Patients in both cohorts must have progressive disease following prior therapy; specifically:\r\n* Cohort 1 (NSCLC): Patients must have evidence of radiologic or clinical disease progression during previous treatment with systemic PD-1 directed therapy and/or have been deemed not to derive clinical benefit from PD-1 directed treatment; this includes patients who demonstrated an initial response and subsequent progression; no prior treatment with chemotherapy or targeted agents are required; intervening therapy is allowed between previous PD-1 directed treatment and there is no required interval from prior PD-1 treatment required; PD-1 directed treatment includes treatment with antibodies targeting the PD-1 receptor such as pembrolizumab or nivolumab, as well as PD-L1 targeted antibodies such as MEDI4736 (durvalumab), atezolizumab and avelumab; these agents may have been administered as part of a clinical trial\r\n* Cohort 2 (colorectal cancer): Patients must have progressed on >= one line chemotherapyXx_NEWLINE_xXPrior exposure to immune-mediated therapy, including durvalumab and tremelimumab, except for anti-PD-1 or anti-PD-L1 therapy (including durvalumab) in NSCLC patients; this includes anti-CTLA-4 agents (prior treatment with these agents is NOT allowed in either cohort) and, excludes therapeutic anticancer vaccines, excluding therapeutic anticancer vaccines; exposure to other investigational agents may be permitted after discussion with the study principal investigator (PI)Xx_NEWLINE_xXPatient has received prior therapy with an anti- programmed death receptor 1 (anti-PD-1), anti-PD-1- ligand-1 (anti-PD-L1), or anti-PD-1 ligand-2 (anti-PD- L2) agent.Xx_NEWLINE_xXPatients may have received prior anti-CTLA4 or other anti-PD-1/anti-PD-L1 therapy, not both, provided that it is completed >= 4 weeks prior to registrationXx_NEWLINE_xXNo prior treatment with any therapy on the PD-1/PD-L1 axisXx_NEWLINE_xXPatients must have had prior treatment with anti-PD1 or anti-PD-L1 agents and had documented disease progression either while on these agents or after stopping therapy with these agents without intervening therapy; patients must have discontinued anti-PD-1 or anti-PD-L1 therapy at least 21 days prior to registrationXx_NEWLINE_xXPatients must not have achieved a confirmed partial or complete response to the anti-PD-1 or anti-PD-L1 agents prior to progressionXx_NEWLINE_xXPatients must not have had systemic therapy, excluding anti-PD-1 or anti-PD-L1 agents, within 21 days prior to registrationXx_NEWLINE_xXPatients must not have had:\r\n* Prior treatment with ipilimumab or other CTLA-4 antagonists\r\n* Systemic therapy between progression on the anti-PD-1 or anti-PD-L1 agents and registration\r\n* Note: Systemic therapy (including BRAF-targeting agents) prior to anti-PD-1 or anti-PD-L1 therapy is allowedXx_NEWLINE_xXPatients who have received prior therapy with midostaurin, any anti-PD-1 or anti-PD-L1 therapy, any deoxyribonucleic acid (DNA)-methyltransferase inhibitor (including hypomethylating agents such as azacitidine, decitabine, or other investigational agent that acts by inhibiting DNA or ribonucleic acid [RNA] methylation) for any condition, or prior intensive cytotoxic therapy for myelodysplastic syndrome (MDS), are not eligibleXx_NEWLINE_xXPatients must not have had prior immunotherapy with anti-PD-L1, anti-PD-1, anti-CTLA4 or similar drugs; patients must not be planning to receive any of the prohibited therapies during the screening or treatment phases of the studyXx_NEWLINE_xXPatients must not have had systemic chemotherapy or immunotherapy, including, but not limited to interferon alfa-2b, high dose interleukin 2 (IL-2), pegylated interferon (PEG-IFN), anti-programmed cell death protein 1 (PD-1), anti-PD-L1, intra-tumoral, or vaccine therapies within 6 weeks prior to cycle 1, day 1; patients must not have received or be planning to receive any of the prohibited therapies during protocol treatment; prior intravesical interferon therapy is allowedXx_NEWLINE_xXPrior experimental (non-Food and Drug Administration [FDA] approved) therapies and immunotherapies are allowed; patients must not have received these therapies for 4 weeks prior to the initiation of study treatment and must have recovery =< grade 1 from any adverse events of these therapies (other than alopecia); prior treatment with any PARP inhibitor or any anti-PD-1/anti-PD-L1 antibody is NOT allowedXx_NEWLINE_xXPrior treatment with any PARP inhibitor or any anti-PD-1/anti-PD-L1 antibodyXx_NEWLINE_xXPrior treatment with lenvatinib or any PD-1, anti-PD-L1, or anti-PD-L2 agent, excluding melanoma and NSCLC where prior treatment with one PD-1, anti-PD-L1, or anti-PD-L2 agent is allowedXx_NEWLINE_xXPrior PD-1- or PD-L1-directed therapy.Xx_NEWLINE_xXNo prior therapy with a CDK 4/6 inhibitor; prior anti-PD-1 and anti-PD-L1 therapy is permittedXx_NEWLINE_xXPrior treatment with an agent that blocks the PD-1/PD-Ligand 1 pathway;Xx_NEWLINE_xX6. Part A: Prior exposure to immunotherapy such as but not limited to other anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodies excluding vaccines. Part B: Exclusion of prior immunotherapy exposure will be limited to anti-PD-1, anti-PD-L1, or anti-PD-L2;Xx_NEWLINE_xXReceived any systemic therapy for cancer treatment including immunotherapeutic agents such as anti-PD1 or anti-PD-L1 antibody therapy.Xx_NEWLINE_xXPrior therapy with a PD-1, PD-L1, PD-L2 or CTLA-4 inhibitor or a lung cancer-specific vaccine therapyXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPrior therapy with any antibody or drug targeting T-cell coregulatory proteins (immune checkpoints), such as PD-1, PD-L1, or cytotoxic T lymphocyte antigen-4.Xx_NEWLINE_xXKey Inclusion Criteria Part 1:\n\n          -  Patients with advanced (unresectable) or metastatic solid tumor and have disease\n             progression after treatment with available therapies that are known to confer clinical\n             benefit or who are intolerant to treatment.\n\n          -  Patients must have tumor tissue available.\n\n          -  Female patients must have a negative serum or urine pregnancy test or be of\n             non-childbearing potential.\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to\n             1 and adequate organ function.\n\n        Key Inclusion Criteria Part 2:\n\n        - Patients must have not been previously treated with an anti - LAG - 3, anti - PD - 1,\n        anti - PD - L1, or anti - PD - L2 antibody.\n\n        Key Exclusion Criteria for all:\n\n          -  Known uncontrolled central nervous system metastases and - or carcinomatous\n             meningitis.\n\n          -  History of human immunodeficiency virus (HIV), active Hepatitis B or Hepatitis C.\n\n          -  Participated in another investigational study (drug or device) within 4 weeks of first\n             dose.\n\n          -  Received prior anticancer therapy within 21 days of first dose.\n\n          -  Not recovered from Adverse Events (AEs) and - or complications from major surgery\n             prior to first dose.\n\n          -  Vaccine within 7 days of planned start of study treatment.Xx_NEWLINE_xXPatient with melanoma, ovarian cancer, renal cell carcinoma, colorectal cancer, and other solid tumors who have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL2 antibody; melanoma patients who received anti-PD-1 antibodies in the adjuvant setting are allowed to participate as long as their last anti-PD-1 antibody was given at least 6 months prior to their planned start of study therapyXx_NEWLINE_xXPrior treatment with immune checkpoint inhibitor, including (but not limited to) those targeting PD-1, PD-L1, PD-L2, CTLA-4, CD137, GITR, TIM3, LAG3, or OX40Xx_NEWLINE_xXTissue specimen available for retrospective analysis of PD-1, PD-L1, LAG-3, and MHC-II expressionXx_NEWLINE_xXSubject has already received one of the following therapy/treatment: anti-PD-1, anti-PD-L1, or anti-PD-L2 inhibitor.Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHistologically or cytologically confirmed unresectable or metastatic melanoma that had confirmed progressive disease during treatment with anti-PD-1/PD-L1 therapy. Subjects with BRAF activating mutation could have also received a BRAF inhibitor and/or MEK inhibitor regimen prior to anti-PD-1/PD-L1 therapy.Xx_NEWLINE_xXPrevious exposure to any immunomodulatory agents (e.g., anti- CD40, CTLA-4, PD-1/PD-L1, IDO inhibitors) or any other immunomodulatory agent (with the following (except PD-1/PD-L1 in subjects with unresectable or metastatic melanoma)Xx_NEWLINE_xXHistory of life-threatening toxicity related to prior anti-PD-1/PD-L1 treatment for subjects with metastatic melanomaXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2, or HSP inhibitorXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent; has been on any prior Merck MK-3475 (pembrolizumab) studiesXx_NEWLINE_xXRefractory to prior anti-PD-1/PD-L1 agentXx_NEWLINE_xXThe subject has received prior pembrolizumab or any other anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy, or has participated in any prior studies involving pembrolizumabXx_NEWLINE_xXPrevious therapy with any PD-1 or PD-L1 inhibitor including durvalumab or anti-CTLA4 (including tremelimumab) for any malignancy.Xx_NEWLINE_xXPrior treatment with lenvatinib or any anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXIntolerance to prior anti-PD-1/PD-L1 therapyXx_NEWLINE_xXPrior anti-PD-1 treatment for combination dose expansion cohorts 3e - 3hXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent; please contact the principal investigator for further clarification if neededXx_NEWLINE_xXPrior therapy with PD-1/PDL-1 inhibitors is allowed provided any toxicity attributed to prior PD-1- or PD-L1-directed therapy did not lead to discontinuation of therapy.Xx_NEWLINE_xXPrior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2 oranti-CTLA-4 antibodyXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPatient has received prior immunotherapy with inhibitors of PD-1/PD-L1 axisXx_NEWLINE_xXSubject on prior chemotherapeutic, immunomodulator (such as anti-CTLA-4, anti-PD-1 or anti-PD-L1 inhibitor), investigational, or other therapies for the treatment of cancer must wait at least 28 days after the last dose of these therapies before administration of the first dose of the IMP.Xx_NEWLINE_xXPrior anti-PD-1 or anti-PD-L1 therapy may not be administered after ACT and before study atezolizumab (MPDL3280A) administrationXx_NEWLINE_xXCOHORT 1: Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXCOHORT 2: Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPrior exposure to an anti-PD-1, anti-PD-L1 or anti-PD-L2Xx_NEWLINE_xXPrior therapies targeting PD-1, programmed death-ligand 1 (PD-L1), or PARP.Xx_NEWLINE_xXPrior treatment with combination CTLA-4 and PD-1/PD-L1 blockade.Xx_NEWLINE_xXPrior treatment with PD-1 and programmed death ligand (PD-L)1 inhibitorsXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (only cohort A)Xx_NEWLINE_xXPrior therapy with a PD-1, anti-PD-Ligand 1 (PD-L1), or anti-PD-L2 agent, or previously participated in Merck pembrolizumab (MK-3475) studyXx_NEWLINE_xXSubjects previously treated with any anti-PD-L1 antibody are eligible for study participation).Xx_NEWLINE_xXPrior treatment with the following agents (from last dose of prior treatment to first dose of GSK3174998): Tumor necrosis factor receptor (TNFR) agonists, including OX40, CD27, CD137 (4-1BB), CD357 (GITR): at any time; Checkpoint inhibitors, including PD-1, PD-L1, and anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors: within 4 weeks.Xx_NEWLINE_xXPrior treatment with a PD-1/PD-L1 inhibitorXx_NEWLINE_xXPrevious treatment with any anti-PD-1, PD-L1, or PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor.Xx_NEWLINE_xXPrior therapy with an immune checkpoint inhibitor therapy is allowable. A 6-week washout period will be required for those with prior PD-1 or PD-L1 treatment.Xx_NEWLINE_xXFor patients with mCRPC, prior exposure to any agent (approved or investigational) that blocks the PD-1/PD-L1 pathway.Xx_NEWLINE_xXHas received prior systemic anti-cancer therapy including investigational agents or has used an investigational device within 28 days prior to the first dose of study treatment. (Notes: Participants must have recovered from all AEs due to previous therapies to ?Grade 1 or baseline. Prior exposure to immunotherapeutics is allowed, including programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors, provided the participant did not experience ?Grade 3 drug-related toxicity on monotherapy with a PD-1 or PD-L1 inhibitor.Xx_NEWLINE_xXReceived prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPatient may be second- or later-line NSCLC patient, and must have documented radiological and/or clinical progression on a prior anti-PD-1/PD-L1 containing therapy.Xx_NEWLINE_xXPrior treatment with a platinum-based (cisplatin or carboplatin) regimen and a PD-1 or PD-L1 monoclonal antibody (either in combination or sequentially).Xx_NEWLINE_xXPrior treatment with a PD-1, PD-L1 or PD-L2 inhibitorXx_NEWLINE_xXPrior PD-1/PD-L1 treatment is permitted in Part B of this study, but only subjects who have progressed on their prior PD-1/PD-L1 treatment without a partial or complete response, and without discontinuing for drug-related toxicity are eligible for Part B.Xx_NEWLINE_xXSubjects who have received prior anti-PD-1 or anti-PD-L1 antibody, or an IDO inhibitor; subjects who have received experimental vaccines or other immune therapies should be discussed with the principal investigator to confirm eligibilityXx_NEWLINE_xXPatients undergoing a minimally invasive PD, such as laparoscopic or robotic PDXx_NEWLINE_xXPrior therapy with any of the following: PD-1, PD-L1, CTLA4 antibody, or any other drug targeting T cell checkpoint pathways.Xx_NEWLINE_xXPatients who have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent are not eligibleXx_NEWLINE_xXPrior anti-cancer treatments such as chemotherapy, radiotherapy, hormonal, or immunotherapy (including anti-PD-1/PD-L1) are permittedXx_NEWLINE_xXFor Phase 1a and 1b, prior PD-1 or PD-L1 therapy or other immunotherapy is allowed, if the following criteria are met:Xx_NEWLINE_xXPrior disease progression on anti-PD-1 therapyXx_NEWLINE_xXPrior treatment with PD-1 or PD-L1 inhibitorXx_NEWLINE_xXPatients must have evidence of radiologic or clinical disease progression during or within 6 months of previous treatment with systemic PD-1 directed therapy, or have stable disease on prior PD-1 therapy (at least 6 doses) and/or have been deemed not to derive clinical benefit from PD-1 directed treatment; PD-1 directed treatment includes treatment with antibodies targeting the PD-1 receptor such as pembrolizumab or nivolumab, as well as PD-L1 targeted antibodies such as durvalumab; these agents may have been administered as part of a clinical trial, and/or in combination with other immunologic agents such as CTLA-4 inhibitors or other investigational agentsXx_NEWLINE_xXPrevious treatment with a CTLA-4, PD-1, or PD-L1 inhibitor, including prior treatment with either durvalumab or tremelimumabXx_NEWLINE_xXFor Cohort Expansion, patients who have previously received an immune checkpoint inhibitor (e.g., anti-PD-L1, anti-PD-1, anti-CTLA-4) are not eligible for this study.Xx_NEWLINE_xXPrevious treatment with any anti-PD-1, PD-L1, or PD-L2 agentXx_NEWLINE_xXPrevious treatment with atezolizumab or another programmed death-1 (PD-1)/PD-L1 inhibitorXx_NEWLINE_xXReceived prior therapy with an anti-CTLA-4, anti-PD-1, anti-PD1-ligand-1 (anti-PD-L1), or anti-PD-1 ligand-2 (anti-PD-L2) agent within 8 weeks prior to initiation of study treatment depending on study partXx_NEWLINE_xXINCLUSION CRITERIA - For Parts 1-4:\n\n          -  Willing and able to provide written informed consent\n\n          -  Histologically confirmed diagnosis of a locally advanced (not amenable to curative\n             therapy such as surgical resection) or metastatic melanoma, RCC, NSCLC, urothelial\n             carcinoma, or TNBC\n\n          -  Male or female patients, age 18 years or older at the time of signing the informed\n             consent form (ICF)\n\n          -  Life expectancy > 12 weeks\n\n          -  Patients must not have received prior interleukin-2 (IL-2) therapy\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1\n\n          -  Measurable disease per RECIST 1.1\n\n          -  Demonstrated adequate organ function within 14 days of treatment initiation\n\n          -  Oxygen saturation ? 