A Study to Learn About the Study Medicine PF-07934040 When Given Alone or With Other Anti-cancer Therapies in People With Advanced Solid Tumors That Have a Genetic Mutation.

A Phase 1 Open-Label Study of PF-07934040 as a Single Agent and in Combination With Other Targeted Agents in Participants With Advanced Solid Tumors Harboring Mutations in the KRAS Gene

The purpose of this study is to learn about the safety and effects of the study medicine alone or when given together with other anti-cancer therapies. This study also aims to find the best dose.

This study is seeking participants who have solid tumors (a mass of abnormal cells that forms a lump or growth in the body) that:

• are advanced (cancer that doesn't disappear or stay away with treatment) and
• have a KRAS gene mutation (a change in the DNA of the KRAS gene that can cause cells to grow in very high numbers).

This includes (but limited to) the following cancer types:

Non-Small Cell Lung Cancer (NSCLC): It's a type of lung cancer where the cells grow slowly but often spread to other parts of the body.

Colorectal Cancer (CRC): This is a disease where cells in the colon (a part of large intestine) or rectum grow out of control.

Pancreatic ductal adenocarcinoma (PDAC): This is a cancer that starts in the ducts of the pancreas but can spread quickly to other parts of the body. Pancreas is a long, flat gland that lies in the abdomen behind the stomach. Pancreas creates enzymes that help with digestion. It also makes hormones that can help control your blood sugar levels.

All participants in this study will take the study medication (PF-07934040) as pill by mouth twice a day repeating for 21-day or 28-day cycles.

Depending on which part of the study participants are enrolled into they will receive the study medication (PF-07934040 alone or in combination with other anti-cancer medications). These anti-cancer medications will be given in the study clinic by intravenous (IV) that is directly injected into the veins at various times (depending on the treatment) during the 21-day or 28-day cycle.

Participants can continue to take the study medication (PF-07934040) and the combination anti-cancer therapy until their cancer is no longer responding.

The study will look at the experiences of people receiving the study medicines. This will help see if the study medicines are safe and effective.

Participants will be involved in this study for up to 4 years. During this time, they will come into the clinic between 1 to 4 times in each 21-day or 28-day cycle. After they have stopped taking the study medication (at about at 2 years) they will be followed for another two years to see how they are doing.

Inclusion Criteria:

• Histological or cytological diagnosis of advanced, unresectable, and/or metastatic or relapsed/refractory solid tumor.

ECOG PS 0 or 1

• Presence of at least 1 measurable lesion based on RECIST version 1.1 that has not been previously irradiated.

• Documentation of mutated KRAS gene

  1. PDAC, CRC, Other tumor types: Confirmed KRAS mutation, any variant
  2. NSCLC: Confirmed KRAS mutation, any variant except previously treated G12C. If driver mutation, must have failed precision medicine therapy [eg, inhibitors of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), and others].

• Part 1 and Part 2a: Participant must have progressed on standard treatment(s) for which no additional, effective therapy is available.

  1. PDAC (2-3L): Participants must have received and radiologically progressed on prior lines of systemic therapy for metastatic pancreatic adenocarcinoma. If participants received prior neoadjuvant or adjuvant chemotherapy and progressed within 6 months of the last dose, then this should be considered as a prior line of systemic therapy.
  2. NSCLC (2-3L): Participants must have received prior lines of anti-cancer treatment and progressed on at least a platinum-containing chemotherapy regimen or ICI. Participants may have had only one or two prior lines of therapy in the advanced/metastatic setting. For participants with EGFR, ALK, or other genomic tumor alterations, participants must have progressed on approved therapy for these alterations.
  3. CRC (2-3L): Participants must have had one or two prior lines of therapy for mCRC. For either one or two prior treatments, these regimens must have included a fluoropyrimidine, oxaliplatin, and/or irinotecan for one prior treatment, exposure to VEGF/VEGF receptor (VEGFR) inhibitor is optional;
  4. Other tumors: Participants, in the judgment of the investigator, must have progressed or become intolerant to all available standard therapies, or have refused such therapy.

• Part 2b:

  1. PDAC (1L) Cohort A2: Participants must not have received prior chemotherapy for metastatic disease. Participant could have received neoadjuvant therapy, adjuvant therapy, or adjuvant chemo-radiotherapy. If relapse occurred within 6 months of last dose of adjuvant treatment or neoadjuvant therapy, the participant would be considered 2L, and not 1L.
  2. CRC (2-3L) Cohort B2: Participants must have had one or two prior systemic treatment regimens for mCRC. For either one or two prior treatments, these regimens must have included a fluoropyrimidine, irinotecan, oxaliplatin; for one prior treatment, exposure to a VEGF/VEGF receptor (VEGFR) inhibitor is optional.
  3. CRC (1L) Cohort B3/B4: Participants must not have received prior therapy for metastatic disease and not be a candidate for other targeted therapy or immunotherapy. Participant could have received neoadjuvant therapy, adjuvant therapy, or adjuvant chemo-radiotherapy. If relapse occurred within 6 months of last dose of adjuvant or neoadjuvant therapy, then the participant would be considered 2L, and not 1L.
  4. NSCLC (1L) Cohort C2: Participants must have a TPS ≥50% and must not have received prior systemic treatment setting.
  5. NSCLC (1L) Cohort C3: Participants with any TPS and must not have received prior systemic treatment setting.

Exclusion Criteria:

• Active or history of pneumonitis/ILD or pulmonary fibrosis requiring treatment with systemic steroid therapy.

• Diagnosis of immunodeficiency or an active autoimmune disease that require systemic treatment with chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy in the past 2 years.

• Sensory peripheral neuropathy ≥Grade 2

• Active or history of clinically significant gastrointestinal (GI) disease (including but not limited to inflammatory GI disease [eg, ulcerative colitis, Crohn's disease, inflammatory bowel disease], immune-mediated colitis, peptic ulcer disease, GI bleeding, chronic diarrhea) and other conditions that are unresolved and/or may increase the risk associated with study participation or study treatment administration.

• Active bleeding disorder, including GI bleeding, as evidenced by hematemesis, significant hemoptysis or melena in the past 6 months.

• Major surgery or completion of radiation therapy ≤4 weeks prior to enrollment/randomization or radiation therapy that included >30% of the bone marrow.

• Known sensitivity or contraindication to any component of study intervention (PF 07934040, gemcitabine, nab-paclitaxel, cetuximab, bevacizumab, FOLFOX, 5-FU, pembrolizumab, cisplatin, carboplatin, pemetrexed, SHP2 inhibitor(s), cyclin-dependent kinase (CDK) inhibitor(s), antibody drug conjugates (ADCs) or EGFR inhibitor(s)).

• Hematologic abnormalities.

• Renal impairment.

  • Hepatic abnormalities.