This study will test the safety of a drug called PF-08046054/SGN-PDL1V alone and with pembrolizumab in participants with solid tumors. It will also study the side effects of this drug. A side effect is anything a drug does to your body besides treating your disease.

Participants will have solid tumor cancer that has spread through the body (metastatic) or cannot be removed with surgery (unresectable).

This study will have five parts. Parts A and B of the study will find out how much PF-08046054/SGN- PDL1V should be given to participants. Part C will use the dose found in Parts A and B to find out how safe PF-08046054/SGN-PDL1V is and if it works to treat solid tumor cancers. In Part D and E, participants will be given PF-08046054/SGN-PDL1V with pembrolizumab to find out how safe this combination is and if it works to treat solid tumor cancers.

Inclusion Criteria:

• Parts A and B:

  • Participants must have one of the following histologically- or cytologically-confirmed metastatic or unresectable solid tumor types

    • Non-small cell lung cancer (NSCLC)
    • Head and neck squamous cell carcinoma (HNSCC) (except nasopharyngeal cancer)
    • Esophageal squamous cell carcinoma (SCC)
    • Triple negative breast cancer (TNBC)

  • Participants must have disease that is relapsed or refractory, that has progressed on approved therapies, be intolerant to or refused such therapies, or such and therapies are contraindicated and in the judgement of the investigator, should have no appropriate SoC therapeutic option

  • Participants must have PD-L1 expression based on historical testing

• Part C:

  • Participants must have disease that is relapsed or refractory or be intolerant to SoC therapies and must have one of the following tumor types

    • HNSCC

      • Participants with HNSCC must have histologically or cytologically-confirmed HNSCC

    • NSCLC

      • Participants must have histologically or cytologically-confirmed NSCLC. Participants with SCC and non--SCC histology are eligible. Note: Participants with a neuroendocrine component or histology are not eligible.

    • Esophageal SCC

    • Pancreatic cancer

    • Hepatocellular carcinoma

    • TNBC

    • Gastric cancer

    • Endometrial cancer

  • Participants must have been previously tested for PD-L1 expression and should have PD-L1 expression ≥1 or <1 by CPS or TPS based on historical testing

• Part D and Part E:

  • Participants must have histologically or cytologically-confirmed disease of the HNSCC or NSCLC
  • Participants must have PD-L1 expression based on historical testing
  • Participants with NSCLC; PD-L1 expression ≥ 1% by TPS
  • Participants with HNSCC; PD--L1 expression ≥1 by CPS

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1

• Measurable disease per RECIST v1.1 at baseline

Exclusion Criteria:

• History of another malignancy within 3 years of first dose of study treatment or any evidence of residual disease from a previously diagnosed malignancy.

• Known active central nervous system metastases. Participants with previously-treated brain metastases may participate provided they:

  • Are clinically stable for at least 4 weeks prior to study entry after brain metastasis treatment
  • Have no new or enlarging brain metastases
  • And are off of corticosteroids prescribed for symptoms associate with brain metastases for at least 7 days prior to first dose of study treatment

• Lepto-meningeal disease

• Prior treatment with an anti-PD-L1 agent within less than 5 half-lives. This duration of time will vary according to the half-life of the specific agent.

• Previous receipt of an monomethylauristatin E (MMAE)-containing agent.

• Pre-existing neuropathy ≥Grade 2 per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.

There are additional inclusion 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.