92% on room air.\n\n          -  Subjects must be recovered from the effects of any prior chemotherapy, immunotherapy,\n             other prior system anticancer therapy, radiotherapy, or surgery. Clinically\n             significant toxic effect(s) of the most recent prior chemotherapy must be resolved to\n             Grade 1 or less (except alopecia and sensory neuropathy).\n\n          -  Women of childbearing potential must agree to use highly effective methods of birth\n             control. All participants must agree to use double barrier contraception during study\n             participation for at least 6 months after the last dose of study drugs.\n\n          -  Patients with stable brain metastases may be enrolled if certain criteria are met.\n\n          -  Fresh and archival tumor tissue available\n\n          -  Additional criteria may apply.\n\n        INCLUSION CRITERIA - For Part 2:\n\n          -  MELANOMA:\n\n               -  Histologically confirmed stage III (unresectable) or stage IV melanoma, as per\n                  American Joint Committee on Cancer (AJCC) staging system\n\n               -  Ocular melanoma will be excluded\n\n          -  Melanoma Subpopulation A 1st-line (1L):\n\n               -  Have not received prior anti-cancer therapy for advanced or metastatic melanoma\n\n               -  Known BRAF status, or consent to testing, as per regionally acceptable V600\n                  mutational status testing\n\n          -  Melanoma Subpopulation B (2nd- and 3rd-line (2-3L), anti-PD-1 or anti-PD-L1 therapy\n             relapsed/refractory):\n\n               -  2-3L, patients must have confirmed radiographic disease progression no earlier\n                  than 4 weeks after initial disease progression but within 3 months from last dose\n                  of anti-PD-1 or anti PD-L1 containing regimen. Patients must consent to providing\n                  pre-study scans (if available) to confirm radiographic progression.\n\n               -  Patients may have received no more than 1 prior anti-angiogenic therapy or\n                  cytotoxic chemotherapy regimen.\n\n          -  RENAL CELL CARCINOMA (RCC):\n\n               -  Advanced (not amenable to curative surgery or radiation therapy) or metastatic\n                  (AJCC stage IV) RCC\n\n               -  Histologically confirmed RCC with a clear-cell component.\n\n          -  RCC Subpopulation A (1L):\n\n               -  1L, patients may have not received prior anti-cancer therapy for advanced or\n                  metastatic RCC.\n\n          -  RCC Subpopulation B (2-3L, anti-PD-1 or anti-PD-L1 relapsed/refractory):\n\n               -  2-3L, patients must have confirmed radiographic disease progression no earlier\n                  than 4 weeks after initial disease progression but within 3 months from last dose\n                  of anti-PD-1 or anti-PD-L1 containing regimen. Patients must consent to providing\n                  pre-study scans (if available) to confirm radiographic.\n\n               -  Patients may have received no more than 1 prior anti-angiogenic therapy or\n                  cytotoxic chemotherapy regimen.\n\n          -  NON-SMALL CELL LUNG CANCER (NSCLC):\n\n               -  Histologically confirmed or cytologically confirmed diagnosis of stage IV NSCLC\n\n                    -  Patients with nonsquamous NSCLC must lack epidermal growth factor receptor\n                       (EGFR)-sensitizing mutation and/or anaplastic lymphoma kinase (ALK)\n                       translocation\n\n          -  NSCLC Subpopulation A (1L):\n\n               -  1L, patients must not have received prior anti-cancer therapy for advanced or\n                  metastatic NSCLC. Patients must have known PD-L1 status as per validated\n                  immunohistochemistry testing. Up to 20 patients will be enrolled in each\n                  subgroup:\n\n                    -  PD-L1 negative (PD-L1 < 1%),\n\n                    -  PD-L1 positive (PD-L1 ? 50%),\n\n                    -  PD-L1 low/intermediate (PD-L1 ? 1% - < 50%).\n\n               -  For patients who do not have known PD-L1 status, testing must be done using an\n                  FDA-approved PD-L1 test.\n\n          -  NSCLC Subpopulation B (2L, I-O therapy naïve):\n\n               -  2L, patients must have experienced disease recurrence or progression during or\n                  after one prior platinum doublet-based chemotherapy regimen for advanced or\n                  metastatic disease. Patients who received platinum-containing adjuvant,\n                  neoadjuvant, or definitive chemoradiation therapy given for locally advanced\n                  disease and developed recurrent (local or metastatic) disease within 6 months of\n                  completing therapy are eligible. Patients must not have received any prior\n                  immune-oncology regimens, including but not limited to checkpoint inhibitors such\n                  as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any\n                  other antibody or drug specifically targeting T cell co-stimulation or checkpoint\n                  pathways, indoleamine 2,3 dioxygenase pathway inhibitors, cancer vaccines,\n                  adoptive cell therapies, or other cytokine therapies.\n\n          -  NSCLC Subpopulation C (2-3L, anti-PD-1 or anti-PD-L1 relapsed/refactory):\n\n               -  2-3L, patients must have confirmed radiographic disease progression no earlier\n                  than 4 weeks after initial disease progression but within 3 months from last dose\n                  of anti-PD-1 or anti-PD-L1 containing regimen. Patients must consent to providing\n                  pre-study scans (if available) to confirm radiographic.\n\n          -  UROTHELIAL CARCINOMA (UC)\n\n               -  Histologically or cytologically documented locally advanced or transitional cell\n                  carcinoma of the urothelium including renal pelvis, ureters, urinary bladder, or\n                  urethra. Patients with mixed histologies are required to have a dominant\n                  transitional cell pattern.\n\n               -  For patients who received prior adjuvant/neoadjuvant chemotherapy or\n                  chemo-radiation for urothelial carcinoma, a treatment-free interval of more than\n                  12 months between the last treatment administration and the date of recurrence is\n                  required to be considered treatment naive in the metastatic setting.\n\n          -  UC Subpopulation A (1L)\n\n               -  Enrollment of urothelial carcinoma 1L patients will target accrual of up to 20\n                  patients who are cis-ineligible and up to 20 patients, who after consultation\n                  with the Investigator, choose to forego front-line chemotherapy\n\n               -  Treatment naive and cisplatin-eligible patients who refuse standard of care.\n\n          -  UC Subpopulation B (1L) cisplatin-ineligible\n\n               -  Treatment naive and cisplatin-ineligible patients who meet at least one of the\n                  following criteria:\n\n                    -  Creatinine clearance (calculated or measured) < 60 mL/min\n\n                    -  Common Terminology Criteria for Adverse Events (CTCAE) v4.03 Grade ? 2\n                       audiometric hearing loss\n\n                    -  CTCAE v4.03 Grade ? 