This is a Phase 1b/2 study evaluating the anti-PD1 antibody, cemiplimab, in combination with either S095018 (anti-TIM3 antibody), S095024 (anti-CD73 antibody), or S095029 (anti-NKG2A antibody) in adult participants with previously untreated advanced/metastatic non-small cell lung cancer (NSCLC) with high PD-L1 expression. The study includes two parts: part A, the combination-therapy safety lead-in phase to determine the recommended dose for expansion (RDE) for S095018, S095024, and S095029 in combination with cemiplimab and part B, the randomized dose expansion phase to assess the efficacy of S095018, S095024, or S095029 in combination with cemiplimab. Study treatment will be administered for a maximum of 108 weeks, or until confirmed disease progression per iRECIST and/ or until meeting other treatment discontinuation criteria.

Inclusion Criteria:

• Adult patient aged ≥ 18 years
• Written informed consent
• Histologically (squamous or non-squamous) or cytologically documented locally advanced NSCLC not eligible for surgical resection and/or definitive chemoradiation, or metastatic NSCLC
• No prior systemic treatment for locally advanced or metastatic NSCLC
• High tumor cell PD-L1 expression [Tumor Proportion Score (TPS) ≥50%] based on documented status as determined by an approved test
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Measurable disease as determined by RECIST v1.1

Exclusion Criteria:

• Tumors harboring driver mutations/genetic aberrations for which targeted therapies are approved as frontline treatment (e.g. EGFR mutation, ALK fusion oncogene, ROS1 aberrations)
• Prior immune checkpoint inhibitor therapy
• Active brain metastases
• Participants with active and uncontrolled hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
• Uncontrolled HIV infection. Participants with HIV who have controlled infection (undetectable viral load and CD4 count above 350 either spontaneously or on a stable antiviral regimen) are allowed to enroll
• Active, known or suspected autoimmune disease or immune deficiency
• History of hypersensitivity reactions to any ingredient of the investigational medicinal product (IMP) and other monoclonal antibody (mAbs) and/or their excipients
• History of interstitial lung disease, idiopathic pulmonary fibrosis, drug-induced pneumonitis, idiopathic pneumonitis or active pneumonitis ≥ grade 2
• History of inflammatory bowel disease or colitis ≥ grade 2
• History of hemophagocytic lymphohistiocytosis.
• Systemic chronic steroid therapy (>10mg/d prednisone or equivalent)
• Clinically significant infection, as assessed by the investigator
• Pregnant or breast-feeding (lactating) women
• Participants with a history of allogeneic organ transplantation (e.g., stem cell or solid organ transplant)
• Any medical condition that would in the investigator's judgement prevent the participant's participation in the clinical study

Qualified scientific and medical researchers can request access to anonymized patient-level and study-level clinical trial data.

Access can be requested for all interventional clinical studies:

• used for Marketing Authorization (MA) of medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US).
• where Servier is the Marketing Authorization Holder (MAH). The date of the first MA of the new medicine (or the new indication) in one of the EEA Member States will be considered for this scope.

In addition, access can be requested for all interventional clinical studies in patients:

• sponsored by Servier
• with a first patient enrolled as of 1 January 2004 onwards
• for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for which development has been terminated before any Marketing authorization (MA) approval.

After Marketing Authorization in EEA or US if the study is used for the approval.

Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.