This is a global, multicenter, open-label study that aims to assess the efficacy and safety of zelenectide pevedotin in participants with previously treated NECTIN4-amplified advanced or metastatic non-small cell lung cancer (NSCLC) who have received at least one prior line of systemic therapy in the advanced/metastatic setting (see inclusion criteria below). The study will comprise of 2 cohorts: Cohort A (non-squamous NSCLC) and Cohort B (squamous NSCLC).

Key Inclusion Criteria

• Histologically or cytologically confirmed advanced or metastatic NSCLC.

  1. Cohort A: Histologically or cytologically confirmed non-squamous NSCLC.
  2. Cohort B: Histologically or cytologically confirmed squamous NSCLC.

• Confirmed NECTIN4 gene amplification by an analytically validated clinical trial assay.

• Participants must have received at least 1 prior line of systemic therapy in the advanced/metastatic setting.

  • Participants with no known actionable genomic alterations must have received both platinum based therapy and immunotherapy given either sequentially or in combination for advanced/metastatic NSCLC. Must not have received more than 3 prior lines of systemic therapy in the advanced/metastatic setting.
  • Participants with known actionable genomic alterations (eg, EGFR, ALK, BRAF, MET, ROS1, NTRK1/2/3, RET, etc.) are eligible provided they have received or are not candidates for available standard targeted therapy in the advanced/metastatic setting.

• Measurable disease as defined by RECIST v1.1.

• Adequate archival or fresh tumor tissue comprised of advanced or metastatic NSCLC should be available for submission to central laboratory, if not provided during prescreening.

• Life expectancy ≥ 12 weeks.

• Eastern Cooperative Oncology Group Performance Status of ≤ 1.

Key Exclusion Criteria

• Evidence of mixed small cell lung cancer (SCLC) and NSCLC histology.
• Prior treatment with monomethyl auristatin E (MMAE) (vedotin) based therapy.
• Known hypersensitivity or allergy to any of the ingredients of any of the study interventions, or to MMAE.
• Ongoing clinically significant toxicity (Grade ≥ 2) associated with prior treatment for NSCLC (including radiotherapy or surgery), with the exception of well-controlled immuno-oncology related endocrine disorders on supportive or replacement therapy, and alopecia. (Note: Immunosuppressive therapies should be stopped or tapered down to ≤10 mg/day prednisone or equivalent before first study drug administration.)
• Active keratitis or corneal ulcerations.
• Active or untreated central nervous system (CNS) metastases.
• Uncontrolled diabetes or hypertension.
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent draining procedures (monthly or more frequently).
• Active interstitial lung disease or pneumonitis requiring ongoing treatment with steroids (>10mg/day of prednisone or equivalent) or other immunosuppressive medications; or any prior history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids.
• History of another active malignancy, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other malignancies curatively treated with no evidence of disease for ≥3 years.
• Known requirement, while on study, for treatment with strong inhibitors or strong inducers of human cytochrome P450 3A ([cytochrome P450 3A] CYP3A) including herbal- or food-based inhibitors/inducers.
• Prior treatment with any systemic anticancer therapy within 28 days or 5 half-lives, whichever is shorter, prior to first dose of study treatment.

Note: Additional protocol defined Inclusion/Exclusion criteria apply