Inclusion Criteria:
* Age ≥ 18 years of age
* Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* Subjects with histologically or cytologically confirmed stage IIIB-IV NSCLC
* Subjects lacking actionable genetic mutations must have been previously treated with (a) anti-PD-1/PD-L1 therapy; and (b) platinum-based chemotherapy, either as combination or sequentially for metastatic disease and have progressed on or after therapy. Individuals who cannot tolerate or have previously refused platinum-based chemotherapy or who are unable to receive it are eligible to enroll based on progression after anti-PD-1/PD-L1 therapy alone
* NSCLC with known actionable genomic alteration (e.g., EGFR, ALK, ROS1, BRAF) must have received all approved targeted therapies and have progressed (data capture not necessary for ALK, ROS1, BRAF)
* Subjects have at least two lesions of measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
* At least one site of disease accessible to photoimmunotherapy. Thus, the therapeutic 690-nm laser light can be administered via insertion of optical fiber/s in the target tumor for interstitial photoimmunotherapy (I-PIT), or target tumors can be illuminated with external beam photoimmunotherapy (EB-PIT)
* Absolute neutrophil count: ≥ 1,000/µL
* Platelets: ≥ 100,000/µL
* Total bilirubin: ≤ institutional upper limit of normal (ULN)
* Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase \[SGPT\]): ≤ 3 x institutional ULN
* Creatinine clearance (CrCl) ≥ 50 mL/min (Cockcroft-Gault)
* Patient has not received a transfusion within 2 weeks prior to screening
* Female patients of childbearing potential must have a negative pregnancy test at screening and must be willing to use 2 methods of highly effective birth control while on study or be surgically sterile, or abstain from heterosexual sexual activity for the course of the study through 120 days after the last dose of anti-PD1 treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
* Male participants must agree to use a highly effective method of contraception starting with the first dose of study medication through 120 days after the last dose of anti-PD1 treatment
* Participant must understand the investigational nature of this study and sign an independent ethics committee/institutional review board approved written informed consent form prior to receiving any study related procedures
Exclusion Criteria:
* Has received an investigational agent within 30 days prior to initial treatment or less than 4 half-lives of a previous drug
* Had a major surgery, (e.g., requiring general anesthesia) within 4 weeks before the first dose of study treatment or, will not have fully recovered from surgery prior to the first dose
* Patients who received chemotherapy or chemoimmunotherapy within 21 days or those who have not recovered from reversible adverse events prior to the scheduled surgery and interstitial or intraoperative PIT
* The participants received high dose or curative radiotherapy to the target tumor/s within 30 days prior to the planned I-PIT or EB-PIT
* Toxicity related to prior anticancer therapy that has not returned to grade ≤ 1 or baseline levels (except for alopecia, vitiligo, grade ≤ 2 peripheral neuropathy, and endocrinopathies that are stable on hormone replacement, which may be grade 2)
* History of immune-related adverse events (irAEs) from prior anticancer therapy leading to permanent treatment discontinuation
* History of solid organ or hematologic stem cell transplantation
* Prolonged corrected QT interval by Fredericia (QTcF) \> 470 msec or clinically significant cardiac arrhythmia or electrophysiologic disease (e.g., placement of implantable cardioverter defibrillator or atrial fibrillation with uncontrolled rate or abnormalities in conduction or morphology of electrocardiogram \[ECG\] \[e.g., complete left bundle branch block, third- or second-degree heart block, PR interval \> 250 msec\]). Note: Participants with cardiac pacemakers who are clinically stable are eligible
* Clinically significant cardiovascular disease, including any of the following within 6 months prior to signature of informed consent:
* Myocardial infarction, severe or unstable angina, or coronary artery bypass surgery
* Clinically significant arrhythmias (e.g., ventricular arrhythmias or atrial fibrillation with uncontrolled heart rate)
* Congestive heart failure (New York Heart Association \[NYHA\] class III/IV)
* Cerebrovascular accident, transient ischemic attack, or other arterial thromboembolic event
* Myocarditis
* Active bleeding diathesis or requirement for therapeutic anticoagulation that cannot be interrupted or altered for procedures
* Patients with untreated or symptomatically unstable treated brain metastases or history of leptomeningeal disease should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with treated and stable brain metastases (at least 28 days from last radiotherapy treatment) are eligible as long as steroids are not required for symptom management
* Known history of hepatitis B, hepatitis C or human immunodeficiency virus (HIV). Exceptions include past or resolved hepatitis B (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of hepatitis B virus surface antigen \[HBsAg\]) and patients positive for hepatitis C (hepatitis C virus \[HCV\]) antibody if polymerase chain reaction is negative for HCV ribonucleic acid (RNA). HIV testing is not required in absence of clinical suspicion of HIV
* History of, or active autoimmune disorder, requiring systemic steroids or immunosuppressive agents. Exceptions allowed: Patients with autoimmune dermatologic conditions not requiring systemic steroids or immunosuppressive agents (e.g. vitiligo, eczema, etc.), endocrine-related autoimmune conditions receiving appropriate hormonal supplementation
* Use of immunosuppressant drugs such as steroids, azathioprine, tacrolimus, cyclosporine, etc. is not permitted within 4 weeks before recruitment (exception allowed is use of steroids as hormone replacement therapy or as supportive medication e.g. anti-emesis, contrast allergy, pre-medication, etc. or other short-course therapy less than 2 weeks continuously within 4 weeks of study treatment)
* History of significant (≥ grade 3) cetuximab infusion reactions
* Evidence of interstitial lung disease or current active, noninfectious pneumonitis
* Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g. colitis or Crohn's disease\], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.\]). The following are exceptions to this criterion:
* Patients with vitiligo or alopecia
* Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement
* Any chronic skin condition that does not require systemic therapy
* Patients without active disease in the last 5 years may be included
* Patients with celiac disease controlled by diet alone
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive ASP-1929
* Any condition which in the investigator's opinion deems the subject an unsuitable candidate to receive the experimental PIT or immunotherapy
* Pregnant or nursing female participants
* Unwilling or unable to follow protocol requirements
