Feasibility of Surgery and Durvalumab Consolidation Post-Chemoradiotherapy in Stage III NSCLC Patients

The primary objective of this study is to evaluate the **safety** of surgical intervention in patients with initially unresectable stage III non-small cell lung cancer (NSCLC) who are deemed resectable by a multidisciplinary team within 12 weeks following the completion of high-dose chemoradiotherapy (CRT). Additionally, the study aims to assess the feasibility of proceeding to durvalumab consolidation therapy post-surgery. These objectives are clinically relevant as they address the potential for surgical resection and subsequent immunotherapy in a patient population traditionally considered inoperable, potentially improving treatment outcomes and survival rates.

Secondary objectives include:

• Assessing the rate of complete surgical resection (R0), which is crucial for determining the success of the surgical intervention in achieving tumor-free margins.
• Evaluating disease-free survival (DFS) at 2 years, providing insight into the long-term efficacy of the treatment regimen in preventing cancer recurrence.

The clinical trial involves participants diagnosed with **Stage III non-small cell lung cancer** (NSCLC). The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants are not from a vulnerable population. The trial population was selected based on specific inclusion criteria, such as having histologically or cytologically confirmed stage III (non-N3) NSCLC before the start of chemoradiotherapy. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified. The trial aims to assess the safety of surgery in patients initially deemed unresectable by a multidisciplinary team and to evaluate the feasibility of proceeding to durvalumab consolidation therapy post-surgery.

The clinical trial is designed to evaluate the **safety** and feasibility of surgery followed by consolidation therapy with **durvalumab** in patients with stage III non-small cell lung cancer (NSCLC). This is a phase IV, low-intervention trial, which is randomized, double-blind, and controlled. The trial is expected to commence recruitment in June 2024 and conclude by June 2027. Participants will be involved in the study for a maximum treatment period of 12 months, with the possibility of early termination if severe adverse events occur or if the participant is unable to proceed to the consolidation phase.

The trial will include several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on histological or cytological confirmation of stage III NSCLC and other criteria. Following the screening, participants will undergo chemoradiotherapy (CRT) and, if deemed resectable by a multidisciplinary team, will proceed to surgery. Post-surgery, participants will be assessed for their ability to continue to the durvalumab consolidation phase. Follow-up visits will be scheduled to monitor the safety and efficacy of the treatment, with primary endpoints focusing on surgical morbidity and mortality rates, as well as the incidence of treatment-related adverse events within 90 days post-surgery. Secondary endpoints include the rate of complete surgical resection and disease-free survival (DFS) at two years from the day of surgery.

The trial's design ensures that the investigational medicinal product, durvalumab, is administered intravenously as a solution for infusion, with a maximum daily dose of 10 mg/kg and a total dose not exceeding 1500 mg. The trial is categorized as low-intervention due to the use of an already authorized medicinal product, supported by existing scientific evidence, and the minimal additional risk posed by the diagnostic and monitoring procedures compared to standard clinical practice. Participants' involvement will be closely monitored, and any deviations from the protocol or adverse events will be addressed promptly to ensure participant safety and data integrity.

The clinical trial involves the administration of **IMFINZI** (durvalumab), a **concentrate for solution for infusion**. This experimental medication is provided in a concentration of 50 mg/mL and is intended for intravenous administration. The dosing regimen specifies a maximum daily dose of 10 mg/kg, with a total maximum dose not exceeding 1500 mg. The treatment period is capped at 12 weeks. Durvalumab, the active substance, is a protein-based therapeutic agent, specifically classified under the ATC code L01XC28. The pharmaceutical form is a solution for infusion, and it is manufactured by AstraZeneca AB.

In this trial, durvalumab is used as a consolidation therapy following chemoradiotherapy, with or without surgery, in patients with initially unresectable stage III non-small cell lung cancer (NSCLC). The trial aims to assess the safety of surgery and the feasibility of proceeding to durvalumab consolidation therapy post-surgery. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial protocol. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment regimen.

Efficacy in the clinical trial titled "ChemoRadiotherapy with Or Without surgery followed by consolidation Durvalumab (CROWD): a phase IV feasibility trial" will be assessed using specific primary and secondary endpoints. The primary endpoints include the safety defined as the rates of severe surgical morbidity and mortality (Clavien-Dindo grade 3-5) and the percentage of patients with treatment-related adverse events (Grade III-V) within 90 days of surgery, as well as the number of patients able to proceed to **durvalumab** consolidation after surgery. Secondary endpoints will evaluate the rate of complete surgical resection (R0) and disease-free survival (DFS) in 2 years, defined from the day of surgery.