The goal of this clinical trial is to evaluate the safety and tolerability profile of dostarlimab in combination with belrestotug when compared with pembrolizumab and placebo in participants with previously untreated, unresectable, locally advanced or metastatic PD-L1 high NSCLC.

Inclusion Criteria:

• Has a histologically or cytologically confirmed diagnosis of locally advanced, unresectable NSCLC (not eligible for curative surgery and/or definitive radiotherapy with or without chemotherapy), or Metastatic NSCLC
• Has not received prior systemic therapy for their locally advanced or metastatic NSCLC.
• Provides a fresh tumor tissue sample obtained at the time of or after the initial diagnosis of locally advanced or metastatic NSCLC.
• Has a PD-L1-high (Tumor cells [TC] ≥50%) tumor
• Has measurable disease (at least 1 target lesion) based on RECIST 1.1
• Has an Eastern Cooperative Oncology Group (ECOG) Performance status (PS) score of 0 or 1.
• Has adequate organ function

Exclusion Criteria:

• Has NSCLC with a tumor that harbors any of the following molecular alterations:

  1. Epidermal growth factor receptor (EGFR) mutations that are sensitive to available targeted inhibitor therapy
  2. Anaplastic lymphoma kinase (ALK) translocations that are sensitive to available targeted inhibitor therapy
  3. Any other known genomic aberrations or oncogenic driver mutations for which a locally approved targeted therapy is available for first line treatment of locally advanced or metastatic NSCLC.

• Has had surgery within 4 weeks of the first dose of study intervention and has not recovered from AEs (i.e., has any ongoing surgery-related events ≥ Grade 1)/complications related to surgery or has received lung radiation therapy of >30 gray (Gy) within 6 months

• Has received prior therapy with any immune checkpoint inhibitors, including antibodies or drugs targeting PD-(L)1, Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and ITIM domain (TIGIT), or other checkpoint pathways.

• Has never smoked, defined as smoking <100 tobacco cigarettes in a lifetime.

• Has an invasive malignancy or history of invasive malignancy other than the disease under study within the last 5 years, with the exception of those with a negligible risk of metastasis or death and/or treated with expected curative outcome.

• Has symptomatic, untreated, or actively progressin g brain metastases or leptomeningeal disease

• Has autoimmune disease or syndrome (current or history thereof) that required systemic treatment within the past 2 years.

• Has received any live vaccine within 30 days prior to first dose of study intervention.

• Has any history of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis.

• Has symptomatic ascites, pleural effusion, or pericardial effusion.

• Has active inflammatory bowel disease

• Has a history of significant acute or chronic cardiac diagnosis requiring intervention/treatment in the last 6 months.

• Has severe infection or complication thereof 4 weeks prior to randomisation including active tuberculosis.

• Has a history of allogeneic tissue/stem cell transplant or solid organ transplant.

Qualified researchers may request access to anonymized individual patient-level data (IPD) and related study documents of the eligible studies via the Data Sharing Portal. Details on GSK's data sharing criteria can be found at: https://www.gsk.com/en-gb/innovation/trials/data-transparency/

Anonymized IPD will be made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or terminated asset(s) across all indications.

Anonymized IPD is shared with researchers whose proposals are approved by an Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension may be granted, when justified, for up to 6 months.