2 peripheral neuropathy\n\n                    -  New York Heart Association (NYHA) Class III heart failure\n\n               -  No prior chemotherapy for inoperable locally advanced or metastatic urothelial\n                  carcinoma. Prior local intravesical chemotherapy is allowed if completed at least\n                  4 weeks prior to the initiation of study treatment.\n\n               -  Patients must not have received any prior immune-oncology regimens, including but\n                  not limited to checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2,\n                  anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically\n                  targeting T cell co-stimulation or checkpoint pathways, indoleamine\n                  2,3-dioxygenase pathway inhibitors, cancer vaccines, adoptive cell therapies, or\n                  other cytokine therapies.\n\n          -  UC Subpopulation C (3L, anti-PD-1 or anti-PD-L1 relapse/refractory)\n\n               -  Patients must have progressed on only one prior line of therapy that contains\n                  platinum-based chemotherapy in the metastatic setting or post platinum-based\n                  chemotherapy in an adjuvant setting with progression < 6 months.\n\n               -  Patients must have received only one prior line of therapy with an anti-PD-1 or\n                  anti-PD-L1 containing regimen, which must be their most recent anti-cancer\n                  treatment.\n\n               -  Patients must have confirmed radiographic disease progression no earlier than 4\n                  weeks after initial disease progression but within 3 months from last dose of\n                  anti-PD-1 or anti-PD-L1 containing regimen. Patients must consent to providing\n                  pre-study scans (if available) to confirm radiographic.\n\n          -  TRIPLE-NEGATIVE BREAST CANCER (1-2L, I-O therapy naïve)\n\n               -  Less than 1% of tumor cell nuclei test positive for estrogen and progesterone\n                  receptors determined by using standard immunohistochemistry (IHC)\n\n               -  Human epidermal growth factor 2 (HER2) negative as determined by local\n                  pathologist, using IHC or in situ hybridization\n\n               -  Patients may have received only 1 prior line of therapy with chemotherapy,\n                  adjuvant setting excluded, or patient refuses standard of care.\n\n               -  Must not have received any prior immune-oncology regimens, including but not\n                  limited to checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2,\n                  anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically\n                  targeting T cell co-stimulation or checkpoint pathways, indoleamine 2,\n                  3-dioxygenase pathway inhibitors, cancer vaccines, adoptive cell therapies, or\n                  other cytokine therapies.\n\n        INCLUSION CRITERIA - For Parts 3 and 4:\n\n          -  RENAL CELL CARCINOMA (1L):\n\n               -  Advanced (not amenable to curative surgery or radiation therapy) or metastatic\n                  (AJCC stage IV) RCC.\n\n               -  Histologically confirmed RCC with a clear-cell component.\n\n               -  Patients must not have received prior anti-cancer therapy for advanced or\n                  metastatic RCC\n\n          -  NON-SMALL CELL LUNG CANCER (1L):\n\n               -  Histologically confirmed or cytologically confirmed diagnosis of stage IV NSCLC\n\n               -  Patients with nonsquamous NSCLC must lack epidermal growth factor receptor\n                  (EGFR)-sensitizing mutation and/or anaplastic lymphoma kinase (ALK)\n                  translocation.\n\n               -  Patients must not have received prior anti-cancer therapy for advanced or\n                  metastatic NSCLC.\n\n        EXCLUSION CRITERIA - For Parts 1-4:\n\n          -  Use of an investigational agent or an investigational device within 28 days before\n             administration of first dose of NKTR--214\n\n          -  Females who are pregnant or breastfeeding\n\n          -  Participants who have an active autoimmune disease requiring systemic treatment within\n             the past 3 months or have a documented history of clinically severe autoimmune disease\n             that requires systemic steroids or immunosuppressive agents\n\n          -  History of organ transplant that requires use of immune suppressive agents\n\n          -  History of allergy or hypersensitivity to study drug components\n\n          -  Active malignancy not related to the current diagnosed malignancy\n\n          -  Evidence of clinically significant interstitial lung disease or active, noninfectious\n             pneumonitis\n\n          -  Prior surgery or radiotherapy within 14 days of therapy\n\n          -  Participants who have had < 28 days since the last chemotherapy, biological therapy,\n             or < 14 days from approved tyrosine kinase inhibitor (TKI) therapy (sunitinib,\n             sorafenib, vemurafenib, dabrafenib, cobimetinib, erlotinib, gefitinib, afatinib,\n             osimertinib), or systemic or inhaled steroid therapy at doses greater than 10mg of\n             prednisone or equivalent before administration of the first dose of study medication\n\n          -  Participant's inability to adhere to or tolerate protocol or study procedures\n\n          -  Additional criteria may apply.Xx_NEWLINE_xXPrior treatment with anti-PD-1 or PD-L1 therapiesXx_NEWLINE_xXInclusion Criteria (Phase 1 and 2 Melanoma and HNSCC patients)\n\n          -  Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.\n\n          -  Life expectancy of at least 6 months.\n\n          -  Have provided tissue biopsy sample enough for PD-L1 expression level testing and RNA\n             expression profiling.\n\n        Inclusion Criteria: Phase 2 Melanoma patients\n\n          -  Histologically or cytologically confirmed unresectable or metastatic (stage IV)\n             melanoma.\n\n          -  Have at least 2 sites that qualify as measurable target lesions per RECIST 1.1 of\n             which 1 must be palpable or visualized by ultrasound and easily accessible to multiple\n             intratumoral injections.\n\n          -  For patients with progressive disease (PD) while receiving anti-PD-1/L1 therapy, must\n             have documented PD per RECIST v1.1 while receiving a prior anti-PD-1/L1 therapy.\n\n        Inclusion Criteria: Phase 2 HNSCC patients\n\n          -  Histologically or cytologically confirmed recurrent or metastatic HNSCC that could not\n             be treated with curative intent.\n\n          -  Have at least 1 measurable target lesion per RECIST 1.1, which must be accessible and\n             amenable to multiple intratumoral injections.\n\n          -  Must have documented PD per RECIST v1.1 while receiving a prior anti-PD-1/L1 therapy.\n\n        Exclusion Criteria: (Phase 1 and 2 Melanoma and HNSCC patients)\n\n          -  Received systemic chemotherapy or biological cancer therapy (except anti-PD-1/L1\n             therapy) within 3 weeks prior to study enrollment.\n\n          -  Received prior radiotherapy within 2 weeks of start of study therapy.\n\n          -  Received small molecule inhibitor targeted therapy, such as tyrosine kinase\n             inhibitors, within 2 weeks prior to study enrollment.\n\n          -  Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other\n             form of immunosuppressive therapy (including immune modulators or systemic\n             corticosteroids) within 7 days prior to study enrollment\n\n          -  Is expected to require any other form of anti-cancer therapy while in the trial.\n\n          -  Positive for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).\n\n          -  History of or current uveal or ocular melanoma.\n\n          -  Active infection including cytomegalovirus.