A Study to Assess Adverse Events, Change in Disease Activity of Intravenous Telisotuzumab Adizutecan in Combination With Osimertinib as First-Line Treatment in Adult Participants With Locally Advanced Unresectable or Metastatic EGFR-Mutated Non-Squamous Non-Small Cell Lung Cancer

Inclusion Criteria

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 during the screening period and prior to dosing of study treatment on Cycle 1 Day 1.
• Must consent to provide recently obtained formalin-fixed, paraffin-embedded (FFPE) tumor tissue (ideally collected during or after locally advanced or metastatic diagnosis) or archived tissue during screening for c-Met immunohistochemistry (IHC) testing and study stratification. c-Met IHC results are required prior to randomization.
• Must have at least one non-irradiated measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. If only one measurable lesion exists, it is acceptable to be used (as a target lesion) as long as it has not been previously irradiated and as long as it has not been biopsied within 14 days of the baseline tumor assessment scans.
• Any toxicities from prior systemic anti-cancer therapy must have resolved to common terminology criteria for adverse events (CTCAE) Grade 1 or baseline level (except for alopecia [any grade] or Grade <= 2 peripheral neuropathy).
• Should not have any major, life-threatening conditions and life expectancy as determined by the investigator should be at least 3 months.
• No prior estimated glomerular filtration rate (EGFR) tyrosine kinase inhibitor (TKI) in the locally advanced and/or metastatic setting (except for when it is allowed on study prior to C1D1). Participants treated with prior EGFR TKI in the adjuvant setting are allowed to enroll provided that >= 126 months (since last dose of e.g., adjuvant osimertinib) have passed before Cycle 1, Day 1.
• Diagnosis of histologically or cytologically confirmed metastatic/locally advanced non-squamous NSCLC with documented classical EGFR mutation (Exon 19 Del or Exon 21 L858R) either alone or in combination with other EGFR mutations as detected by an Food and Drug Administration (FDA)-approved or other validated test in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory (sites in the US) or an accredited Laboratory (sites outside of the US) in accordance with site standard of care. A copy of the test report documenting the EGFR mutation must be available in the participant records.

Exclusion Criteria

• History of interstitial lung disease (ILD), pneumonitis that required treatment with systemic steroids, or any evidence of active ILD/pneumonitis on screening chest computed tomography (CT) scan.
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis.
• Participants has leptomeningeal disease, or participant has spinal cord compression not definitively treated with surgery or radiation.
• History of any malignancy other than disease under study except for
• Malignancy treated with curative intent and with no known active disease present for 2 years before the first dose of study treatment and felt to be at low risk for recurrence by investigator.
• Successfully treated nonmelanoma skin cancer.
• Localized carcinoma in situ of the cervix.
• Breast Cancer; lobular carcinoma in situ or ductal carcinoma in situ that is considered completely cured.