A Study of PRT3789 in Combination With Pembrolizumab in Patients With Advanced or Metastatic Solid Tumors With a SMARCA4 Mutation

Inclusion Criteria:

* Patients who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations and other study procedures, including providing informed consent.
* Patients must either progress on standard of care therapy or be ineligible for standard of care therapy in order to be eligible for enrollment on the study.
* Part 1 Safety Run-in: Patients with advanced, recurrent, or metastatic histologically or cytologically confirmed solid tumor malignancy and any mutation of SMARCA4 detected by next generation sequencing in tumor tissue or blood, or absence of SMARCA4 protein (BRG1). Part 2 Main Study: Patients with advanced, recurrent, or metastatic histologically confirmed esophageal cancer or NSCLC and have a deleterious SMARCA4 mutation, or absence of SMARCA4 protein (BRG1) detected by immunohistochemistry in tumor tissue using a clinically validated laboratory test.
* Part 1 Run-in: Measurable or non-measurable (but evaluable) disease per RECIST v1.1 as assessed by the local site investigator/radiologist. Part 2 Main Study: Measurable disease per RECIST v1.1 as assessed by the local site investigator/radiologist. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions.
* Willingness and ability to provide tumor tissue (i.e., archived or fresh tumor biopsy if archived tumor tissue is unavailable)
* Adequately controlled blood pressure with or without antihypertensive medications.
* Patients with HIV must have well-controlled HIV on antiretroviral therapy.
* Adequate organ function

Exclusion Criteria:

* Patients who have adverse events due to previous anticancer therapies and/or complications from prior surgical intervention must have recovered to ≤ Grade 1 or baseline before starting study treatment. Patients with endocrine-related AEs who are adequately treated with hormone replacement or patients who have ≤ Grade 2 neuropathy are eligible.
* Other acute or chronic medical or psychiatric conditions that would make the patient inappropriate for entry into this study.
* Patients with solid tumors with a known concomitant SMARCA2 mutation or loss of protein expression.
* Uncontrolled or symptomatic central nervous system (CNS) metastases or leptomeningeal disease and/or carcinomatous meningitis).
* History of or current (noninfectious) pneumonitis/interstitial lung disease
* Diagnosis of immunodeficiency disease/disorder.
* Known additional malignancy that is progressing or has required active treatment within the past 3 years.
* Patients who received prior treatment with an agent directed to a stimulatory or co-inhibitory T-cell receptor.
* Currently taking a strong or moderate CYP3A4 inhibitor or inducer and St. John's Wort and are unable to discontinue use within 15 days of the first dose of study treatment.
* Receipt of any targeted therapy directed against BRM/BRG1 (SMARCA2/SMARCA4).
* Pregnant or breastfeeding or plan to become pregnant during the duration of the study.