CAN-2409 Plus Prodrug With Standard of Care Immune Checkpoint Inhibitor for Stage III/IV NSCLC

Inclusion Criteria: 1. Patients with Stage III/IV NSCLC on first line treatment with anti-PD-1/PD-L1 (ICI) +/- chemotherapy for their current stage of disease and fits into one of the following cohorts as determined by investigator, preferably as per RECIST 1.1: Cohort 1) have persistent but stable disease at least 18 weeks after starting ICI treatment, or Cohort 2) have radiographic progressive disease at least 18 weeks after starting ICI treatment 2. RECIST evaluable disease including a lesion that is amenable to injection 3. Able and willing to undergo a pre-treatment and on-treatment biopsies, if feasible 4. ECOG Performance status of 0 or 1 5. 18 years of age or older 6. Granulocyte count (ANC) ≥ 1,000/mm3 7. Hemoglobin ≥ 8 g/dl (patients may be transfused to meet this criterion) 8. Platelets ≥ 75,000/mm3 9. Total bilirubin ≤ 1.5 x upper limit of normal, except for patients with known Gilbert disease who must have total bilirubin ≤ 3 x upper limit of normal 10. SGOT (AST) ≤ 5x upper limit of normal and if elevated, not clinically significant such that ICI can continue 11. INR no more than 0.2 above upper limit of normal and aPTT not \>1.2 x upper limit of normal, and value is acceptable for patient to undergo injection procedure. If on anti-coagulation, it must be clinically acceptable to hold anti-coagulation for the injection procedures per investigator discretion 12. Serum creatinine \< 2mg/dl and calculated creatinine clearance \> 30ml/min 13. Clinically stable and able to continue ICI for at least the 12-week treatment period 14. Within 6 months of enrollment, no change of ICI therapy or prior interruptions of more than 4 weeks of current ICI 15. Patients should not have received focal therapy (e.g., radiotherapy) at more than three different sites of disease within 12-months prior to enrollment 16. Patients must give study specific informed consent prior to enrollment and any study specific procedures Exclusion Criteria: 1. Patients with a history of severe immune related adverse events related to ICI 2. Patients who require ongoing therapy with disease-modifying antirheumatic drugs (DMARDs), immunomodulators or systemic immunosuppressive drugs including systemic corticosteroids (\>10 mg prednisone per day or equivalent) - premedication for ICI or chemotherapy is allowed 3. Patients with a history of active autoimmune disease requiring treatment in the past 2 years 4. Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, active hepatitis, or psychiatric illness/social situations that would limit compliance with study requirements 5. Women who are pregnant, lactating or intend to become pregnant during the study 6. Patients who are known to be HIV positive 7. Patients with a history of hypersensitivity or allergic reactions to valacyclovir or acyclovir 8. Patients with significant heart disease (New York Heart Association Functional Classification III or IV) 9. Patients with continuous oxygen dependence \>2L/min at rest 10. Tumor impinging on a neurovascular structure such that inflammation in the site may put patient at risk of compromise as determined by the investigator 11. Patients with uncontrolled brain metastases as per investigator 12. Patients with liver metastases involving more than half of the liver 13. Patients with known EGFR mutation, ALK fusion, or ROS1 fusion positive NSCLC, or that are receiving tyrosine kinase inhibitor (TKI) agents/ALK/ROS1 inhibitors 14. Patients with known interstitial lung diseases (ILDs) requiring active therapy (Radiographic fibrosis not requiring therapy is allowed) 15. Patients receiving vascular endothelial growth factor (VEGF) inhibitors (including bevacizumab, ramucirumab) within the past 2 months or five half-lives, whichever is longer 16. Patients must have no concurrent malignancy requiring treatment (except squamous or basal cell skin cancers) 17. Patients without contrast enhanced imaging at baseline or those with contraindication to the use of contrast. 18. Patients who are pregnant, breastfeeding, or plan to become pregnant.