Evaluation of Durvalumab Plus Oleclumab and Durvalumab Plus Monalizumab in Stage III Unresectable Non-Small Cell Lung Cancer Post-Platinum-Based Chemoradiation

The primary objective of this study is to evaluate the **superiority** of durvalumab combined with oleclumab and durvalumab combined with monalizumab compared to durvalumab with placebo in patients with unresectable Stage III non-small cell lung cancer (NSCLC) who have not progressed following prior platinum-based concurrent chemoradiation therapy (cCRT). This is assessed by progression-free survival (PFS) as evaluated by a blinded independent central review (BICR). The clinical relevance of this objective lies in potentially improving treatment outcomes for patients with this advanced stage of NSCLC, offering new therapeutic options that may enhance survival and disease management.

Secondary objectives include:

• Demonstrating the superiority of the combination therapies relative to placebo in terms of overall survival (OS), overall response rate (ORR), duration of response (DoR), and various time-to-event endpoints such as PFS at different time points (PFS6, PFS12, PFS18, PFS24, PFS2), time to distant metastasis (TTDM), and time to first subsequent therapy (TFST).
• Investigating the relationship between patients' PD-L1 expression on tumor cells and efficacy outcomes with the combination therapies.
• Assessing the pharmacokinetics (PK) of durvalumab, oleclumab, and monalizumab when used in combination.
• Evaluating the immunogenicity of the study drugs.
• Assessing the time to deterioration in pulmonary symptoms.

The clinical trial involves a total of **1252 participants** diagnosed with **locally advanced (Stage III), unresectable non-small cell lung cancer (NSCLC)**. The study population includes both male and female subjects, aged 18 years and older, who have not shown disease progression following prior platinum-based concurrent chemoradiotherapy (cCRT). Participants were selected based on specific criteria, including histologically or cytologically documented NSCLC, provision of a tumor tissue sample obtained prior to cCRT, and documented tumor PD-L1 status. Additionally, participants must have received at least two cycles of platinum-based chemotherapy concurrent with radiation therapy, with a total radiation dose of 60 Gy ±10% administered. The trial includes individuals with a WHO performance status of 0 or 1 at randomization and adequate organ and marrow function. The study population is characterized by a diverse age range and includes vulnerable populations, ensuring a comprehensive evaluation of the investigational treatments. Lifestyle factors such as diet and physical activity were not specified by the sponsor.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled, multicenter, international study. It aims to evaluate the efficacy of **durvalumab** in combination with **oleclumab** or **monalizumab** in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) who have not progressed following definitive, platinum-based concurrent chemoradiation therapy. The trial is expected to last until May 2030, with recruitment starting in January 2024. The primary endpoint is progression-free survival (PFS) as assessed by blinded independent central review (BICR), with assessments continuing up to five years after the first patient is randomized.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of NSCLC, and previous treatment with concurrent chemoradiation therapy. Following successful screening, participants will be randomized to receive either the investigational combination therapies or placebo. Study visits will include regular follow-up assessments to monitor safety, efficacy, and disease progression. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected length of participant involvement is up to 12 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. Participants must meet specific inclusion criteria, such as being 18 years or older, having a WHO performance status of 0 or 1, and having adequate organ and marrow function. Exclusion criteria are not specified in the provided data. The trial will utilize intravenous administration of the investigational products, with **sodium chloride** and **glucose** serving as placebo controls. The study is not classified as a low-intervention trial and is categorized as a Phase III trial.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Durvalumab**, marketed as IMFINZI, is a **concentrate for solution for infusion** with a concentration of 50 mg/mL. It is administered via **intravenous use**. The maximum total dose is 1500 mg, and the treatment period is up to 12 months. Durvalumab is a protein-based therapeutic agent developed by AstraZeneca AB, and it is used in combination with other investigational drugs in this study.

**Oleclumab** is another investigational drug used in this trial. It is a **concentrate for solution for infusion** and is administered through **intravenous use**. The treatment period for Oleclumab is also up to 12 months. This protein-based agent is being evaluated for its efficacy in combination with Durvalumab in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC).

**Monalizumab** is included in the study as a **solution for infusion**. It is administered via **intravenous use**. The treatment duration is up to 12 months. Monalizumab, a protein-based therapeutic, is being tested in combination with Durvalumab to assess its potential benefits in the same patient population.

**Sodium Chloride** is used as a **solution for injection** and serves as a saline placebo in the trial. It is administered **intravenously**. The use of sodium chloride as a placebo helps in maintaining the double-blind nature of the study.

**Glucose** is utilized as a **solution for infusion** and acts as a glucose placebo. It is administered **intravenously**. Similar to sodium chloride, glucose is used to ensure the study remains double-blind.

**Mycophenolate Mofetil** is provided in the form of a **film-coated tablet** and is administered **orally**. It is included as a non-experimental treatment in the study, with a treatment period of up to 12 months. Mycophenolate Mofetil is a chemical-based agent used as a standard-of-care therapy in certain conditions.

**Infliximab** is administered as a **powder for concentrate for solution for infusion** via **intravenous infusion**. It is included as a non-experimental treatment with a treatment period of up to 12 months. Infliximab is a therapeutic agent used in various inflammatory conditions.

Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol. The trial aims to evaluate the efficacy and safety of the investigational combinations in patients with unresectable, Stage III NSCLC who have not progressed following definitive, platinum-based concurrent chemoradiation therapy.

Efficacy in this clinical trial will be assessed primarily through **Progression-Free Survival (PFS)**, as evaluated by Blinded Independent Central Review (BICR) according to RECIST 1.1 criteria. The assessment of PFS will be conducted up to five years following the randomization of the first patient. This endpoint is designed to demonstrate the superiority of the combination therapies, durvalumab plus oleclumab and durvalumab plus monalizumab, compared to durvalumab plus placebo in patients with unresectable, Stage III non-small cell lung cancer (NSCLC) who have not progressed following definitive, platinum-based concurrent chemoradiation therapy.