Inclusion Criteria
Histological or cytological evidence of stage IV NSCLC (any histology)
Must have progressed on or after previous platinum-based chemotherapy
Must have also progressed on or after receiving any single-agent PD-1 or PD-L1 inhibitor (including pembrolizumab) as their most recent therapy and must have had at least a 3-month PFS on this therapy
Must be enrolled on the trial within 6 weeks of their last infusion of PD-1 or PD-L1 inhibitor therapy
Subjects whose tumors harbor a mutation in EGFR exon 19 or 21 or have gene rearrangements in ALK or ROS1 must have already been treated with standard targeted therapies
ECOG Performance Status 0-1 within 28 days prior to registration for protocol therapy
Must be fit enough to receive next-line chemotherapy (either gemcitabine, docetaxel, or pemetrexed [non-squamous only]) according to the discretion of the treating physician
Adequate laboratory values obtained within 28 days prior to registration for protocol therapy
Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test within 7 days prior to study registration and/or within 72 hours of first dose of study drugs
WOCBP must be willing to use two methods of contraception or abstain from heterosexual activity from the point of registration through 120 days after the last dose of study drug
Male subjects capable of fathering a child must agree to use an adequate method of contraception starting with first dose of the study drug through 120 days after the last dose of the study drug
Exclusion Criteria
Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
Active central nervous system (CNS) metastases
Treatment with any investigational agent within 28 days prior to registration for protocol therapy with the exception of PD-1 or PD-L1 inhibitors
No active second cancers with the exception of localized non-melanoma skin cancer, in-situ cervical or in-situ bladder cancer
Evidence of active autoimmune disease requiring systemic treatment within the past 90 days or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents
History of (non-infections) pneumonitis requiring treatment with corticosteroids, evidence of interstitial lung disease or active, non-infectious pneumonitis
History of an immune-related toxicity requiring treatment with corticosteroids during prior PD-1/PD-L1 inhibitor treatment
Diagnosis of immunodeficiency or is receiving chronic systemic corticosteroid therapy or other immunosuppressive therapy (excludes inhaled corticosteroids) within 7 days of study registration
History of psychiatric illness or social situations that would limit compliance with study requirements
Clinically active infection as judged by the site investigator
Known history of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C
History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the site investigator
Known history of active TB
History of hypersensitivity to pembrolizumab, docetaxel, gemcitabine, pemetrexed or any of their excipients
Has received a live vaccine within 30 days prior to planned start of study therapy