Inclusion Criteria:

* Histologically- or cytologically-documented advanced (Stage III not eligible for resection or curative radiation) or metastatic non-squamous NSCLC with specific mutations.
* Documentation of locally assessed radiological disease progression while on or after last treatment based on Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1.
* Participants with genome mutations must have received 1 or 2 prior lines of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), including a third generation TKI for participants with a T790M mutation; and 1 platinum-based therapy after progression on or after EGFR TKI.
* Measurable disease per RECIST 1.1 as assessed by the local site investigator.
* Archival tumor tissue sample or newly obtained core, incisional, or excisional biopsy of a tumor lesion not previously irradiated has been provided
* Participants who have AEs due to previous anticancer therapies must have recovered to Grade ≤1 or baseline.
* Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received HBV antiviral therapy for at least 4 weeks, and have undetectable HBV viral load prior to randomization.
* Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy.
* Have an ECOG performance status of 0 or 1 within 3 days before randomization.

Exclusion Criteria:

* Has predominantly squamous cell histology NSCLC.
* Has mixed tumor(s) with small cell elements.
* Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease.
* Has Grade ≥2 peripheral neuropathy.
* Has history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or corneal disease that prevents/delays corneal healing.
* Has uncontrolled, significant cardiovascular disease or cerebrovascular disease.
* Has an EGFR T790M mutation and has not received a third generation EGFR TKI (eg, osimertinib).
* Received prior systemic anticancer therapy including investigational agents within 4 weeks or 5 half-lives (whichever is shorter) before randomization.
* Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention.
* Completed palliative radiotherapy within 7 days of the first dose. Participants must have recovered from all radiation-related toxicities and not require corticosteroids.
* Received radiation therapy to the lung that is \>30 Gy within 6 months of the first dose of study intervention.
* Received prior treatment with a trophoblast cell-surface antigen 2 (TROP2)-targeted antibody-drug conjugate (ADC).
* Received prior treatment with a topoisomerase I-containing ADC.
* Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
* Known additional malignancy that is progressing or has required active treatment within the past 3 years.
* Active infection requiring systemic therapy.
* History of noninfectious pneumonitis/ILD that required steroids or has current pneumonitis/ILD.
* Has known active central nervous system metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are clinically stable for at least 2 weeks, and are off steroids 3 days prior to dosing with study medication.
* HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease.
* Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 11/25/2024. Questions regarding updates should be directed to the study team contact.