Participants must meet all of the following criteria to be eligible for inclusion in this study. - Sign and date the tissue informed consent form (ICF) and the main ICF, prior to the start of any study-specific qualification procedures. - Male or female participants aged ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is >18 years old). - Histologically or cytologically documented locally advanced or metastatic NSCLC not amenable to curative surgery or radiation. - Documentation of radiological disease progression while on/after receiving most recent treatment regimen for locally advanced or metastatic disease. Participants must have received both of the following: - Prior treatment with osimertinib. Participants receiving an EGFR TKI at the time of signing informed consent should continue to take the EGFR TKI until 5 days prior to Cycle 1 Day 1. Participants in South Korea known to harbor a clinically actionable genomic alteration in addition to EGFR mutation (e.g., anaplastic lymphoma kinase [ALK] or ROS1 protocol oncogene 1 [ROS1] fusion) for which treatment is available must have also received prior treatment with at least 1 approved genotype-directed therapy, unless unable (i.e., if contraindicated). No new testing for these genomic alterations (e.g., ALK or ROS1 fusion) is required for Screening. - Systemic therapy with at least 1 platinum-based chemotherapy regimen. - Documentation of an EGFR-activating mutation detected from tumor tissue or blood sample: exon 19 deletion or L858R. - At least 1 measurable lesion confirmed by BICR as per RECIST v1.1 - Consented and willing to provide required tumor tissue of sufficient quantity and of adequate tumor tissue content. Required tumor tissue can be provided as either: - Pretreatment tumor biopsy from at least 1 lesion not previously irradiated and amenable to core biopsy OR - Archival tumor tissue collected from a biopsy performed within 3 months prior to signing of the tissue consent and since progression while on or after treatment with the most recent cancer therapy regimen. - Eastern Cooperative Oncology Group Performance Standard of 0 or 1 at Screening. - Has adequate bone marrow reserve and organ function based on local laboratory data within 14 days prior to Cycle 1 Day 1: - Platelet count : ≥100,000/mm^3 or ≥100 × 10^9/L (platelet transfusions are not allowed up to 14 days prior to Cycle 1 Day 1 to meet eligibility) - Hemoglobin: ≥9.0 g/dL (transfusion and/or growth factor support is allowed) - Absolute neutrophil count: ≥1500/mm^3 or ≥1.5 × 10^9/L - Serum creatinine (SCr) or creatinine clearance (CrCl): SCr ≤1.5 × upper limit of normal (ULN), OR CrCl ≥30 mL/min as calculated using the Cockcroft-Gault equation or measured CrCl - Aspartate aminotransferase/alanine aminotransferase: ≤3 × ULN (if liver metastases are present, ≤5 × ULN) - Total bilirubin: ≤1.5 × ULN if no liver metastases (<3 × ULN in the presence of documented Gilbert's syndrome [unconjugated hyperbilirubinemia] or liver metastases) - Serum albumin: ≥2.5 g/dL - Prothrombin time (PT) or PT-International normalized ratio (INR) and activated partial thromboplastin time (aPTT)/PTT: ≤1.5 × ULN, except for subjects on coumarin-derivative anticoagulants or other similar anticoagulant therapy, who must have PT-INR within therapeutic range as deemed appropriate by the Investigator
Participants meeting any exclusion criteria for this study will be excluded from this study. - Any previous histologic or cytologic evidence of small cell OR combined small cell/non-small cell disease in the archival tumor tissue or pretreatment tumor biopsy. - Any history of interstitial lung disease (including pulmonary fibrosis or radiation pneumonitis), has current interstitial lung disease (ILD), or is suspected to have such disease by imaging during screening. - Clinically severe respiratory compromise (based on Investigator's assessment) resulting from intercurrent pulmonary illnesses including, but not limited to: - Any underlying pulmonary disorder (eg, pulmonary emboli within 3 months prior to the study enrollment, severe asthma, severe chronic obstructive pulmonary disease [COPD]), restrictive lung disease, pleural effusion); - Any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis); OR prior complete pneumonectomy. - Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or equivalent anti-inflammatory or any form of immunosuppressive therapy prior to enrollment. Participants who require use of bronchodilators, inhaled or topical steroids, or local steroid injections may be included in the study. - Evidence of any leptomeningeal disease. - Evidence of clinically active spinal cord compression or brain metastases. - Inadequate washout period prior to Cycle 1 Day 1, defined as: - Whole brain radiation therapy <14 days or stereotactic brain radiation therapy <7 days; - Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) from a previous cancer treatment regimen or clinical study (other than EGFR TKI), <14 days or 5 half-lives, whichever is longer; - Monoclonal antibodies, other than immune checkpoint inhibitors, such as bevacizumab (anti-VEGF) and cetuximab (anti-EGFR) <28 days; - Immune checkpoint inhibitor therapy <21 days; - Major surgery (excluding placement of vascular access) <28 days; - Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation <28 days or palliative radiation therapy <14 days; or - Chloroquine or hydroxychloroquine <14 days. - Prior treatment with an anti-human epidermal growth factor receptor 3 (HER3) antibody or single-agent topoisomerase I inhibitor. - Prior treatment with an antibody drug conjugate (ADC) that consists of any topoisomerase I inhibitor - Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0, Grade ≤1 or baseline. Participants with chronic Grade 2 toxicities may be eligible at the discretion of the Investigator after consultation with the Sponsor Medical Monitor or designee. - Has history of other active malignancy within 3 years prior to enrollment, except: - Adequately treated non-melanoma skin cancer; - Superficial bladder tumors (Ta, Tis, T1); - Adequately treated intraepithelial carcinoma of the cervix uteri; - Low risk non-metastatic prostate cancer (with Gleason score <7, and following local treatment or ongoing active surveillance); - Any other curatively treated in situ disease. - Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day 1 - Active hepatitis B and/or hepatitis C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1 Day 1. - Participant with any human immunodeficiency virus (HIV) infection.