Evaluation of PD-1 Inhibitor Discontinuation Strategy with Nivolumab and Pembrolizumab in Advanced Melanoma Patients Achieving Complete or Partial Response

The primary objective of this study is to evaluate the **rate of ongoing response** in patients with advanced and metastatic **melanoma** who discontinue first-line monotherapy with nivolumab or pembrolizumab upon achieving a complete response (CR) or partial response (PR). This is clinically relevant as it aims to determine the sustainability of treatment effects after cessation of therapy, which could inform treatment duration and management strategies for patients with melanoma.

Secondary objectives include the evaluation of:

• Duration of response after discontinuation of PD-1 blockade
• Outcome of patients after discontinuation of PD-1 blockade
• Need and feasibility of rechallenge of PD-1 blockade
• Disease control after rechallenge of PD-1 blockade
• Outcome of patients after rechallenge of PD-1 blockade
• Overall outcome after discontinuation and rechallenge of PD-1 blockade
• Impact of treatment discontinuation on adverse events (AEs)
• Change in tumor burden since start and after discontinuation of PD-1 blockade
• Change in quality of life (QoL) after discontinuation of PD-1 blockade measured at different time points
• Impact of early discontinuation of PD-1 blockade on fear of disease recurrence/progression
• Impact of early discontinuation of PD-1 blockade on productivity with respect to paid and unpaid work
• Impact of early discontinuation of PD-1 blockade on healthcare resource utilization
• Impact of early discontinuation of PD-1 blockade on hours of informal care
• Changes in QoL at disease progression and restart of systemic therapy (when applicable)
• Changes in QoL in relation to tumor response
• Changes in QoL in relation to toxicity
• Changes in QoL in relation to the number of hospital visits
• Differences in QoL in this trial as compared to QoL of patients without early discontinuation of PD-1 blockade
• Differences in productivity loss in this trial as compared to productivity loss of patients without early discontinuation of PD-1 blockade
• Changes in QoL after discontinuation of radiological follow-up

The clinical trial involves participants diagnosed with **advanced and metastatic melanoma**. The study population includes both male and female subjects aged 18 years and older. Participants are currently undergoing first-line treatment with nivolumab or pembrolizumab. The trial does not include a vulnerable population. The sponsor has not provided the total number of participants. Participants were selected based on their current treatment status and documented tumor response evaluations. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. Key inclusion criteria include the presence of documented target lesions and willingness to discontinue treatment within a specified timeframe after achieving a complete or partial response. The trial does not focus on any specific lifestyle considerations beyond the medical treatment regimen.

The clinical trial is designed to evaluate the rate of ongoing response in patients with advanced and metastatic **melanoma** who discontinue first-line monotherapy with **nivolumab** or **pembrolizumab** upon achieving a complete response (CR) or partial response (PR). This is a Phase II, observational study employing a randomized, double-blind, controlled trial design. The trial is expected to span from January 1, 2019, to August 10, 2033, with the primary endpoint being the rate of ongoing responses at 24 months after the initial start of treatment.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), diagnosis of advanced or metastatic melanoma, and current treatment with the specified drugs. The screening will include a documented target lesion evaluation according to RECIST v1.1 and an MRI brain scan to screen for brain metastases. Following the screening, participants will have follow-up visits every 12±1 weeks to assess tumor response and other health parameters. The end-of-study visit will occur at the conclusion of the trial or upon early termination.

The expected length of participant involvement is up to 24 months, with conditions for early termination including disease progression, withdrawal of consent, or adverse events. Secondary endpoints include the total duration of tumor response, progression-free survival (PFS), and the rate of reintroduction of monotherapy or other systemic salvage therapies upon disease progression. The study will also assess changes in quality of life, fear of disease recurrence, and healthcare resource utilization. Participants will be monitored for grade 3-4 adverse events following early discontinuation or reintroduction of therapy.

The clinical trial involves the administration of **OPDIVO**, a concentrate for solution for infusion, containing the active substance **nivolumab**. Nivolumab is a protein-based therapeutic agent classified under the ATC code L01FF01. The pharmaceutical form is a solution for infusion, and it is administered intravenously. The maximum daily dose of OPDIVO is 480 mg, with a total maximum dose of 20,160 mg over a treatment period of 21 days. The product is manufactured by Bristol-Myers Squibb Pharma EEIG and is not a paediatric formulation. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

Another experimental medication used in the trial is **KEYTRUDA**, also a concentrate for solution for infusion, with the active substance **pembrolizumab**. Pembrolizumab is similarly a protein-based therapeutic agent, classified under the ATC code L01FF02. The pharmaceutical form is a solution for infusion, administered via intravenous infusion. The maximum daily dose for KEYTRUDA is 400 mg, with a total maximum dose of 11,200 mg over a 21-day treatment period. This product is manufactured by Merck Sharp & Dohme B.V. and is also not formulated for paediatric use. The administration and dosing schedules are strictly monitored to ensure participant compliance and safety throughout the trial.

Both OPDIVO and KEYTRUDA are utilized as monotherapies in the study, with the primary objective being to evaluate the rate of ongoing response in patients with advanced and metastatic melanoma who discontinue first-line monotherapy upon achieving a complete or partial response. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial protocol. The trial is designed to ensure rigorous monitoring of drug administration and participant adherence to the treatment regimen.

Efficacy in this clinical trial will be assessed primarily through the rate of ongoing responses, specifically complete response (CR) and partial response (PR), in patients with advanced and metastatic melanoma. These responses will be evaluated according to the RECIST v1.1 criteria at 24 months after the initial administration of nivolumab or pembrolizumab. Secondary endpoints include the total duration of tumor response after the first documented CR or PR followed by treatment interruption, and the duration of tumor response after discontinuation of PD-1 blockade. Progression-free survival (PFS) will also be measured from the start of first-line monotherapy with PD-1 blockade until the first progression of disease (PD), as well as after reintroduction of monotherapy or other systemic salvage therapy.

Additional secondary endpoints involve the rate of reintroduction of monotherapy with PD-1 blockade upon first PD, the rate of introduction of other systemic salvage therapies, and the best tumor response on rechallenge with monotherapy or after introduction of other systemic therapies. The trial will also assess the rate of grade 3-4 adverse events following early discontinuation or reintroduction of nivolumab or pembrolizumab monotherapy. Changes in tumor burden, quality of life (QoL), fear of disease recurrence, productivity, healthcare resource utilization, and hours of informal care after discontinuation of PD-1 blockade will be evaluated. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial duration, ensuring a comprehensive assessment of the treatment's impact on patients.