Evaluation of Nivolumab Efficacy in Active Surveillance Post-Neoadjuvant Chemoradiation for Esophageal Cancer: SANO-3 Study

The primary objective of this study is to assess the **efficacy** of nivolumab during active surveillance in patients with a complete clinical response (cCR) following neoadjuvant chemoradiation for **esophageal cancer**. This is clinically relevant as it aims to determine the potential benefits of nivolumab in maintaining disease control and potentially improving outcomes in this patient population.

Secondary objectives include:

• Assessing **toxicity** during and after the treatment to evaluate the safety profile of nivolumab in this context.
• Assessing 2-year overall and distant metastases-free **survival**, which provides insights into the long-term effectiveness and potential survival benefits of the treatment.

The clinical trial involves participants diagnosed with **oesophageal cancer**, specifically those with locoregionally advanced squamous cell or adenocarcinoma of the esophagus or esophagogastric junction. The study population includes both male and female subjects aged 18 years and older. Participants are required to have completed neoadjuvant chemoradiotherapy and achieved a clinically complete response 10-14 weeks post-treatment, as part of an active surveillance protocol. The trial does not include vulnerable populations. The sponsor has not provided information regarding the total number of participants. Participants must provide written, voluntary, informed consent to be included in the study. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the **efficacy** of **nivolumab** during active surveillance in patients with clinically complete response (cCR) after neoadjuvant chemoradiation for **oesophageal cancer**. This study is a randomized, double-blind, controlled trial, ensuring that neither the participants nor the researchers know who is receiving the treatment or placebo, thus minimizing bias. The trial is expected to run until December 31, 2026, with recruitment having commenced on September 1, 2022. Participants will be involved in the study for a maximum treatment period of 12 months, during which they will receive **nivolumab** intravenously, with a maximum daily dose of 480 mg and a total dose not exceeding 6240 mg.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as operable patients with locoregionally advanced squamous cell or adenocarcinoma of the esophagus or esophagogastric junction, completion of neoadjuvant chemoradiotherapy, and a clinically complete response at 10-14 weeks post-treatment. Participants must be aged 18 or older and provide written, voluntary, informed consent. Follow-up visits will be scheduled to monitor the primary endpoint of disease-free survival (DFS), defined as the time from inclusion to locoregional or distant disease recurrence or death. Secondary endpoints include the proportion of patients developing locoregional disease recurrence, distant metastases, and the occurrence of serious adverse events and grade 3-4 adverse events as per the Common Terminology Criteria for Adverse Events (CTCAE version 5.0).

The end-of-study visit will conclude the participant's involvement, assessing the overall outcomes and any long-term effects of the treatment. Conditions that may lead to early termination from the study include the recurrence of disease, withdrawal of consent, or the occurrence of unacceptable adverse events. The trial is not categorized as low intervention and is conducted as an efficacy trial in the target population, exploring new indications for an existing product that already has marketing authorization.

The clinical trial involves the administration of **nivolumab**, marketed under the name OPDIVO, which is a **concentrate for solution for infusion**. This experimental medication is provided in a concentration of 10 mg/mL and is intended for **intravenous use**. The maximum daily dose of nivolumab is 480 mg, with a total maximum dose of 6240 mg over the course of the treatment. The treatment period is set to a maximum of 12 months. Nivolumab is a protein-based therapeutic agent, specifically classified under the ATC code L01FF01, and is produced by Bristol-Myers Squibb Pharma EEIG. The medication is re-packaged and re-labeled for the purposes of this trial.

In this study, nivolumab is being evaluated for its efficacy during active surveillance in patients with a complete clinical response (cCR) following neoadjuvant chemoradiation for esophageal cancer. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

The efficacy of **nivolumab** during active surveillance in patients with clinically complete response (cCR) after neoadjuvant chemoradiation for esophageal cancer will be assessed in this clinical trial. The primary endpoint for evaluating efficacy is **disease-free survival (DFS)**, defined as the time elapsed between inclusion and the occurrence of locoregional or distant disease recurrence or death, whichever occurs first. Secondary endpoints include the proportion of patients who develop locoregional disease recurrence, the proportion of patients who develop distant metastases, and the incidence of serious adverse events and grade 3-4 adverse events from the time of their first treatment with nivolumab, assessed according to the Common Terminology Criteria for Adverse Events (CTCAE version 5.0).