A Study of PF-08046052/SGN-EGFRd2 in Advanced Solid Tumors

Inclusion Criteria:

* Tumor types:

  * For Part A: Participants must have disease that is relapsed, refractory, or be intolerant to standard of care therapies, and in the judgement of the investigator must have no appropriate standard therapy available at the time of enrollment. Participants must have histologically- or cytologically confirmed metastatic or unresectable solid malignancy from one of the following tumor types:

    * Colorectal cancer (CRC)
    * Non-small cell lung cancer (NSCLC)
    * Head and neck squamous cell cancer (HNSCC)-non-nasopharyngeal subtype ONLY; nasopharyngeal subtype is not eligible.
  * For Part B: Participants must have disease that is relapsed, refractory, or be intolerant to standard of care therapies, and in the judgement of the investigator must have no appropriate standard therapy available at the time of enrollment.

    * The tumor type(s) to be enrolled in dose optimization will be identified by the sponsor from among those specified in Part A.
  * For Part C: Participants must have disease that is relapsed or refractory or be intolerant to standard of care therapies as specified below, unless contraindicated:

    * CRC

      * Participants must have unresectable locally advanced or metastatic CRC.
      * Prior therapy: Participants must have received prior fluoropyrimidine, oxaliplatin and irinotecan. Participants with defective mismatch repair and microsatellite instability high (dMMR/MSI-H) should have received prior treatment with pembrolizumab, a nivolumab-containing regimen, or other available anti-PD-1 (programmed cell death protein 1) or anti PD L1 (programmed cell death 1 ligand) agents.
    * NSCLC

      * Participants must have unresectable locally advanced or metastatic NSCLC.
      * Prior therapy: Participants must have received platinum-based therapy and at least 1 PD-1/PD-L1 inhibitor. These agents may have been administered either as single agents or in combination. Participants with an activating mutation or rearrangement (eg, EGFR, anaplastic lymphoma kinase \[ALK\], etc.) must have received available targeted agents if eligible by biomarker status and local standard of care.
    * HNSCC

      * Participants must have unresectable locally advanced or metastatic HNSCC - non-nasopharyngeal subtype ONLY; nasopharyngeal subtype is not eligible.
      * Prior therapy: Participants must have received platinum-based therapy and a PD-1/PD-L1 inhibitor, if eligible by biomarker status and local standard of care. These agents may have been administered either as single agents or in combination.
    * Pancreatic ductal adenocarcinoma (PDAC)

      * Participants must have unresectable locally advanced or metastatic PDAC.
      * Prior therapy: Participants must have received gemcitabine- or FOLFIRINOX-based therapy.
* Participants should provide archival tumor tissue if available and also agree to biopsies, if medically feasible
* An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
* Measurable disease at baseline per RECIST 1.1 criteria.

Exclusion Criteria:

* History of another malignancy within 3 years before the first dose of study treatment, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death
* Known active central nervous system metastases or leptomeningeal disease. Participants with previously treated brain metastases may participate provided they are

  * clinically stable for at least 4 weeks prior to study entry after brain metastases treatment,
  * they have no new or enlarging brain metastases,
  * and are off of corticosteroids prescribed for symptoms associated with brain metastases for at least 7 days prior to the first dose of study drug.
* Treatment with an aminobisphosphonate IV (eg ibandronate, pamidronate, zoledronate, etc.) within 4 weeks of the first dose of study treatment.
* Participants with history of thromboembolic phenomena within 6 months prior to the first dose of study intervention, or with contraindication to thromboembolism prophylaxis (if clinically indicated) for a previous history of thrombus.