Inclusion Criteria

• Histologically or cytologically confirmed diagnosis of NSCLC with locally advanced, unresectable Stage IIIB or IIIC not eligible for definitive chemoradiotherapy or metastatic (Stage IV: M1a, M1b, or M1c) disease per the American Joint Committee on Cancer (AJCC) Staging Manual, Version 8.0, and the Union for International Cancer Control (UICC) Staging System. Note: Participants with a neuroendocrine component or histology are not eligible.

• PD-L1 expression on ≥1% of tumor cells based on local immunohistochemistry (IHC) testing with an assay utilizing the anti-PD-L1 monoclonal antibody clones 22C3 or SP263.

• Participants who have NSCLC with known AGAs are permitted.

• Able to provide any of the following tumor tissues for biomarker analysis:

  • Archival specimen (preferably collected within 12 months after the last anticancer therapy) (see laboratory manual for details); or
  • De novo biopsy from a tumor lesion, if medically feasible.

• Participants must have received the following therapies and progressed during or relapsed after receiving their most recent prior therapy, or have been intolerant to their most recent 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 unless contraindicated, a PD-(L)1 monoclonal antibody (concurrently or sequentially with platinum-based chemotherapy).
• Experienced disease progression within 6 months of the last dose of platinum-based chemotherapy in the adjuvant, neoadjuvant, or chemoradiotherapy setting and received a PD-(L)1 monoclonal antibody at any time during the course of treatment.

Participants with known AGAs (eg, EGFR mutations, ALK translocations, or other relevant actionable mutations) must fulfill the following conditions:

• Must have received at least 1 relevant AGA-targeted therapy if locally available 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, neoadjuvant, or chemoradiotherapy setting.
• May have received PD-(L)1 monoclonal antibody (concurrently or sequentially with platinum-based chemotherapy).

Exclusion Criteria

• History of another malignancy within 3 years before the first dose of PF-08046054, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (eg, 5-year overall survival [OS] ≥90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.

• Any central nervous system (CNS) lesions, unless definitively treated with CNS-directed local therapy (surgery and/or radiotherapy). Participants with definitively treated brain metastases are eligible if they meet the following criteria:

  • The participant is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least >14 days prior to randomization (if requiring steroid treatment).
  • No clinical or radiographic progression in the CNS following CNS-directed definitive radiotherapy and/or surgery.
  • Time since CNS-directed treatment is ≥28 days prior to randomization.

• Participants with a history of leptomeningeal metastasis are excluded.

• Prior treatment with an anti-PD-L1 agent (where indicated per protocol) within 5 half-lives.

• Previous receipt of an MMAE-containing agent or prior docetaxel.

There are additional inclusion and exclusion criteria. The study center will determine if criteria for participations are met.