A Phase II/III, Randomized, Double-Blind, Placebo-Controlled Study of Tiragolumab in combination with Atezolizumab plus Pemetrexed and Carboplatin/Cisplatin versus Pembrolizumab plus Pemetrexed and Carboplatin/Cisplatin in Patients with previously Untreated Advanced Non-Squamous Non-Small-Cell Lung Cancer

The primary objective of this study is to evaluate the **efficacy** of **tiragolumab** in combination with **atezolizumab** plus pemetrexed and carboplatin/cisplatin (Arm A) compared with placebo in combination with pembrolizumab plus pemetrexed and carboplatin/cisplatin (Arm B). This evaluation is based on the confirmed objective response rate (ORR) and progression-free survival (PFS), as assessed by investigators according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) in Phase 2, and on PFS and overall survival (OS) in Phase 3. The clinical relevance of this objective lies in determining the potential of tiragolumab and atezolizumab as a therapeutic option for patients with previously untreated advanced non-squamous non-small cell lung cancer (NSCLC), potentially improving survival outcomes and response rates.

Secondary objectives include:

• Evaluating the efficacy of Arm A compared with Arm B based on OS, duration of response (DOR), and time to confirmed deterioration (TTCD) in patient-reported physical functioning and global health status/quality of life (GHS/QoL) in Phase 2.
• Assessing the efficacy of Arm A compared with Arm B based on PFS, as determined by an independent review facility according to RECIST v1.1, PFS and OS in patients with PD-L1 expression at TC ≥ 50% and TC ≥ 1% cut-off, PFS rate at 6 months and 12 months, OS rate at 12 months and 24 months, confirmed ORR, DOR, and TTCD in patient-reported physical functioning and GHS/QoL in Phase 3.
• Evaluating the safety of tiragolumab in combination with atezolizumab plus pemetrexed and carboplatin/cisplatin compared with placebo in combination with pembrolizumab plus pemetrexed and carboplatin/cisplatin.
• Characterizing the pharmacokinetics of tiragolumab and atezolizumab.
• Evaluating the immune response to tiragolumab and atezolizumab.

The clinical trial involves a total of **351 participants** diagnosed with **non-squamous 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 were selected based on specific criteria, including an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial includes individuals with histologically or cytologically documented locally advanced unresectable or metastatic non-squamous NSCLC, who have not received prior systemic treatment for metastatic disease. Participants must have a known tumor PD-L1 status and measurable disease as defined by RECIST v1.1. Additionally, they must test negative for HIV and have negative serology for active hepatitis B and C viruses. The trial population also includes vulnerable groups, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographics. Lifestyle factors such as diet and physical activity are not specified in the data provided.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy of **tiragolumab** in combination with **atezolizumab** plus pemetrexed and carboplatin/cisplatin compared to **pembrolizumab** plus pemetrexed and carboplatin/cisplatin in patients with previously untreated advanced non-squamous non-small cell lung cancer (NSCLC). The trial is structured in two phases: Phase II and Phase III, with the primary objectives being the assessment of confirmed objective response rate (ORR) and progression-free survival (PFS) in Phase II, and PFS and overall survival (OS) in Phase III. The trial is expected to conclude by December 15, 2027, with recruitment having commenced on January 31, 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, documented advanced non-squamous NSCLC, and measurable disease as per RECIST v1.1. Following the screening, participants will be randomized into one of the study arms and will receive treatment via **intravenous infusion**. Regular follow-up visits will be scheduled to monitor the participants' response to treatment, assess any adverse events, and evaluate the primary and secondary endpoints. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted.

The expected duration of participant involvement is up to 84 weeks, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or any other reason deemed appropriate by the investigator. The study aims to provide comprehensive data on the efficacy and safety of the investigational treatments, contributing valuable insights into the management of advanced non-squamous NSCLC.

The clinical trial involves the administration of **Tiragolumab**, a **concentrate for solution for infusion**. This investigational medication is administered via **intravenous infusion**. The maximum daily dose is 600 mg, with a total maximum dose of 72.6 g over a treatment period of 84 days. Tiragolumab is a protein-based therapeutic developed by F. Hoffmann-La Roche Ltd, and it is not formulated for pediatric use.

A **placebo** is also utilized in the study, referred to as the Tiragolumab placebo. This placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know who is receiving the active treatment versus the placebo. The pharmaceutical form and administration details of the placebo are not specified.

**Pembrolizumab**, marketed as KEYTRUDA, is used as a comparator treatment in the trial. It is provided as a **25 mg/mL concentrate for solution for infusion** and is administered via **intravenous infusion**. The maximum daily dose is 200 mg, with a total maximum dose of 24.2 g over the same 84-day treatment period. Pembrolizumab is a protein-based therapeutic developed by Merck Sharp & Dohme B.V.

**Atezolizumab**, marketed as Tecentriq, is another comparator treatment in the study. It is available as a **1,200 mg concentrate for solution for infusion** and is also administered via **intravenous infusion**. The maximum daily dose is 1,200 mg, with a total maximum dose of 145.2 g over the 84-day treatment period. Atezolizumab is a protein-based therapeutic developed by Roche Registration GmbH.

The efficacy of the investigational treatment in this clinical trial will be assessed using several key endpoints. The primary endpoints include the **Investigator-Assessed Confirmed Objective Response Rate (ORR)** and **Progression-Free Survival (PFS)** for Phase 2, and **Overall Survival (OS)** for Phase 3. These endpoints will be evaluated according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), as assessed by investigators.

Secondary endpoints will further explore efficacy and include OS in Phase 2, PFS as determined by an independent review facility in Phase 3, and PFS and OS in patients with specific PD-L1 expression levels, as determined by central testing with the Ventana PD-L1 (SP263) assay in Phase 3. Additional secondary endpoints include PFS at 6 and 12 months, OS rate at 12 and 24 months, and the duration of response for patients with a confirmed objective response. Patient-reported outcomes will be measured using the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) and the Lung Cancer Module (QLQ-LC13) to assess time to confirmed deterioration in physical functioning and global health status/quality of life, as well as lung cancer symptoms such as cough, dyspnea, and chest pain.

Other secondary endpoints include the percentage of participants with adverse events, the frequency of patients' responses regarding treatment symptoms, serum concentrations of tiragolumab and atezolizumab, and the percentage of participants with anti-drug antibodies to tiragolumab and atezolizumab. These assessments will be conducted throughout the trial to provide a comprehensive evaluation of the treatment's efficacy and safety profile.