Overview

The purpose of this study is to assess the safety and efficacy of multiple study interventions including novel-novel combinations or novel agents in combination with standard therapy for the treatment of metastatic NSCLC.

Eligibility

Inclusion Criteria (both sub study 1 and sub study 2):

• Participants with confirmed squamous or non-squamous NSCLC with a current Stage IV mNSCLC.
• Provision of acceptable archival tumour tissue (or fresh tumour tissue biopsy if archival tumour tissue is not available and if clinically feasible) is mandatory at screening.
• Measurable disease as defined by at least one lesion that can be accurately measured at baseline as ≥ 10 mm at the longest diameter.
• Minimum life expectancy of 12 weeks in the opinion of the investigator.
• Adequate organ and marrow function.
• Contraceptive use by male or female participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Adequate organ and marrow function and minimum body weight of 30 Kg.
• PD-L1 tumour proportion score (TPS) ≥ 1% (per local report).

Inclusion Criteria for Sub Study 2:

• Adequate coagulation and urinalysis.

Exclusion Criteria (both sub study 1 and sub study 2):

• Participants with epidermal growth factor receptor mutations, anaplastic lymphoma receptor fusions or any other known genomic alteration for which targeted therapy is approved in the first line per local standard of care.
• Any severe or uncontrolled systemic diseases, including uncontrolled hypertension, and active bleeding diseases, ongoing or active known infection; serious chronic gastrointestinal conditions associated with diarrhoea, active non-infectious skin disease or substance abuse.
• Has had a prior stem cell, bone marrow, allogenic tissue, or solid organ transplant.
• Has an active autoimmune disease that has required systemic treatment in the past 2 years.
• History of clinically significant arrhythmia, cardiomyopathy of any aetiology or symptomatic congestive heart failure.
• History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥ 2 years before the first dose of study intervention or presence of small cell and neuroendocrine histology components.
• Unresolved toxicities of Grade ≥ 2 from prior anti-cancer therapy, spinal cord compression or symptomatic brain metastases.
• Any prior systemic therapy received for advanced or mNSCLC or treatment with any other anti-cancer agents or immunosuppressive medication.
• Palliative radiotherapy with a limited field of radiation within 2 weeks or with a wide field of radiation or to more than 30% of the bone marrow within 4 weeks, prior to the first dose of study intervention.
• Active tuberculosis infection.
• Any prior exposure to an anti-T-cell immunoreceptor with Ig and Immunoreceptor Tyrosine-based Inhibition Motif (ITIM) domains (TIGIT) therapy or any other anticancer therapy targeting immune-regulatory receptors or mechanisms.
• Any prior systemic treatment with an immune-oncology agent, including but not limited to anti-PD-1, anti-PD-L1, anti-Cytotoxic T-lymphocyte Associated Antigen 4 (CTLA-4).

Exclusion Criteria for Sub Study 1:

• Has a known history of human immunodeficiency virus (HIV) infection.
• Has either a known history of Hepatitis B virus (HBV) or has active Hepatitis C virus (HCV).
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis/interstitial lung disease.
• Any concomitant medication known to be associated with Torsades de pointes.

Exclusion Criteria for Sub Study 2:

• Known active hepatitis A.
• Acute hepatitis B infection (anti-hepatitis B core antibody [HBc] immunoglobulin M [IgM] positive) or chronic hepatitis B infection with HBV DNA ≥ 2000 IU/mL.
• Active hepatitis C infection (anti-HCV positive with HCV RNA detectable) or antiHCV positive with HCV RNA undetectable for less than 12 weeks following treatment for HCV.
• Known HIV infection that is not well controlled.
• Evidence of Grade ≥ 1 central nervous system (CNS) haemorrhage.
• Uncontrolled arterial hypertension ≥ 150 and/or ≥ 100 mm Hg.
• Radiographic evidence of major blood vessel invasion or encasement by cancer, intratumour cavitation or direct tumour penetration into the trachea or bronchus.
• Has experienced any arterial thrombotic event, a Grade ≥ 3 bleeding event or has gross haemoptysis.
• Has significant bleeding disorders, serious or nonhealing wound, ulcer or clinically relevant congestive heart failure.
• Has a bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection.
• Under chronic therapy with antiplatelet agents.
• Any prior exposure to anti-vascular endothelial growth factor (VEGF) therapy.
• Known allergy or hypersensitivity to rilvegostomig or any of the excipients of rilvegostomig, cisplatin, carboplatin, paclitaxel or nab-paclitaxel or pemetrexed or ramucirumab.