The purpose of this study is to understand if PF-08046054 alone works well compared to standard-of-care docetaxel alone in participants with non-small cell lung cancer (NSCLC) with PD-L1 expression greater than or equal to 1% and had cancer progression during or after treatment with PD-L1 or PD-1 inhibitors, platinum-based chemotherapy, and targeted treatment regimen(s) for participants with known actionable genomic alterations (AGAs). Participants in this study must have cancer that has spread through their body or can't be removed with surgery or treated with definitive radiation.

Participants will randomly (like a flip of the coin) be assigned to either the PF-08046054 treatment group or the docetaxel treatment group. Participants in the PF-08046054 treatment group will receive an IV infusion (injected directly into the veins) twice during each 21-day cycle. Participants in the docetaxel treatment group will receive an IV infusion once during each 21-day cycle. Study participation may be up to 5 years if the participant's NSCLC is responding to treatment. The study team will see how each participant is doing with the study treatment during regular visits at the clinic.

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.

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.