\n\n          -  Active autoimmune disease requiring systemic treatment in the past 2 years or a\n             disease that requires immunosuppressive medication. Replacement therapy is not\n             considered a form of systemic treatment.\n\n          -  Current pneumonitis or history of (non-infectious) pneumonitis that required steroids.\n\n          -  Known active central nervous system metastases or carcinomatous meningitis.\n\n          -  Use of any investigational agent within the last 28 days prior to study enrollment.\n\n          -  Has received a live-virus vaccination within 30 days of planned treatment start.\n             Seasonal flu vaccines that do not contain live virus are permitted.\n\n          -  Any known additional malignancy that is progressing or requires active treatment,\n             except for melanoma and HNSCC.\n\n        Exclusion Criteria (Phase 2, Melanoma Expansion Cohorts 1 and 5 only)\n\n          -  Any prior combination therapy targeting immunoregulatory receptors or mechanisms and\n             an anti-PD-1/L1 agent or an investigational agent targeting immunoregulatory receptors\n\n          -  Prior therapy with an anti PD 1/L1 agent\n\n        Exclusion Criteria: (Phase 2, Melanoma Expansion Cohort 2 only)\n\n        • Any prior combination therapy involving agents given by intratumoral injection that\n        target the innate immune pathway or system.\n\n        Exclusion Criteria: (Phase 2, HNSCC Expansion Cohorts 3 and 6 only)\n\n          -  Prior therapy with an anti PD 1/L1 agent\n\n          -  Require treatment on anticoagulation therapy.\n\n        Exclusion Criteria (Phase 2, HNSCC Expansion Cohorts 4 and 7 only)\n\n          -  Any prior combination therapy involving agents given by intratumoral injection that\n             target the innate immune pathway or system.\n\n          -  Require treatment on anticoagulation therapyXx_NEWLINE_xXThe participant has received prior pembrolizumab or any other anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy, or has participated in any prior studies involving pembrolizumabXx_NEWLINE_xXPrior therapy with specific antibody/drug targeting immune or coregulatory or costimulatory proteins (such as checkpoints e.g., PD-1 or PD L1, 4-1BB, OX40 or CTLA-4 antibodies).Xx_NEWLINE_xXPrior treatment with anti?PD-1, or anti?PD-L1 therapeutic antibody or pathway-targeting agentsXx_NEWLINE_xXPatients can be treated either in first line or in the refractory setting; PD-L1 positivity is not required for enrollmentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPatient has received immunotherapy with inhibitors of PD-1 or PD-L1, or CTLA-4 blocking antibodies within 4 months prior to study day 1Xx_NEWLINE_xXPatient must have previously received one (but no more) line of previous therapy with an anti-PD-1/PD-L1 mAb therapy either alone or in combination and have either progressed or responded and then stopped responding.Xx_NEWLINE_xXPatients must have previously received at least one line (and not more than 2 lines) of previous therapy with an anti-PD-1/PD-L1 mAb therapy, either alone or in combination, and have either progressed or responded and then stopped responding.Xx_NEWLINE_xXPrevious treatment with a PD-1 or PD-L1 inhibitor with documented progression of disease on most recent computed tomography (CT) scan; progression of disease is defined as 1) the appearance of a new measureable lesion (> 10 mm) on cross-sectional imaging or physical exam OR 2) enlargement of previously detected lesions on two consecutive imaging studies OR 3) enlargement of a previously detected lesion with correlative symptomatology on one cross-sectional imaging study; patients remain eligible if they had a previous response to a PD-1 inhibitor, including patients who had a complete response, partial response or stable disease; primary progressing patients are defined as those who received anti-PD-1 therapy within 2 months of study enrollment; patients with relapsed disease are defined as those who received their last dose of PD-1 blocking antibody >= 2 months prior to enrollmentXx_NEWLINE_xXPatients who received adjuvant PD-1 therapy who then develop measurable disease are eligible; however, they must have received their last dose of PD-1/PD-L1 blockade within two months of enrollment in this trial; they will be stratified with patients who have progressive diseaseXx_NEWLINE_xXPreviously treated with a PD-1/PD-L1-blocking antibody or a histone deacetylase inhibitorXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent\r\n* This criterion does not apply to eligibility for second course treatmentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPrevious therapy with histone deacetylase (HDAC) inhibitor and/or anti PD 1, anti PD L1, or anti CTLA4 immunotherapy.Xx_NEWLINE_xXHave available evaluable archival tumor tissue for PD-L1 biomarker assessment; presence of PD-L1 antigen on tumors is NOT required for study entryXx_NEWLINE_xXLast dose of prior immunotherapies including but not limited to: interferon alpha, interferon-beta, interleukin (IL)-2, conjugated IL-2, cergutuzumab amunaleukin (CEA-IL2v) , cytokines, anti-cytotoxic T lymphocyte antigen-4, anti-PD-L1, or anti-PD-1 <28 days prior to first cergutuzumab amunaleukin infusionXx_NEWLINE_xXHistory of severe immune-related adverse effects from CEA-IL2v or anti-PD-1 (nivolumab, pembrolizumab) or anti-PD-L1 (atezolizumab) therapies (Common Terminology Criteria for Adverse Events Grade 3 and 4)Xx_NEWLINE_xXPatients who are receiving or have been treated with antibody to CTLA4 (e.g. ipilimumab), PD-1, PD-L1, CD137, or CD27 within the prior 12 months. Any patient who has had one or more of these therapies greater than 12 months prior and is clinically free of disease and totally recovered from toxicities related to those therapies can be eligible.Xx_NEWLINE_xXGrade 3 or 4 major organ immune-related adverse events (IRAEs) following treatment with anti-PD-1/PD-L1Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.Xx_NEWLINE_xXPrior therapy with anti-PD-L1 and anti-PD1 antibodies, MEK inhibitors or MDM2 antagonists.Xx_NEWLINE_xXPatients must not have had prior immunotherapy with anti-PD-L1, anti-PD-1, anti-CTLA4 or similar drugs.Xx_NEWLINE_xXPhase 2: Patients with histologically or cytologically confirmed diagnosis of one of the following and with progressive disease during or after treatment with a PD-1 or PD-L1-inhibitor:Xx_NEWLINE_xXPrior immunotherapy including anti-PD-1, anti-PD-L1, or anti-PD-L2 agentsXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXFor Cohort A: Subjects who have radiographically confirmed disease progression during or following treatment with an anti-PD-1/PD-L1 based therapy;Xx_NEWLINE_xXKnown hypersensitivity allergy or contraindication to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the PD-1/PD-L1 inhibitor formulation;Xx_NEWLINE_xXDocumented disease refractory to at least one PD1/PD-L1 (+/- CTLA-4) inhibitor treatment, or intolerance to these drugsXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)Xx_NEWLINE_xXPrior immunotherapy including but not limited to anti-CTLA4, including tremelimumab anti-PD-1, and anti-PD-L1, including durvalumab.Xx_NEWLINE_xXRefractory patients who are naïve to anti-PD-1/PDL-1 therapy OR Relapsed after 3 or more lines of therapies; and are naïve to anti-PD-1/PDL-1 therapy ORXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXMeet criteria for either the acquired resistance OR the suboptimal benefit cohort\r\n* Acquired resistance is defined as (must both be met):\r\n** Prior benefit from anti-PD-1/PD-L1 therapy defined as a) prior response, and/or b) ? 5 months of stable disease (SD); intervening therapies are allowed\r\n** Progressive disease (PD) on recent scans\r\n* Suboptimal benefit is defined as (must both be met):\r\n** Prolonged stable disease ? 