Evaluation of Early Discontinuation of Nivolumab in Patients with Unresectable Stage III or Metastatic Melanoma Treated with First-Line Ipilimumab-Nivolumab Therapy

The primary objective of the Safe Stop IPI-NIVO Trial is to evaluate the rate of ongoing response at 12 months in patients with **irresectable stage III or metastatic melanoma** who are treated with first-line **ipilimumab-nivolumab** and who early discontinue **nivolumab** upon achieving a complete or partial response according to RECIST v1.1. This objective is clinically relevant as it aims to determine the efficacy of early discontinuation of nivolumab in maintaining response, potentially reducing treatment duration and associated toxicities.

Secondary objectives include:

• Patient outcomes such as ongoing response at 24 months, disease control at various time points, duration of response, melanoma-specific survival, overall survival, impact of treatment discontinuation on adverse events, overall response rate in retreated patients, and disease control after restarting treatment.
• Cost-effectiveness analysis focusing on the impact on productivity, healthcare resources, and informal care hours due to early treatment discontinuation.
• Assessment of Quality of Life (QoL).

The clinical trial involves participants diagnosed with **melanoma**, specifically those with irresectable stage III or metastatic conditions. The study population includes both male and female subjects aged 18 years and older. Participants are required to have been treated with at least one dose of first-line ipilimumab-nivolumab and must be candidates for maintenance treatment with nivolumab. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants' general health status is not specified beyond the inclusion criteria related to their melanoma condition. Lifestyle considerations such as diet, physical activity, or habits are not detailed in the available data. Key inclusion criteria include the presence of MRI brain screening for brain metastases and the requirement for participants to have achieved a complete or partial response according to RECIST v1.1 criteria. The trial does not focus on any specific lifestyle modifications or restrictions beyond the medical treatment protocol.

The clinical trial is designed to evaluate the efficacy of early discontinuation of **nivolumab** in patients with irresectable stage III or metastatic **melanoma** who have achieved a complete or partial response. This is a randomized, double-blind, controlled trial with an estimated duration from February 2023 to February 2033. The trial involves the administration of **ipilimumab** and **nivolumab** as first-line treatment, with the option to switch to **pembrolizumab** for maintenance therapy. Participants will be monitored for ongoing response at 12 months, with secondary endpoints including response duration, melanoma-specific survival, and overall survival.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, involves confirming eligibility criteria such as age, disease stage, and previous treatment history. Participants must have a diagnostic CT scan to document target lesions, and an MRI is required for those with asymptomatic brain metastases. Follow-up visits occur every 12 weeks in the first year, every 4 months in the second year, and every 6 months in the third year, with a final set of assessments in the fifth year. These visits include response evaluations and quality of life assessments.

The expected length of participant involvement is up to 9 months for the initial treatment phase, with ongoing follow-up for up to 5 years. Early termination from the study may occur if there is disease progression, unacceptable toxicity, or withdrawal of consent. Participants are required to discontinue **nivolumab** within 4 weeks after achieving a confirmed complete or partial response, and no later than 9 months after starting treatment. The trial aims to provide insights into the cost-effectiveness and quality of life impacts of early discontinuation of PD-1 blockade therapy.

The clinical trial involves the administration of **OPDIVO** (nivolumab), a concentrate for solution for infusion, with a concentration of 10 mg/mL. This pharmaceutical form is intended for **intravenous administration**. The maximum daily dose of OPDIVO is 480 mg, with a total maximum dose of 3840 mg over a treatment period of up to 9 months. Nivolumab is a protein-based therapeutic agent, specifically classified under the ATC code L01FF01. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

**YERVOY** (ipilimumab) is another experimental medication used in this trial, provided as a 5 mg/mL concentrate for solution for infusion. Like OPDIVO, YERVOY is administered intravenously. The maximum daily dose is 250 mg, with a total maximum dose of 1000 mg over a treatment period of up to 3 months. Ipilimumab is also a protein-based therapeutic agent, categorized under the ATC code L01FX04. The administration of YERVOY is carefully monitored to maintain compliance with the prescribed dosing schedule.

The trial also includes the use of **KEYTRUDA** (pembrolizumab), which is available as a 25 mg/mL concentrate for solution for infusion. This medication is administered via the intravenous route. The maximum daily dose for KEYTRUDA is 400 mg, with a total maximum dose of 2400 mg over a treatment period of up to 9 months. Pembrolizumab is a protein-based therapeutic agent, identified under the ATC code L01FF02. Compliance with the dosing schedule is monitored to ensure the effectiveness and safety of the treatment.

All medications in this trial are provided by their respective manufacturers, with OPDIVO and YERVOY supplied by Bristol-Myers Squibb Pharma EEIG, and KEYTRUDA by Merck Sharp & Dohme B.V. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The focus is on the efficacy and safety of the experimental medications in patients with irresectable stage III or metastatic melanoma.

Efficacy in the clinical trial titled "Safe Stop IPI-NIVO Trial" will be assessed primarily by evaluating the rate of ongoing response at 12 months in patients with irresectable stage III or metastatic melanoma. These patients are treated with first-line ipilimumab-nivolumab and discontinue nivolumab early upon achieving a confirmed complete response (CR) or partial response (PR) according to RECIST v1.1 criteria. The primary endpoint is defined as the absence of disease progression or melanoma-specific mortality at 12 months after treatment initiation.

Secondary endpoints include patient outcomes such as ongoing response at 24 months, response rates (CR/PR) at various time points, duration of response until disease progression or recurrence, melanoma-specific survival from the start of treatment until melanoma-related death, and overall survival from the start of combination treatment until death. Additionally, a cost-effectiveness analysis will be conducted, assessing the impact on productivity, healthcare resources, and hours of informal care. Quality of life will also be evaluated through patient-reported outcomes using QoL questionnaires administered at specified intervals: at inclusion, every 12 weeks in the first year, every 4 months in the second year, every 6 months in the third year, and once in the fifth year.