Phase III Randomized Double-Blind Study of Durvalumab and Domvanalimab in Stage III Unresectable NSCLC Post-Platinum-Based Chemoradiation Therapy

The primary objective of this study is to demonstrate the superiority of **durvalumab** plus **domvanalimab** compared to durvalumab plus placebo in participants with locally advanced, unresectable non-small cell lung cancer (NSCLC) who have not progressed on prior platinum-based concurrent chemoradiation therapy (cCRT), with PD-L1 tumor cell (TC) expression ≥ 50%. The primary endpoint is progression-free survival (PFS) assessed by Blinded Independent Central Review (BICR). This is clinically relevant as it aims to improve outcomes in a challenging patient population with limited treatment options.

Secondary objectives include demonstrating the superiority of durvalumab plus domvanalimab relative to durvalumab plus placebo in participants with TC ≥ 1% or TC ≥ 50% in the following outcomes:

• Overall response rate (ORR)
• Duration of response (DoR)
• Time to second progression (PFS2)
• Time to death or distant metastasis (TTDM)
• Time to first subsequent therapy (TFST)
• PFS at 6, 12, 18, and 24 months
• Overall survival at 24 months (OS 24)
• Overall survival (OS)
• PFS as assessed by the investigator
• Time to deterioration in pulmonary symptoms
• Pharmacokinetics (PK) and immunogenicity of durvalumab and domvanalimab
• Safety and tolerability of durvalumab plus domvanalimab compared to durvalumab plus placebo

The clinical trial involves a total of **580 participants** diagnosed with locally advanced (Stage III), unresectable non-small cell lung cancer (**NSCLC**), whose tumors express PD-L1 TC ≥ 1% as determined by a central reference laboratory using the VENTANA PD-L1 (SP263) IHC assay. The study population includes both male and female subjects aged 18 years and older. Participants have not shown disease progression following definitive platinum-based concurrent chemoradiotherapy (cCRT). The trial population was selected based on specific criteria, including histologically or cytologically documented NSCLC, documented tumor PD-L1 status ≥ 1%, and EGFR and ALK wild-type status. Participants must have received at least two cycles of platinum-based chemotherapy concurrent with radiation therapy and a total radiation dose of 60 Gy ±10% as part of the chemoradiation therapy. The study includes individuals with a WHO performance status of 0 or 1 at randomization and those with adequate organ and marrow function. The trial does not exclude vulnerable populations, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy of **durvalumab** plus **domvanalimab** in participants with locally advanced, unresectable non-small cell lung cancer (NSCLC) who have not progressed following definitive platinum-based concurrent chemoradiation therapy. The trial aims to demonstrate the superiority of the combination therapy over durvalumab plus placebo, with progression-free survival (PFS) as the primary endpoint, assessed by Blinded Independent Central Review (BICR). The study is expected to run until August 2030, with recruitment having started in November 2023.

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 PD-L1 expression status. Following randomization, participants will receive intravenous infusions of the investigational products or placebo. Regular follow-up visits will be conducted to monitor safety, efficacy, and disease progression, with assessments including imaging studies and laboratory tests. The end-of-study visit will occur after the final treatment cycle or upon disease progression, whichever comes first.

The expected duration of participant involvement is up to 52 weeks, with conditions for early termination including significant adverse events, withdrawal of consent, or disease progression as defined by RECIST 1.1 criteria. Participants will be closely monitored throughout the trial to ensure adherence to the protocol and to address any safety concerns promptly. The trial's design and procedures are structured to maintain scientific rigor and ensure the reliability of the collected data.

The clinical trial involves the administration of several treatments, including **INFLIXIMAB**, which is provided as a **solution for infusion**. This experimental medication is administered via **intravenous use**. The specific dosage and frequency of administration are not detailed in the provided data. **INFLIXIMAB** is not a pediatric formulation and is classified as an auxiliary product in the trial.

**IMFINZI** (durvalumab) is another experimental medication used in the trial. It is available as a **50 mg/mL concentrate for solution for infusion** and is administered intravenously. The maximum treatment period for **IMFINZI** is 12 months. This medication is not a pediatric formulation and is classified as a test product in the study.

The trial also includes the use of a **PLACEBO**, which serves as a comparator treatment. The placebo is not specified in terms of pharmaceutical form, active substance, or route of administration. It is classified as a test product in the trial.

**DOMVANALIMAB** is administered as a **concentrate for solution for infusion** and is given intravenously. The maximum daily dose is 20 mg/kg, and the treatment period can extend up to 52 weeks. **DOMVANALIMAB** is not a pediatric formulation and is classified as a test product in the trial.

Additionally, **MYCOPHENOLATE MOFETIL** is used as an auxiliary treatment. It is provided in the form of **capsules** and administered orally. The specific dosage and frequency of administration are not detailed in the provided data. **MYCOPHENOLATE MOFETIL** is not a pediatric formulation and is classified as an immunosuppressive agent in the trial.

The efficacy of the clinical trial will be assessed primarily through **Progression-Free Survival (PFS)**, evaluated by Blinded Independent Central Review (BICR) according to RECIST 1.1 criteria. This assessment will focus on participants with PD-L1 Tumor Cell (TC) expression levels of 50% or higher. PFS evaluations will occur at regular intervals from randomization until radiological progression is defined by RECIST 1.1, with additional follow-up scans as necessary.

Secondary efficacy endpoints include PFS in participants with PD-L1 TC expression of 1% or higher, as well as comparisons of overall survival (OS) and PFS between the treatment groups (durvalumab plus domvanalimab versus durvalumab plus placebo) in both TC ≥ 1% and TC ≥ 50% subgroups. Additional secondary endpoints encompass PFS at various time points (6, 12, 18, and 24 months), OS at 24 months, objective response rate (ORR), duration of response (DoR) by BICR, and other measures such as PFS2, time to deterioration of pulmonary symptoms, and pharmacokinetics and immunogenicity of the investigational drugs.