A Platform Study of Novel Immunotherapy Combinations in Participants With Previously Untreated, Advanced/Metastatic Non-Small-Cell Lung Cancer

This study will evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PDy) of novel immunotherapy combinations compared with immunotherapy monotherapy in participants with Programmed death ligand-1 (PD L-1) high (Tumor cells \[TC\]/ Tumor proportion score \[TPS\] \>= 50%), previously untreated, unresectable, locally advanced or metastatic non-small cell lung cancer (NSCLC). Drug name mentioned as Belrestotug, GSK4428859A, and EOS884448 are all interchangeable for the same compound. In the rest of the document, the drug will be referred to as Belrestotug.


Eligibility Criteria:
Inclusion Criteria:

* 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 (squamous or non squamous)
* No prior systemic therapy for their locally advanced or metastatic NSCLC
* Provides a fresh tumor tissue sample or archival sample collected within 2 years prior to screening
* PD-L1-high (TC/TPS \>= 50%) tumor
* Measurable disease based on RECIST 1.1, as determined by the investigator
* Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
* Adequate Baseline organ function
* Female participants of childbearing potential must use adequate contraception

Exclusion Criteria:

* Presence of Epidermal growth factor receptor (EGFR) mutations, Anaplastic lymphoma kinase (ALK) translocations, or other known genomic aberrations or oncogenic driver mutations for which a locally approved targeted therapy is available.
* Has NSCLC with a tumor that harbors any of the following molecular alterations: EGFR and /or ALK translocations mutations that are sensitive to available targeted inhibitor therapy, 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.
* Had major surgery within 4 weeks or lung radiation of \>30 Gy therapy within 6 months prior to the first dose of study intervention
* Received prior therapy with any immune checkpoint inhibitors
* 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 (clinical exceptions apply as per protocol)
* Symptomatic, untreated, or actively progressing, brain metastases or any leptomeningeal disease (regardless of symptomatology, treatment status, or stability)
* Autoimmune disease or syndrome that required systemic treatment within the past 2 years
* Receiving systemic steroid therapy \<= 3 days prior to first dose of study intervention or any form of immunosuppressive medication
* Received any live vaccine \<= 30 days prior to first dose of study intervention
* Any history of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis
* History or evidence of cardiac abnormalities
* Current unstable liver or biliary disease
* Severe infection within 4 weeks prior to the first dose of study intervention
* Positive for tuberculosis, human immunodeficiency virus (HIV) infection, hepatitis B surface antigen, or hepatitis C
* Has advanced, symptomatic, or visceral spread and is considered to be at imminent risk of life-threatening complications (including, but not limited to, massive uncontrolled effusions \[e.g., pleural, pericardial, peritoneal\])
* Is currently participating in or has participated in a study of an investigational therapy within 4 weeks prior to the first dose of study intervention
* Has a history of allogeneic tissue/stem cell transplant or solid organ transplant