A Phase III, Randomized, Double-Blinded, Placebo-Controlled Study of Tiragolumab, an Anti-Tigit Antibody, in Combination with Atezolizumab Compared with Placebo in Combination with Atezolizumab in Patients With Previously Untreated Locally Advanced Unresectable or Metastatic PD-L1-Selected Non-Small Cell Lung Cancer

The primary objective of this study is to evaluate the **efficacy** of tiragolumab in combination with atezolizumab compared to placebo plus atezolizumab in patients with previously untreated locally advanced unresectable or metastatic PD-L1-selected non-small cell lung cancer (NSCLC). This is assessed based on progression-free survival (PFS) and overall survival (OS) in the primary analysis population. The clinical relevance of this objective lies in determining whether the addition of tiragolumab to atezolizumab can improve survival outcomes in this patient population, potentially offering a more effective treatment option.

Secondary objectives include: - Evaluating the efficacy of tiragolumab plus atezolizumab compared with placebo plus atezolizumab based on investigator-assessed PFS and OS in the secondary analysis population, confirmed objective response rate (ORR), duration of response (DOR), PFS rate at 6 and 12 months, OS rate at 12 and 24 months, time to confirmed deterioration, and global health status/quality of life. - Assessing the safety and tolerability of tiragolumab plus atezolizumab compared with placebo plus atezolizumab. - Characterizing the pharmacokinetics of tiragolumab and atezolizumab. - Evaluating the immune response to tiragolumab plus atezolizumab. - Assessing the impact of health status utility scores in patients treated with tiragolumab plus atezolizumab compared with placebo plus atezolizumab.

The clinical trial involves a total of **428 participants** diagnosed with **non-small cell lung cancer (NSCLC)**. The study population includes both male and female subjects, aged 18 years and older, with an Eastern Cooperative Oncology Group Performance Status of 0 or 1. Participants were selected based on specific criteria, including histologically or cytologically documented locally advanced or recurrent NSCLC not eligible for curative surgery and/or definitive radiotherapy, or metastatic Stage IV non-squamous or squamous NSCLC, with no prior systemic treatment for metastatic NSCLC. Tumor PD-L1 expression was required, as determined by specific assays. The trial population includes individuals with measurable disease per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), and adequate hematologic and end-organ function. The study also considers vulnerable populations, ensuring a comprehensive evaluation of the treatment's efficacy across diverse groups. Lifestyle factors such as diet, physical activity, and habits were not specified in the available data.

The clinical trial is a **Phase III**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy of **tiragolumab** in combination with **atezolizumab** compared to placebo in combination with atezolizumab in patients with previously untreated locally advanced unresectable or metastatic **non-small cell lung cancer (NSCLC)**. The primary objectives are to assess progression-free survival (PFS) and overall survival (OS) in the primary analysis population. The trial is expected to run from July 2020 to February 2025, with a maximum treatment period of 59 weeks for participants.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and tumor characteristics. 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 pharmacokinetics, with assessments including imaging studies and laboratory tests. The end-of-study visit will occur after the final treatment cycle or upon early termination.

The expected length of participant involvement is approximately 59 weeks, contingent upon individual response and tolerability. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The trial will adhere to rigorous standards to ensure the integrity of data and the safety of participants, with adverse events monitored and graded according to established criteria.

The clinical trial involves the administration of **Tecentriq** (atezolizumab), a **concentrate for solution for infusion**. This experimental medication is provided in a pharmaceutical form suitable for intravenous infusion. The maximum daily dose of Tecentriq is 1200 mg, with a total maximum dose of 102,000 mg over a treatment period of up to 59 weeks. The administration of Tecentriq is conducted via intravenous infusion, and the medication is supplied by Roche Registration GmbH. The active substance, atezolizumab, is a protein of non-chemical origin, specifically classified under the ATC code L01FF05. The secondary packaging and labeling have been modified for clinical trial use.

Another experimental medication used in the trial is **Tiragolumab**, also a **concentrate for solution for infusion**. This medication is administered intravenously, with a maximum daily dose of 600 mg and a total maximum dose of 51,000 mg over a treatment period of up to 59 weeks. Tiragolumab is supplied by F. Hoffmann-La Roche Ltd, and its active substance is a protein of non-chemical origin. The sponsor product code for Tiragolumab is RO 709-2284/F03-01.

The study also includes a **placebo** for Tiragolumab, referred to as Placebo Tiragolumab. This placebo is used as a comparator treatment in the trial. The placebo does not contain any active substance and is intended to match the experimental medication in appearance and administration route to maintain the double-blind nature of the study. The placebo is administered in a manner consistent with the experimental treatments to ensure the integrity of the trial's design.

The efficacy of the clinical trial will be assessed by evaluating the **progression-free survival (PFS)** and **overall survival (OS)** in the primary analysis population. These primary endpoints will be determined by the investigator according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). Secondary endpoints include investigator-assessed PFS and OS in the secondary analysis population, confirmed objective response rate (ORR), duration of response (DOR) for patients with confirmed ORR, PFS rate at 6 and 12 months, OS rate at 12 and 24 months, and time to confirmed deterioration (TTCD) in patient-reported physical functioning and global health status/quality of life. These will be measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer.

Additional secondary endpoints involve the incidence and severity of adverse events, with severity determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0, and the severity for cytokine release syndrome (CRS) will be determined according to the ASTCT CRS consensus grading scale. Serum concentrations of tiragolumab and atezolizumab will be measured at specified timepoints, along with the prevalence and incidence of anti-drug antibodies (ADAs) to both tiragolumab and atezolizumab. Changes in EQ-5D-5L index-based and visual analog scale (VAS) scores will also be assessed at specified timepoints during the study, including post-progression.