This clinical trial is studying nonsquamous non-small cell lung cancer (NSCLC). Participants in this study must have cancer that has spread through their body or can't be removed with surgery. Participants in this study must have been treated with no more than a platinum-based chemotherapy and an anti-PD-(L)1 drug. Participants with tumors that have certain treatable genomic alterations must have had at least 1 drug for that genomic alteration, in addition to platinum-based chemotherapy.

This clinical trial uses an experimental drug called sigvotatug vedotin, which is a type of antibody drug conjugate or ADC. ADCs are designed to stick to cancer cells and kill them. This clinical trial also uses a drug called docetaxel. Docetaxel is an anticancer drug that has been approved to treat non-small cell lung cancer. It is usually given to patients who previously received another anticancer treatment. In this study, one group of participants will get sigvotatug vedotin on Days 1 and 15 during each 28-day-cycle. A second group of participants will get docetaxel on Day 1 during each 21-day cycle.

This study is being done to see if sigvotatug vedotin works better than docetaxel to treat participants with NSCLC. This study will also test what side effects happen when participants take these drugs. A side effect is anything a drug does to the body besides treating the disease.

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of locally advanced, unresectable (Stage IIIB, IIIC), or metastatic Stage IV (M1a, M1b, or M1c) NSCLC American Joint Committee on Cancer (AJCC) Staging Manual, Version 8.0, and the Union for International Cancer Control (UICC) Staging System (Eighth edition).

• Participants must have NSCLC with nonsquamous histology

  • Tumors with squamous, or predominantly squamous histology are excluded.
  • Tumors with small cell elements are excluded.

• Participants who have NSCLC with known actionable genomic alteration (AGAs) are permitted

• Participants must have received the following prior therapies and progressed during or relapsed after receiving their most recent prior therapy:

  • Participants with no known AGAs must fulfill 1 of the following conditions:

    • Received a platinum-based combination therapy for the treatment of metastatic or recurrent disease and a PD-(L)1 monoclonal antibody (concurrently or sequentially with platinum-based chemotherapy), unless contraindicated.
    • Experienced disease progression within 6 months of the last dose of platinum-based chemotherapy in the adjuvant or neoadjuvant setting and received a PD-(L)1 monoclonal antibody at any time during the course of treatment.

  • Participants with known AGAs must fulfill the following conditions:

    • Must have received at least 1 relevant AGA targeted therapy and in the opinion of the investigator, additional AGA targeted therapy is not in the best interest of the participant.
    • Received a platinum-based combination therapy for the treatment of metastatic or recurrent disease, or experienced disease progression within 6 months of the last dose of platinum-based chemotherapy in the adjuvant or neoadjuvant setting
    • May have received up to 1 PD-(L)1 monoclonal antibody (concurrently or sequentially with platinum-based chemotherapy).

• Measurable disease based on RECIST v1.1

• Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, with adequate baseline hematologic, hepatic, and renal function and measurable disease according to RECIST v1.1

Exclusion Criteria:

• Life expectancy of less than (<) 3 months

• Known allergies/hypersensitivity/intolerance to or contraindication of taxanes, docetaxel, or any excipient contained in the drug formulation of sigvotatug vedotin

• History of another malignancy within 3 years before Cycle 1 Day 1, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death

• Participants with any of the following respiratory conditions:

  • Evidence of noninfectious interstitial lung disease (ILD) or pneumonitis that:

    • Was previous diagnosed and required systemic steroids, or
    • Is currently diagnosed and managed, or
    • Is suspected on radiologic imaging at screening

  • Known diffusing capacity of the lung for carbon monoxide (DLCO) < 50%

  • Any Grade greater than or equal to (≥) 3 pulmonary disease unrelated to underlying malignancy

• Pre-existing peripheral neuropathy Grade greater than or equal to (≥) 2

• Uncontrolled diabetes mellitus

• Prior therapy:

  • Prior treatment with antimicrotubule agents (taxanes, vinca alkaloids, or MMAEs) in the locally advanced, unresectable/refractory, or metastatic setting
  • Prior antimicrotubule agent exposure in curative settings (including adjuvant, neoadjuvant, or chemoradiotherapy) is permissible.
  • Received more than 1 prior line of cytotoxic chemotherapy in the locally advanced, unresectable/refractory, or metastatic setting
  • Prior cytotoxic chemotherapy in curative settings is permissible
  • At least 14 days must have elapsed from the last dose of radiotherapy until Cycle 1 Day 1.
  • Prior radiation therapy to the lung parenchyma that is >30 Gray (Gy) within 6 months of Cycle 1 Day 1.
  • Any systemic anticancer therapy (standard or experimental) within 21 days prior to Cycle 1 Day 1.

• Active central nervous system (CNS) lesions, including leptomeningeal metastasis, are excluded. Participants with definitively treated brain metastases are eligible in they meet the following criteria:

  • Have been clinically stable for at least 4 weeks prior to treatment initiation and baseline scans show no evidence of new or enlarged metastasis
  • On a stable dose of less than or equal to (≤) 10mg/day of prednisone or equivalent for a least 2 weeks (if requiring steroid treatment)
  • Treatment with corticosteroids greater than (>) 1 month prior to Screening visit
  • No evidence of clinical and radiographic disease progression in the CNS for ≥ 21 days after definitive radiotherapy and/or surgery

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical\_trials/trial\_data\_and\_results/data\_requests.