This is a Single arm, Simon's two stage pilot study in which patients with Non-Small Cell Lung Cancer (NSCLC) with metastatic disease 2L and beyond will receive OncoChoice-informed chemotherapy following National Cancer Care Network (NCCN) treatment guidelines on dosage and scheduling for NSCLC FDA approved drugs.

This is a Single arm, Simon's two stage pilot study in which patients with Non-Small Cell Lung Cancer (NSCLC) with metastatic disease 2L and beyond will receive OncoChoice-informed chemotherapy following National Cancer Care Network (NCCN) treatment guidelines on dosage and scheduling for NSCLC FDA-approved drugs. After confirmation of patient eligibility and patient consent receival, patients will undergo biopsy and/or removal of malignant fluids (paracentesis/ thoracentesis/ PleurX catheter) as part of standard of care procedures. Biosamples will be shared in a timely fashion (within 24 hr post collection) with study sponsors (OncoOptima) to test drug responsiveness. Participants will undergo additional testing as deemed necessary by the treating provider. Any additional treatments will be at the discretion of the treating provider.

Inclusion Criteria:

• Age ≥ 18 years of age at time of consent
• ECOG performance status score of ≤2
• Advanced non-small cell lung cancer to meet histologically confirmed Stage IV NSCLC documented by biopsy.
• Patients have received at least 1 prior line of systemic therapy for Stage IV NSCLC, including but not limited to targeted therapy, and are currently candidates for 2L or later SOC chemotherapy. Exceptionally, patients with Stage III NSCLC who have received at least 1 line of systemic therapy may be considered eligible, pending principal investigator approval.
• Demonstrates adequate organ function; labs must be within treatment parameters for the individual institutional treatment plans for specific therapeutic agents. All screening labs to be obtained within 30 days prior to registration.
• Must have not received any cancer treatment for at least 2 weeks.
• Must be a candidate for small molecule drug treatment.
• Participants or their LAR must be able to provide written informed consent and HIPAA authorization for release of personal health information, via an approved UIC Institutional Review Board (IRB) informed consent form and HIPAA authorization.
• Women of childbearing potential must not be pregnant or breast-feeding. A negative serum or urine pregnancy test is required per institutional practice guidelines.
• As determined at the discretion of the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.

Exclusion Criteria:

• Active infection requiring systemic therapy within 7 days of enrollment.
• Uncontrolled HIV/AIDS or active viral hepatitis (e.g., HBV, HCV)
• Any ongoing significant toxicity resulting from prior anticancer therapy that, as determined by the treating provider, has the potential to interfere with the safety or efficacy assessment of this investigational regimen.
• ECOG performance status score >2
• Clinically significant lung, heart, or autoimmune disease
• Life expectancy <12 weeks
• Prior solid organ or bone marrow transplant
• Antibiotics, live vaccines or other type of surgery within 4 weeks prior intervention treatment
• Pregnant or nursing
• Any prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of this investigational regimen, as determined by the treating provider.
• Any mental or medical condition that prevents the patient from giving informed consent or participating in the trial.
• Another major comorbidity, as determined by treating provider.