Phase III Randomized Study of Rilvegostomig vs. Pembrolizumab with Platinum-based Chemotherapy in PD-L1 Expressing Metastatic Non-squamous NSCLC

The primary objective of this study is to demonstrate the **efficacy** of rilvegostomig in combination with chemotherapy compared to pembrolizumab plus chemotherapy in patients with metastatic non-squamous non-small cell lung cancer (NSCLC) whose tumors express PD-L1. This will be assessed by evaluating overall survival (OS) and progression-free survival (PFS). The clinical relevance of this objective lies in potentially improving treatment outcomes for this patient population, offering an alternative therapeutic option that may enhance survival rates and delay disease progression.

Secondary objectives include:

• Characterizing the efficacy of rilvegostomig plus chemotherapy relative to pembrolizumab plus chemotherapy by assessing OS, PFS, and duration of response (DoR).
• Comparing the efficacy of rilvegostomig plus chemotherapy to pembrolizumab plus chemotherapy by evaluating progression-free survival 2 (PFS2).
• Characterizing and comparing the efficacy of rilvegostomig plus chemotherapy relative to pembrolizumab plus chemotherapy by assessing the overall response rate (ORR).
• Assessing the pharmacokinetics (PK) of rilvegostomig, patient-reported physical functioning, global health status/quality of life (GHS/QoL), and lung cancer symptoms in NSCLC.
• Investigating the immunogenicity of rilvegostomig.
• Assessing the safety and tolerability of rilvegostomig plus chemotherapy compared to pembrolizumab plus chemotherapy.

The clinical trial involves a total of **637 participants** diagnosed with **Metastatic Non-squamous Non-small Cell Lung Cancer** whose tumors express PD-L1. 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 were selected based on specific inclusion criteria, such as having histologically or cytologically documented non-squamous NSCLC, stage IV mNSCLC not amenable to curative treatment, and absence of certain genetic mutations and rearrangements. The trial also requires the provision of a tumor sample to confirm PD-L1 expression and the presence of at least one measurable lesion. Adequate organ and bone marrow function are necessary for participation. The trial population includes a vulnerable population, indicating that additional ethical considerations are in place. Lifestyle factors such as diet, physical activity, and habits are not specified in the available data.

The clinical trial is a **Phase III**, randomized, double-blind, multicenter study designed to evaluate the efficacy of **rilvegostomig** in combination with platinum-based chemotherapy compared to **pembrolizumab** with the same chemotherapy regimen in patients with metastatic non-squamous non-small cell lung cancer (NSCLC) whose tumors express PD-L1. The trial aims to assess overall survival (OS) and progression-free survival (PFS) as primary endpoints, with secondary endpoints including overall response rate (ORR), duration of response (DoR), and adverse events (AEs) among others. The study is expected to commence recruitment on November 29, 2024, and conclude by May 14, 2029.

Participants will undergo a series of study visits beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically or cytologically documented non-squamous NSCLC, absence of specific genetic mutations, and adequate organ function. Following randomization, participants will receive either rilvegostomig or pembrolizumab in combination with chemotherapy drugs such as **carboplatin** or **cisplatin** administered via intravenous infusion. The trial includes regular follow-up visits to monitor treatment response and safety, with assessments including imaging studies to measure tumor size, laboratory tests, and physical examinations. The end-of-study visit will evaluate the final outcomes and any long-term effects of the treatment.

The expected duration of participant involvement is determined by the treatment regimen and response, with a maximum treatment period of 66 weeks for rilvegostomig. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Participants will be closely monitored throughout the trial to ensure safety and adherence to the protocol. The study is not classified as low intervention, reflecting the complexity and potential risks associated with the investigational treatments.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Rilvegostomig**, also known by its sponsor product code AZD2936, is a bispecific IgG1 monoclonal antibody targeting PDCD1 and TIGIT. It is provided as a solution for infusion and administered via **intravenous use**. The dosing schedule is determined by the trial protocol, with a maximum treatment period of 66 weeks. Participant compliance is monitored through regular assessments and infusion records.

**Pembrolizumab**, marketed as KEYTRUDA, is a monoclonal antibody used as a comparator in this study. It is supplied as a 25 mg/mL concentrate for solution for infusion and administered intravenously. The maximum daily dose is 200 mg, with a total maximum dose of 17,000 mg over a treatment period of 59 weeks. Compliance is ensured through infusion logs and patient monitoring.

**Carboplatin** is utilized as part of the chemotherapy regimen. It is provided as a concentrate for solution for infusion and administered intravenously. The maximum daily dose is 6 mg, with a total maximum dose of 24 mg over a 12-week period. Dosing schedules are adhered to as per the trial protocol, with compliance monitored through infusion records.

**Cisplatin** is another chemotherapy agent used in the trial. It is available as a concentrate for solution for infusion and administered via intravenous infusion. The maximum daily dose is 75 mg/m², with a total maximum dose of 300 mg/m². The treatment period extends up to 99999 weeks, with compliance monitored through regular assessments.

**Pemetrexed** is included in the chemotherapy regimen, provided as a powder for concentrate for solution for infusion. It is administered intravenously, with dosing based on body surface area (mg/m²). The treatment period is up to 99999 weeks, with compliance monitored through infusion records and patient assessments.

**Mycophenolate mofetil** is used as an auxiliary treatment. It is provided in capsule form and administered orally. The dosing schedule and treatment period are determined by the trial protocol, with compliance monitored through patient logs and regular assessments.

**Infliximab** is another auxiliary treatment, supplied as a powder for concentrate for solution for infusion. It is administered via intravenous infusion, with dosing schedules and treatment periods specified in the trial protocol. Compliance is monitored through infusion records and patient assessments.

The efficacy of the clinical trial will be assessed through the primary endpoints of **Overall Survival (OS)** and **Progression-Free Survival (PFS)**. These endpoints are critical in evaluating the effectiveness of the treatment regimens being tested, which include rilvegostomig plus chemotherapy and pembrolizumab plus chemotherapy, in patients with metastatic non-squamous non-small cell lung cancer (NSCLC) expressing PD-L1.

Secondary endpoints will provide additional insights into the treatment's efficacy and include landmark OS and PFS rates, time to second progression or death (PFS2), overall response rate (ORR), and duration of response (DoR). The concentration of rilvegostomig in serum and the presence of antidrug antibodies (ADAs), including titer and neutralizing antibodies, will also be measured. Furthermore, the trial will assess the proportion of participants with maintained or improved physical functioning, time to deterioration of global health status/quality of life (QoL) and pulmonary symptoms, and adverse events (AEs) graded by CTCAE version 5.0.

Data collection will involve clinical laboratory assessments, vital signs, physical examinations, and the Eastern Cooperative Oncology Group (ECOG) performance status. These assessments will be conducted at specified intervals throughout the trial to ensure comprehensive monitoring of the participants' health and the treatment's impact. The trial is designed to provide robust data on the efficacy of the investigational treatments, contributing to the understanding of their potential benefits in the specified patient population.