A Phase III, Open-Label, Randomized Study of Atezolizumab and Tiragolumab Compared with Durvalumab in Patients with Locally Advanced, Unresectable Stage III Non-Small Cell Lung Cancer who have not Progressed after Concurrent Platinum-Based Chemoradiation (SKYSCRAPER-03)

The primary objective of this study is to evaluate the **efficacy** of tiragolumab plus atezolizumab compared with durvalumab in patients with locally advanced, unresectable Stage III non-small cell lung cancer (NSCLC) who have not progressed after concurrent platinum-based chemoradiation. This evaluation is based on progression-free survival (PFS) as assessed by an independent review facility (IRF). The clinical relevance of this objective lies in determining whether the combination of tiragolumab and atezolizumab can provide a superior therapeutic benefit in terms of delaying disease progression compared to the current standard treatment with durvalumab.

The secondary objectives include:

• Evaluating the efficacy of tiragolumab plus atezolizumab compared with durvalumab based on overall survival (OS), PFS as assessed by the investigator, confirmed objective response rate (ORR) as assessed by an IRF and investigator, and duration of response (DOR) as assessed by an IRF and investigator.
• Assessing the quality of life of patients treated with tiragolumab plus atezolizumab compared with durvalumab, based on time to confirmed deterioration (TTCD).
• Evaluating the efficacy of tiragolumab plus atezolizumab compared with durvalumab based on PFS rate at 12, 18, and 24 months, OS rate at 12, 24, 36, and 48 months, and time to distant metastasis (TTDM).
• Assessing the safety and tolerability of tiragolumab plus atezolizumab compared with durvalumab.

The clinical trial involves a total of **567 participants** diagnosed with **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 Performance Status of 0 or 1, and a histologically or cytologically documented NSCLC with locally advanced unresectable Stage III disease. The trial includes individuals who have completed at least two prior cycles of platinum-based chemotherapy administered concurrently with radiotherapy, with no progression during or following this treatment. 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 were not specified in the available data.

The clinical trial is designed as a **randomized**, open-label, controlled study to evaluate the efficacy of **tiragolumab** plus **atezolizumab** compared with **durvalumab** in patients with locally advanced, unresectable Stage III **non-small cell lung cancer** (NSCLC) who have not progressed after concurrent platinum-based chemoradiation. The trial aims to assess progression-free survival (PFS) as the primary endpoint, with secondary endpoints including overall survival, objective response rate, and duration of response, among others. The study is expected to run until December 31, 2027, with recruitment having commenced on October 12, 2020.

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 Performance Status of 0 or 1, documented NSCLC, and completion of at least two prior cycles of platinum-based chemotherapy with radiotherapy. Following randomization, participants will receive treatment via **IV infusion** and will be monitored through regular follow-up visits to assess treatment efficacy and safety. The end-of-study visit will conclude the participant's involvement, which is anticipated to last up to 52 weeks, unless early termination is warranted due to disease progression, adverse events, or withdrawal of consent.

Key elements of the research methodology include the use of independent review facilities to assess PFS and other endpoints, ensuring objective evaluation. The trial's design incorporates a comprehensive set of inclusion and exclusion criteria to select a suitable patient population, and the study's endpoints are aligned with established criteria such as the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Participants' involvement may be terminated early if they experience significant adverse events or if the disease progresses, as determined by the independent review facility.

The clinical trial involves the administration of **Tiragolumab**, an investigational medication formulated as a **concentrate for solution for infusion**. The active substance, tiragolumab, is a protein-based compound developed by F. Hoffmann-La Roche Ltd. The maximum daily dose is 840 mg, with a total dose not exceeding 10.92 grams over a treatment period of up to 52 weeks. The medication is administered via **intravenous infusion**. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

**Tecentriq** (atezolizumab) is another investigational medication used in this study. It is provided as an 840 mg concentrate for solution for infusion, with the active substance being atezolizumab, a protein-based compound. The maximum daily dose is 1680 mg, with a total dose limit of 21.84 grams over a 52-week period. The administration route is also via intravenous infusion. The product is manufactured by Roche Registration GmbH, and secondary packaging and labeling are adapted for clinical trial use.

**IMFINZI** (durvalumab) serves as the comparator treatment in this trial. It is available as a 50 mg/mL concentrate for solution for infusion, with the active substance durvalumab, a protein-based compound. The maximum daily dose is 1500 mg, with a total dose not exceeding 19.5 grams over the course of 52 weeks. The administration is conducted through intravenous infusion. The product is manufactured by AstraZeneca AB, with modifications in secondary packaging and labeling for trial purposes.

The efficacy of the clinical trial will be assessed primarily through **progression-free survival (PFS)**, as evaluated by an independent review facility (IRF). PFS is defined as the time from randomization to the first occurrence of disease progression, according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), or death from any cause, whichever occurs first. This assessment will be conducted for both the programmed death ligand 1 positive analysis set (PPAS) and the full analysis set (FAS).

Secondary efficacy endpoints include overall survival (OS), PFS as assessed by the investigator, confirmed objective response rate (ORR), duration of response (DOR), time to confirmed deterioration (TTCD), PFS rate at 12, 18, and 24 months, OS rate at 12, 24, 36, and 48 months, and time to deterioration of metastasis (TTDM). These parameters will be evaluated in both the FAS and PPAS. Additionally, the incidence and severity of adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0).