SBRT and Oncolytic Virus Therapy Before Pembrolizumab for Metastatic TNBC and NSCLC

Inclusion Criteria

• Willing and able to provide written informed consent/assent for the trial.
• Male or female aged ≥18 years on the day of informed consent signing.
• Histologically confirmed locally advanced or metastatic TNBC that has relapsed on or is refractory to standard of care therapy OR histologically or cytologically confirmed metastatic NSCLC that is immunotherapy and chemotherapy naïve or previously treated with 1 cycle of platinum-containing chemotherapy. Epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutation-negative NSCLC patients and NSCLC patients with EGFR or ALK genomic tumor aberrations that have failed FDA-approved targeted therapy for these aberrations will be eligible for enrollment in the study.
• Measurable disease based on RECIST 1.1, a target lesion of suitable diameter (at least 1 cm) for SBRT, and a non-target lesion (visceral metastatic lesion) at least 1 cm in diameter for abscopal effect evaluation.
• Willing to provide biopsy tissues as required by the study.
• Eastern Cooperative Oncology Group performance status of 0 or 1.
• Adequate organ function as defined by the following laboratory values:
• Absolute neutrophil count ≥1, 500/µL (without granulocyte colony stimulating factor support within 14 days of assessment)
• Platelets ≥100,000/µL
• Hemoglobin ≥8 g/dL or ≥5.6 mmol/L without transfusion or erythropoietin dependency (within 7 days of assessment)
• White blood cell count >2, 500/µL and 2.5 X ULN
• Albumin >2.5 mg/dL
• International normalized ratio or prothrombin time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants
• aPTT ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
• Life expectancy ≥ 6 months.
• ≥ 4 weeks since any major surgery, completion of radiation therapy, or completion of all prior systemic anticancer therapy (adequately recovered from the acute toxicities of any prior therapy).
• Female subjects of childbearing potential should have a negative serum pregnancy (beta-human chorionic gonadotropin) within 7 days prior to receiving the first dose of the trial treatment and should not be lactating.
• Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study therapy.
• Male subjects of childbearing potential must agree to use an adequate method of contraception for the course of the study through 120 days after the last dose of study therapy.

Exclusion Criteria

• Unwilling or unable to comply with the study protocol.
• Subjects for who bone metastases are the only available non-target lesions for abscopal effect evaluation.
• Subjects with tumors for which SBRT is not considered appropriate standard therapy. This includes subjects with target lesions less than 1 cm in diameter and those with large central lung lesions.
• Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of trial treatment.
• Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Known history of active tuberculosis (Bacillus Tuberculosis).
• Known or suspected hypersensitivity to pembrolizumab or any of its excipients or any component of the proposed regimen (gene vector/valacyclovir).
• Known gallbladder or bile duct disease (i.e., infection or cholecystitis) or acute or chronic pancreatitis.
• Eastern Cooperative Oncology Group performance status of ≥2 or oxygen dependence (e.g., advanced chronic obstructive pulmonary disease).
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