is also 24 months. Compliance with the infusion schedule will be closely monitored to maintain the integrity of the trial data.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for this study. The trial aims to assess the non-inferiority of treatment pause compared to treatment continuation in patients with metastatic renal cell carcinoma (mRCC) who have achieved an objective response. The study will ensure that all participants adhere to the specified dosing schedules and administration routes to maintain consistency and reliability of the trial outcomes.

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the percentage of participants without progression up to 12 months after randomization, evaluated through a blinded independent central review (BICR) according to RECIST v1.1 criteria. This endpoint will provide a measure of the treatment's ability to maintain disease stability over a specified period.

Secondary endpoints include a variety of measures to provide a comprehensive assessment of efficacy and safety. These include the proportion of participants experiencing an adverse event or serious adverse event, and the mean number of such events up to 12 months post-randomization. Additionally, the mean change in quality of life will be measured using the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), and mean scores in the Hospital Anxiety and Depression Scale will be evaluated up to 12 months after randomization. Other secondary endpoints include quality-adjusted time without symptoms of disease or toxicity (Q-TWiST), 2-year overall survival, and 2-year progression-free survival.

For patients in the experimental arm, further assessments will include the site and distribution of progression sites, treatment modality distribution after progression, and the percentage of patients with stable disease (SD) or an objective response at 6 months when restarting PD-1/PD-L1 ICI + VEGFR-TKI. In France, healthcare resource utilization will also be measured by medication use and hospitalizations up to 12 months after randomization. These endpoints will collectively provide a detailed evaluation of the treatment's efficacy in managing **metastatic renal cell carcinoma** (mRCC).