A Study of JNJ-86974680 in Participants With Advanced Non-small Cell Lung Cancer

Eligibility Criteria

• * Individuals with histologically or cytologically confirmed stage IIIB-IV non-small cell lung cancer (NSCLC)
• * Must have been treated with (a) anti-programmed death protein 1 (anti-PD-1) or programmed cell death ligand 1 (PD-L1) therapy and (b) platinum-based chemotherapy and have progressed. Individuals who cannot tolerate or have previously refused platinum-based chemotherapy are eligible to enroll based on progression after anti-PD-1/PD-L1 therapy alone
• * Can have a prior or concurrent second malignancy (other than the disease under study), which due to natural history or treatment is unlikely to interfere with any study endpoints of safety or the efficacy of the study treatment(s)
• * Have an eastern cooperative oncology group (ECOG) performance status of 0 or 1
• * Adequate liver function:
• 1. Participants with no underlying hepatic metastases are eligible if they have: i) aspartate aminotransferase (AST) less than (\<)3 x upper limit of normal (ULN), ii) alanine aminotransferase (ALT) \<3 x ULN, and iii) Total bilirubin \<1.5 x ULN
• 2. Participants with known hepatic metastases are eligible if they have: i) AST \<5 x ULN, ii) ALT \<5 x ULN, and iii) Total bilirubin \<3 x ULN
• * Part 1: NSCLC with a known actionable genetic mutation (for example, epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 \[ROS1\], v-raf murine sarcoma viral oncogene homolog B1 \[BRAF\]) must have received all approved targeted therapies and have progressed. Participants with unknown mutation status due to a failed testing status or lack of access to testing are allowed in the study
• * Part 2: Participants must have at least 3 lesions on baseline scan, one of which is evaluable as a target lesion for response assessment per RECIST Version 1.1
• * Part 2: Agree to submit tumor samples prior to study treatment which can be an archival tumor tissue sample obtained within 3 months prior to start of treatment and without any therapy for NSCLC being administered within these 3 months, or newly obtained core or incisional biopsy of a tumor lesion during screening
• * Active disease involvement of the central nervous system with the exception of definitively locally treated brain metastases that are clinically stable
• * Active autoimmune disease that requires systemic immunosuppressive medications (for example, chronic corticosteroid, methotrexate, or tacrolimus) within the 12 months prior to signing consent
• * Active infection or condition that requires treatment with systemic anti-infective agents (for example, antibiotics, antifungal or antivirals) within 7 days prior to the first dose of study treatment or chronic use of anti-infective agents
• * History of solid organ or hematologic stem cell transplantation
• * Part 2: NSCLC with an actionable genetic mutation for which an approved therapy is available: EGFR, ALK, ROS1, or BRAF. Confirmation of the absence of actionable mutations is required