5 months OR suboptimal response (> 10% & < 50% shrinkage per Response Evaluation Criteria in Solid Tumors [RECIST] at any evaluation timepoint) \r\n** Ongoing stable disease on recent scans\r\n** Last treatment with an anti-PD-1/PD-L1 agent within 6 weeks prior to starting protocol treatmentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPrevious treatment with a PD-1, PD-L1 or CTLA-4 targeted therapy.Xx_NEWLINE_xXPatients with prior treatment with PD-1 or PD-L1 inhibitorXx_NEWLINE_xXDisease progression on prior PD-1/PD-L1 therapy in any line. Subjects must have received a minimum of 4 doses of anti-PD-1/PD-L1 therapy. If subjects have received fewer than 4 doses of anti-PD-1/PD-L1 therapy, documented radiologic progression and sponsor approval is necessary prior to inclusion.Xx_NEWLINE_xX14 days for prior PD-1 therapy.Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXFor Parts B and C, patients who received previous anti- PD-1, anti-PD-(L)1 treatmentXx_NEWLINE_xXPatients may not have received prior anti PD-1 or anti PD-L1 inhibitorsXx_NEWLINE_xXHistory of prior therapy with an IDO1 inhibitor in combination with an anti-PD-1/anti-PD-L1 agent/any other drug specifically targeting checkpoint pathways; patients who have received prior therapy with single agent anti-PD-1/anti-PD-L1 therapy or single agent IDO1 inhibitor will be eligible for this studyXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PDL2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (TCR) (e.g., CTLA-4, OX 40, CD137).Xx_NEWLINE_xXCOHORT 2: TRIPLE NEGATIVE BREAST CANCER: Eligible patients may or may not have received prior chemotherapy and there is no limit to the number of prior chemotherapy; patients are also eligible if they have received treatment with immunotherapy, such PD-1 inhibitors, PD-L1 inhibitors or CTLA4 inhibitorsXx_NEWLINE_xXCOHORT 3: ENDOMETRIAL CANCER: Women with endometrial cancer must have had at least one prior line of therapy in the metastatic/recurrent setting but there is no limit to the number of prior chemotherapy lines; patients are eligible if they have received treatment with immunotherapy, such PD-1 inhibitors, PD-L1 inhibitors or CTLA4 inhibitorsXx_NEWLINE_xXParticipants who have received previous immunotherapy for any cancer (excluding melanoma) including PD-1/PD-L1 inhibitors but not interferons and CTLA-4 inhibitorsXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPrior treatment with CD137 agonists, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway targeting agentsXx_NEWLINE_xXPrior treatment with a combination of cetuximab and a PD-1/PD-L1 inhibitor; prior treatment with cetuximab or a PD-1/PD-L1 inhibitor is allowed as long as not previously given in combinationXx_NEWLINE_xXMust be pembrolizumab/nivolumab refractory/resistant – defined as having received at least 2 doses of pembrolizumab (or 2 doses of nivolumab) with documented systemic disease progression on staging imaging; progressive disease (PD) will be defined as increase in tumor burden > 20% relative to nadir (minimum recorded tumor burden) by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1; once PD is confirmed, initial date of PD documentation will be considered as the date of disease progression; patients can be enrolled at any time following initiation of PD-1 therapy up to 1 yearXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, anti-CTLA4 or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.Xx_NEWLINE_xXSubjects should have PD-L1 expression (tumor proportion score [TPS] >= 50%, determined by the Food and Drug Administration [FDA] approved Merck 22C3 antibody PD-L1 test) in the first-line setting and have a TPS > 1% by 22C3 or equivalent PD-L1 expression by an approved immunohistochemistry (IHC) test, in the second-line setting in order to be eligible for pembrolizumab treatment on the current protocol; patients with < 1% PD-L1 expression are not eligibleXx_NEWLINE_xXSubjects may already be receiving PD-(L)1 (including pembrolizumab or other PD-[L]1 inhibitors such as nivolumab, atezolizumab, avelumab, durvalumab) for the treatment of systemic disease; systemic disease must be in complete remission or be stable by RECIST 1.1; a washout period of at least 3 weeks is required from the last dose of PD-(L)1 inhibitorXx_NEWLINE_xXHas previously progressed on a PD-1 or PD-L1 checkpoint inhibitor for systemic diseaseXx_NEWLINE_xXDocumented progression of disease after initiation of therapy with OR lack of response to therapy with a PD-1- or PD-L1-targeting monoclonal antibody (pembrolizumab, nivolumab, etc) after at least 18 weeks; NOTE: This treatment could have been at any time prior to registrationXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.Xx_NEWLINE_xXNo history of prior treatment with inhibitor of PD-1 or PD-L1 or PDL2Xx_NEWLINE_xXPrior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPrior or concurrent immunotherapy, including treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody; tumor vaccines; interferon, or interleukins.Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.Xx_NEWLINE_xXPrior treatment with anti-PD-1, CTLA-4, or anti-PD-L1 therapeutic antibody or pathway-targeting agentsXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXReceived prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPrevious anti-PD1 or anti-PD-L1Xx_NEWLINE_xXPrevious treatment with PD-1 or PD-L1 directed therapyXx_NEWLINE_xXHas received prior immunotherapy including anti–PD-1, anti–PD-L1, or anti–PD-L2 agents, or if the subject has previously participated in Merck pembrolizumab clinical trialsXx_NEWLINE_xXAny previous treatment with a PD1 or PD-L1 inhibitor, including durvalumabXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent within the prior 24 weeksXx_NEWLINE_xXPatients must have analysis of PD-L1 expression in cancer cells quantitated by immunohistochemistry analysisXx_NEWLINE_xXPatients in Cohort 2 (high PD-L1) must have >= 50% expressionXx_NEWLINE_xXPatients in Cohort 3 (low PD-L1) must have 0-49% expressionXx_NEWLINE_xXPrior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 agent, or mifepristoneXx_NEWLINE_xXHas prior exposure to anti-PD1/PD-L1 or anti-CTLA4 therapyXx_NEWLINE_xXClinical or radiographic evidence of disease progression during treatment with PD-1 or PD-L1 inhibiting therapy\r\n* Note: Both the treating medical oncologist and radiation oncologist must be in agreement with determination of disease progressionXx_NEWLINE_xXAdministration of a PD-1 or PD-L1 inhibitor within 60 days prior to study registrationXx_NEWLINE_xXFor patients who discontinued PD-1 or PD-L1 inhibiting therapy during response to therapy, disease progression must have occurred following at least 8 weeks of re-treatment with PD-1 or PD-L1 inhibiting therapyXx_NEWLINE_xXDetermination by the treating medical oncologist that the patient is a candidate to continue the PD-1 or PD-L1 inhibiting therapy that the patient was receiving at the time of the most recent progressionXx_NEWLINE_xXOther anti-cancer therapy administered between the time of tumor response to PD-1 or PD-L1 therapy and time of study enrollment\r\n* Note: Patients treated with a combination of PD-1 or PD-L1 inhibiting therapy and other immunotherapy are eligible; patients taking hormonal anti-cancer therapies or steroids for central nervous system (CNS) edema management that, in the opinion of the investigator, are appropriate to continue are eligibleXx_NEWLINE_xXAny prior PD-1/PD-L1 therapy-related adverse events (AE) that, in the opinion of the investigator, warrants exclusion from participation in this trialXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXAny previous treatment with a PD-1 or PD-L1 inhibitor, including but not limited to: nivolumab, atezolizumab, pembrolizumab, or durvalumabXx_NEWLINE_xXAny previous treatment with a PD1 or PD-L1 inhibitor, including durvalumabXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXParticipant must have histologically confirmed hepatocellular cancer (HCC) that is advanced or metastatic and have archival tissue available for PD-L1, PD-L2 testing (NOTE: if participant has had prior radiotherapy to the liver, a mandatory fresh biopsy will need to be obtained since radiotherapy could affect PD-1/PD-L1 immune