Chemotherapy With Pembrolizumab Continuation After Progression to PD-1/L1 Inhibitors

After progression to previous PD-1/L1 inhibitors (pembrolizumab, nivolumab, or atezolizumab), physicians' choice chemotherapy plus pembolizumab (or placebo) will be administered (3 weeks per cycle) until disease progression or unacceptable toxicity.

Previous PD-1/PD-L1 inhibitors should be 2nd or 3rd line therapy for advanced NSCLC. There should be no systemic therapy after previous PD-1/PD-L1 therapy, before the enrollment to this study.

Eligibility Criteria:
Inclusion Criteria:

1. Male /female participants who are at least 20 years of age on the day of signing informed consent with histologically confirmed diagnosis of
2. Histologically confirmed non-small cell carcinoma
3. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the date of allocation/randomization.
4. Received one or two cytotoxic chemotherapy for advanced NSCLC including at least one platinum-doublet
5. Has received prior therapy with an anti-PD-1, anti-PD-L1 agents (monotherapy) and progression to last PD-1/PD-L1 inhibitors. The last PD-1/PD-L1 inhibitor should be administered 6 weeks before the study enrollment, and no other systemic therapy should be done between the interval.
6. At least one measurable lesion Have measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
7. Available data for PD-L1 IHC results (any of one tested by 22C3, SP263, or SP142) irrespective of expression level.
8. EGFR and ALK wild type

Exclusion Criteria:

1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to \[randomization/allocation\] (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
2. Has received prior systemic anti-cancer therapy including investigational agents within 3 weeks \[could consider shorter interval for kinase inhibitors or other short half-life drugs\] prior to \[randomization /allocation\].

   Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.

   Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
3. Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
4. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
5. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 3 weeks prior to the first dose of study treatment.

   Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
7. Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, well differentiated thyroid carcinoma, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
8. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment. Patients with oligo (≤5) brain metastasis with size less than 1cm can be enrolled without prior radiotherapy, if the tumors are regarded as asymptomatic and stable, based on follow-up brain MRIs checked intervals of at least 3 months. However, all patients with previously non-irradiated brain metastases should have brain MRI checked within 4 weeks before starting administration of study drugs.
9. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any PD-1/PD-L1 inhibitors.
10. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
11. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
12. Has an active infection requiring systemic therapy.
13. Has a known history of Human Immunodeficiency Virus (HIV)
14. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection.
15. Has a known history of active TB (Bacillus Tuberculosis).
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
17. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.