The purpose of this clinical trial is to learn about the safety and effects of the study medicine (called PF-07220060 and PF-07104091) in people with breast cancer. This clinical study consists of 2 parts (part 1 and part 2). In part 1, we are seeking participants who:

• Have been diagnosed with Breast Cancer (BC) of either types:
• Have HR+, HER2- BC
• Refractory HR-positive/HER2-positive BC
• Have other solid tumors other than BC

In part 2, we are seeking participants who:

-Have HR-positive/HER2-negative BC Part 1 will include increasing doses of PF-07220060 with PF-07104091. In part 2, participants will take 1 of 2 study medicine combinations. This will help us decide the highest amount of study medicines that can be safety given to people. All participants in this study will receive PF-07220060 with PF-07104091 by mouth. We will compare participant experiences to help us determine if PF-07220060 with PF-07104091 is safe and effective. Participants will take part in this study for about 2 years. During this time, they will receive the study medicine, an x-ray imaging, and will be observed for safety and effects of the study medicines.

Inclusion Criteria

• Part 1: Breast Cancer (BC)
• HR+, HER2- BC
• Refractory HR-positive/HER2-positive BC
• Part 1: Solid Tumors other than BC
• Part 2:
• HR-positive/HER2-negative BC
• Lesion:
• Part 1: evaluable lesion (including skin or bone lesion only)
• Part 2: measurable lesion per RECIST v1.1
• Prior systemic Treatment
• Part 1: HR-positive/HER2-negative BC
• At least 1 line of SOC, including CDK4/6 inhibitor therapy and Endocrine Therapy, for advanced or metastatic disease.
• Prior chemotherapy in the metastatic setting is allowed.
• Part 1: HR-positive/HER2-positive BC
• At least 1 prior treatment of approved HER2 targeting therapy.
• Part 1: Solid Tumors other than BC
• Participants with no standard therapy available or for which no local regulatory approved standard therapy is available that would confer significant clinical benefit in the medical judgement of the investigator.
• Part 2A: At least 1 prior systemic therapy for advanced or metastatic disease, including CDK4/6 inhibitor treatment and ET.
• Parts 2B: At least 1 prior endocrine therapy for advanced or metastatic disease. Progression during treatment or within 12 months of completion of adjuvant endocrine therapy is acceptable.
• Part 2B: Up to 1 prior line of chemotherapy for advanced/metastatic disease is allowed.
• General Inclusion Criteria
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1
• Adequate renal, liver, and bone marrow function
• Resolved acute effects of any prior therapy to baseline severity

Exclusion Criteria:

• All Study Parts: Permanent treatment discontinuation from prior CDK 4 and/or CDK2 inhibitor due to treatment related toxicity.

• Part 2B and 1C: Prior treatment with any CDK 4/6 inhibitor, or SERDs (e.g. fulvestrant), or everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway for advanced disease.

• Parts 2B and 2C: Prior treatment with any CDK4/6 inhibitor for advanced disease.

• Parts 2B and 2C: Prior treatment with an investigational endocrine therapy for advanced disease.

• Part 2C: Prior neoadjuvant or adjuvant treatment with a nonsteroidal aromatase inhibitor AI (ie, anastrozole or letrozole) with disease recurrence while on or within 12 months of completing treatment.

• Part 2C: Any prior systemic treatment for advanced disease.

• Prior irradiation to >25% of the bone marrow

• Current use of drugs which have a risk for QTc prolongation

• Current use or anticipated need for food or drugs that are known strong CYP3A4/5, strong UGT2B7 or UGT1A9 inhibitors or inducers

• Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry

  • Participants with any other active malignancy within 3 years prior to enrollment except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix, Bowen's disease
  • Major surgery within 4 weeks prior to study entry
  • Radiation therapy within 4 weeks prior to study entry.
  • Clinically important hypertension
  • Known or suspected hypersensitivity to PF-07220060, PF-07104091, letrozole, fulvestrant, or goserelin (or equivalent to induce chemical menopause if applicable)

• Known abnormalities in coagulation. Anticoagulation with subcutaneous heparin or prophylactic doses of anticoagulant are allowed

• Known active uncontrolled or symptomatic central nervous system (CNS) metastases

• Active inflammatory GI disease

• Current use or anticipated need for Proton Pump Inhibitors (PPI) within 14 days prior to first dose of the study intervention

• Previous high-dose chemotherapy requiring stem cell rescue

• Participants with active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus (HBV), hepatitis C virus (HCV), and known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness

• Other protocol specific exclusion criteria may apply

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.