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, treatmentplan, laboratory tests, lifestyle considerations and other study procedures,including providing informed consent.

• Patients must either progress on standard of care therapy or be ineligible forstandard of care therapy in order to be eligible for enrollment on the study.

• Part 1 Safety Run-in: Patients with advanced, recurrent, or metastatichistologically or cytologically confirmed solid tumor malignancy and any mutation ofSMARCA4 detected by next generation sequencing in tumor tissue or blood, or absenceof SMARCA4 protein (BRG1). Part 2 Main Study: Patients with advanced, recurrent, ormetastatic histologically confirmed esophageal cancer or NSCLC and have adeleterious SMARCA4 mutation, or absence of SMARCA4 protein (BRG1) detected byimmunohistochemistry in tumor tissue using a clinically validated laboratory test.

• Part 1 Run-in: Measurable or non-measurable (but evaluable) disease per RECIST v1.1as assessed by the local site investigator/radiologist. Part 2 Main Study:Measurable disease per RECIST v1.1 as assessed by the local siteinvestigator/radiologist. Lesions situated in a previously irradiated area areconsidered measurable if progression has been shown in such lesions.

• Willingness and ability to provide tumor tissue (i.e., archived or fresh tumorbiopsy 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/orcomplications from prior surgical intervention must have recovered to ≤ Grade 1 orbaseline before starting study treatment. Patients with endocrine-related AEs whoare adequately treated with hormone replacement or patients who have ≤ Grade 2neuropathy are eligible.

• Other acute or chronic medical or psychiatric conditions that would make the patientinappropriate for entry into this study.

• Patients with solid tumors with a known concomitant SMARCA2 mutation or loss ofprotein expression.

• Uncontrolled or symptomatic central nervous system (CNS) metastases orleptomeningeal 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 treatmentwithin the past 3 years.

• Patients who received prior treatment with an agent directed to a stimulatory orco-inhibitory T-cell receptor.

• Currently taking a strong or moderate CYP3A4 inhibitor or inducer and St. John'sWort and are unable to discontinue use within 15 days of the first dose of studytreatment.

• Receipt of any targeted therapy directed against BRM/BRG1 (SMARCA2/SMARCA4).

• Pregnant or breastfeeding or plan to become pregnant during the duration of thestudy.