status)Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPrior treatment with anti-PD-1/PD-L1, and anti-CTLA-4 is NOT allowed; prior intravesical Bacillus Calmette–Guérin (BCG) therapy is allowedXx_NEWLINE_xXAny previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4, including tremelimumab.Xx_NEWLINE_xXAny previous treatment with a PD1 or PD-L1 inhibitor, including durvalumabXx_NEWLINE_xXReceived prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas been receiving anti-PD-1 or anti-PD-L1 immunotherapy for at least four weeksXx_NEWLINE_xXPrior therapies for extracranial metastatic melanoma including chemotherapy, BRAFi/MEKi, cytokine or vaccine therapy as long as it did not include PD-1/PD-L1Xx_NEWLINE_xXAny previous treatment with a PD1 or PD-L1 inhibitor, including durvalumabXx_NEWLINE_xXPrior exposure to any immuno-oncology agents, including CD40/PD-1/PD-L1/CTLA-4 inhibitors (if any ambiguity, should be discussed with study principal investigator)Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPatients who received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent without having had evidence of objective responseXx_NEWLINE_xXAny previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab, and therapeutic anticancer vaccineXx_NEWLINE_xXPrevious treatment with Anti-CTLA-4 including tremelimumab or PD1/PD-L1 inhibitor, including durvalumabXx_NEWLINE_xXAny previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4, including tremelimumabXx_NEWLINE_xXPatients must have received platinum-based therapy with or without bevacizumab, but may not have received a PD-1, PD-L1 or PD-L2 inhibitorXx_NEWLINE_xXPatients with prior therapy with antibodies that modulate T-cell function (e.g., anti-PD-1, anti-PD-L1)Xx_NEWLINE_xXAny previous treatment with an anti-PD-1, anti-PD-L1 or anti-CTLA-4 therapy, including durvalumab and tremelimumabXx_NEWLINE_xXExclusion criteria related to study medication (any cancer immunotherapy including CD137 agonists, anti-PD-1, anti-PD-L1, or anti-CTLA4 or any MEK or ERK inhibitor)Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXAny previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4, including tremelimumabXx_NEWLINE_xXSubjects must have progressed on or after previous platinum-based chemotherapy; subjects 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 therapyXx_NEWLINE_xXSubjects must be enrolled on the trial within 6 weeks of their last infusion of PD-1 or PD-L1 inhibitor therapyXx_NEWLINE_xXTreatment with any investigational agent within 28 days prior to registration for protocol therapy with the exception of PD-1 or PD-L1 inhibitorsXx_NEWLINE_xXHistory of an immune-related toxicity requiring treatment with corticosteroids during prior PD-1/ PD-L1 inhibitor treatmentXx_NEWLINE_xXADDITIONAL INCLUSION CRITERION FOR COHORT 1 (PD-1/PD-L1 INHIBITOR-NAIVE, CETUXIMAB-NAIVE) AND COHORT 2 (PD-1/PD-L1 INHIBITOR-REFRACTORY, CETUXIMAB-NAIVE):Xx_NEWLINE_xXADDITIONAL INCLUSION CRITERION FOR COHORTS 2 AND 3 (PD-1/PD-L1 INHIBITOR-REFRACTORY):Xx_NEWLINE_xXPD-1/PD-L1 inhibitor-refractory patients must have documented disease progression after prior response to anti-PD-1/PD-L1 therapy (response defined as stable disease, partial or complete response)Xx_NEWLINE_xXADDITIONAL EXCLUSION CRITERION FOR COHORTS 1 (PD-1/PD-L1 INHIBITOR-NAIVE, CETUXIMAB-NAIVE) AND 4 (CUTANEOUS):Xx_NEWLINE_xXPatient has received any prior immunotherapy with inhibitors of PD-1 or PD-L1Xx_NEWLINE_xXPrior treatment of PD-1 or PD-L1-directed immune checkpoint blockade is permitted if treatment was not discontinued due to disease progression or life-threatening adverse events per the investigators’ discretion (laboratory abnormalities alone with prior therapy will not exclude patients from this trial)Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPatients may not have had prior therapy with a checkpoint inhibitor (e.g. anti-CTLA-4, anti-PD-1 or anti-PD-L1 therapy)Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPatients may have received any number and type of prior treatment regimens for their NSCLC (aside from patients in arm A, who cannot have had PD-1/PD-L1 inhibitors)Xx_NEWLINE_xXArm A: patients must be treatment naive to single agent PD-1/PD-L1 inhibitors including but not limited to durvalumab, pembrolizumab, atezolizumab, nivolumab, and avelumab\r\n* Arm B: patients’ tumor must be either refractory to or progressed on one of the above agents\r\nNOTE: Patients must be eligible to receive the next line of therapy and not be suspected of having pseudoprogression\r\n* Both cases are defined by initial progressive disease (PD) or PD after CR, PR, or SD using RECIST criteria, respectivelyXx_NEWLINE_xXBoth arms: patients should not have received metformin within 6 months prior to registration\r\n* Arm B: patients who were on metformin while on PD-1/PD-L1 inhibitors are not eligibleXx_NEWLINE_xXPatients should not have received prior immunotherapies (exception; arm B); they include but are not limited to interleukin-2 and other immune checkpoint antagonist targeting CTLA-4, LAG-3, TIM-3, KIR etc. and/or agonists targeting OX40, ICOS, CD137, etc\r\n* NOTE: prior cancer vaccine treatments are permitted; for arm B, exposure to single agent PD-1/PD-L1 inhibitors are allowed >= 14 days from registrationXx_NEWLINE_xXArm B: patients must not have had prior exposure to combination treatment with PD-1/PD-L1 inhibitors and another systemic treatment\r\n* NOTE: radiation therapy and surgery do not count as combination treatmentXx_NEWLINE_xXPatients who are intolerant to PD-1/PD-L1 inhibitors and/or metformin are excludedXx_NEWLINE_xXPrior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXNo treatment with prior sipuleucel-T, PD-1 inhibitor, MPDL3280A or any other PD-L1 inhibitor, taxane-based chemotherapy for metastatic diseaseXx_NEWLINE_xXPrior immunotherapy or treatment with another anti PD 1 agentXx_NEWLINE_xXPrior treatment with ibrutinib or an anti-PD-1, or PD-L1 or PD-L2 agent or ipilimumab in the metastatic settingXx_NEWLINE_xXDose escalation cohorts: Patients with histologically or cytologically confirmed diagnosis of malignancy (including lymphoma) with demonstrated progression of a tumor for whom there is no available therapy likely to convey clinical benefit AND who have not been previously treated with a PD-1/PD-L1 inhibitor. These patients do not require measurable diseaseXx_NEWLINE_xXDose expansion cohorts: Patients with histologically or cytologically confirmed diagnosis of 1 of specified tumors with measurable disease per RECIST 1.1 or Lugano criteria. Some patients may have been previously treated with a PD-1 or PD-L1 inhibitorXx_NEWLINE_xXHave tumor tissue for PD-L1 expression testingXx_NEWLINE_xXPrior treatment with an agent that blocks the PD-1/PD-L1pathwayXx_NEWLINE_xXPrior exposure to PD-1 or PD-L1 inhibitors is not allowedXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXAny previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4, including tremelimumabXx_NEWLINE_xXParticipant must have an advanced solid tumor and must not be a candidate for surgical resection or other approved therapeutic regimen known to provide clinical benefit. For dose escalation, the participant may have been previously treated with a programmed cell death 1 (PD-I) targeting agent. For dose expansion, the participant must be PD-I/PD-L1 targeting agent naïve. For Combination, the participant must be have SCLC with progressive disease and have failed platinum containing therapy and be PD-1/PD-L1 targeting agent naïve.Xx_NEWLINE_xXPrior anti-PD-1/PD-L1 targeted therapy is NOT allowed; prior CTLA-4 therapy or CD40/CD40L targeted therapy is allowedXx_NEWLINE_xXPrior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL-2 antibodyXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPrior therapy with an anti-PD-1/PD-L1 antibody or a TRAIL-DR5 antibodyXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPrevious therapy for this cancer with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent, or any other immunomodulatory agentXx_NEWLINE_xXHas received prior anti-PD-1 or anti-PD-L1 therapyXx_NEWLINE_xXHistory of discontinuation of any previous treatment with PARP inhibitors, including olaparib, or a PD-1 or PD-L1 inhibitor, including durvalumab or anti-CTLA4 antibody, including tremelimumab due to toxicityXx_NEWLINE_xXpatients who have received all therapy known to confer clinical benefit (including anti-PD-1 or anti-PDL1 therapies, if relevant), or for whom no therapy of proven efficacy exists, or who are not amenable to standard therapies. Patients with anti- PD-1 or anti-PDL1 experience must have a minimum of 60 days between the last dose of the previous anti PD-1/PD-L1 and Cycle 1 Day 1 of BI 754091 treatment.Xx_NEWLINE_xXpatients who are anti-PD-1 and anti-PDL-1naïve but have failed conventional treatment (excluding anti-PD-1 treatment), or for whom no therapy of proven efficacy exists, or who are not amenable to standard therapies.Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior immunotherapy including anti-PD-1, anti-PD-L1, or anti-PD-L2 agents, or if the subject has previously participated in Merck pembrolizumab clinical trialsXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior immunotherapy including anti–PD-1, anti–PD-L1, or anti–PD-L2 agents, or if the subject has previously participated in Merck pembrolizumab clinical trialsXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior immunotherapy with agents that target PD-1, PD-L1, PD-L2, CTLA-4, OX-40, or CD-137 agents, or if the subject has previously participated in Merck pembrolizumab clinical trialsXx_NEWLINE_xXAny previous treatment with a PD1 or PD-L1 inhibitor, including durvalumabXx_NEWLINE_xXHas received prior therapy with an anti-programed death receptor 1 (PD-1), anti-PD-L1, anti-program death receptor ligand 2 (PD-L2) agent or anti-CTLA4Xx_NEWLINE_xXHave a PD-L1 positive (either strongly or weakly) tumor as determined by the IHC 22C3 pharmDx test at the study site; if a patient’s initial tumor specimen is not classified as PD-L1 positive by the central laboratory, a newly obtained specimen (different from the sample previously submitted) may be submitted for testing; if the newer specimen is classified as PD-L1 positive by the study site, the patient meets this eligibility criterionXx_NEWLINE_xXAny previous treatment with a PD1 or PD-L1 inhibitor, including durvalumabXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPrior treatment for CLL with CTLA-4, PD-1, PD-L1, or CD137 monoclonal antibody (mAb)Xx_NEWLINE_xXAnti-PD-1, anti-PD-L1, or anti-PD-L2 agentsXx_NEWLINE_xXAny previous treatment with a PD1 or PD-L1 inhibitor, including durvalumabXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L-1, or anti-PD-L2 agentXx_NEWLINE_xXSubjects must have no prior exposure to immunotherapy, such as, but not limited to other anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodies excluding vaccinesXx_NEWLINE_xXFor Phase 1b LY3300054 monotherapy or combination therapy, no prior treatment with a PD-1 or PD-L1 agent is allowed.Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-programmed death-ligand 2 (PD-L2) agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or sEsphB4-HSAXx_NEWLINE_xXAny previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4), including tremelimumabXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXAny number of previous treatments with the exception of previous inhibitors of programmed cell death 1 (PD-1), PD-L1, or programmed cell death 1 ligand 2 (PD-L2); other prior systemic therapies must have been administered at least 2 weeks before administration of pembrolizumab; the exception to this is ipilimumab which must have been administered at least 4 weeks prior to the start of pembrolizumab; patients are not required to have had prior systemic therapyXx_NEWLINE_xXPD-L1 expression in tumor tissue from any site is required for patients with NSCLC; tumor tissue can be archival, however if no archival tissue is available then a biopsy must be obtained for PD-L1 testing; PD-L1 expression will be analyzed by a Merck assay; PD-L1 expression is not required for patients with melanoma, but melanoma patients are required to submit an extra-cerebral specimen for analysis, unless it is not feasible to obtain oneXx_NEWLINE_xXHas had prior treatment with any other anti-PD-1 or PD-L1 or PD-L2 agentXx_NEWLINE_xXPrior treatment with an anti-PD-1, anti-PD-L1 or anti-PD-L2 agentXx_NEWLINE_xXRandomized phase II: tumor proportional score of PD-L1 >= 1%.Xx_NEWLINE_xXPrior treatment with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXGrade 3 or 4 major organ immune-related adverse events (IRAEs) following treatment with anti PD-1/PD-L1Xx_NEWLINE_xXPrior PD-1- or PD-L1-directed therapy or any therapeutic cancer vaccine.Xx_NEWLINE_xXAny previous treatment with a PD1 or PD-L1 inhibitor, including MEDI4736Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.Xx_NEWLINE_xXHistory of previous exposure to an anti-programmed cell death 1 (PD-1)/PD-L1 agentXx_NEWLINE_xXPrior treatment with specific pathway-blockers (PD-1/PD-L1)Xx_NEWLINE_xXPatients who have had prior therapy (BRAF inhibitors, ipilimumab, anti PD-1 antibody or anti PD-L1 antibody) or treatment naive patients are eligible as long as toxicity from therapy is grade =< 1 or at baselineXx_NEWLINE_xXPHASE I STUDY ELIGIBILITY CRITERIA:\r\nPatients who have had prior immune checkpoint inhibitors, such as MEDI4736 or other PD1 or PD-L1 inhibitors or an anti-CTLA4 therapyXx_NEWLINE_xXPHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nPatients who have had prior immune checkpoint inhibitors, such as MEDI4736 or other PD1 or PD-L1 inhibitors or an anti-CTLA4 therapyXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2Xx_NEWLINE_xXPrior immunotherapy is allowed (previous immune checkpoint inhibitors; anti-CTLA-4, anti-PD-1, anti-PD-L1 and/or combinations), except for the patients enrolled to the immunotherapy naïve group of the phase IB dose expansion.Xx_NEWLINE_xXPrior treatment with immune checkpoint inhibitor, including (but not limited to) those targeting PD-1, PD-L1, PD-L2, CTLA-4, CD137, GITR, TIM3, LAG3, or OX40Xx_NEWLINE_xXPatients who have been treated with prior PD-1 and PD-L1 agentsXx_NEWLINE_xXTREATMENT: Patients should have been off conventional therapy for at least 1 week prior to entry in this study (except for lenalidomide, thalidomide, pomalidomide or immune checkpoint inhibitors such as CTLA4 and/or PD-1/PD-L1 inhibitors)Xx_NEWLINE_xXPatient had prior treatment with any other anti-PD-1, or PD-ligand (L1) or PD-L2 agentXx_NEWLINE_xXProgressive disease (PD)Xx_NEWLINE_xXAny number of previous treatments with the exception of previous inhibitors of programmed cell death 1 (PD-1), PD-L1, or programmed cell death 1 ligand 2 (PD-L2); other prior systemic therapies must have been administered at least 2 weeks before administration of MK-3475 with the exception of bevacizumab which must have been administered at least 4 weeks prior to MK-3475; patients are not required to have had prior systemic therapy; the exception to this is patients with NSCLC who test negative for PD-L1 expression or are unevaluable for PD-L1 expression must have received prior platinum-based chemotherapy for entry into cohort 2\r\n* Note: ipilimumab treatment should have been administered at least 4 weeks prior to the start of MK-3475Xx_NEWLINE_xXPD-L1 expression in tumor tissue from any site is required for patients with NSCLC for entry into cohort 1; tumor tissue must be obtained after the last systemic therapy; PD-L1 expression will be analyzed by a Merck assay; for NSCLC cohort 2, patients may test PD-L1 negative or may be unevaluable for PD-L1 expression (i.e. insufficient tumor tissue); PD-L1 expression is not required for patients with melanoma, but melanoma patients are required to submit an extra-cerebral specimen for analysis, unless it is not feasible to obtain oneXx_NEWLINE_xXHas had prior treatment with any other anti-PD-1 or PD-L1 or PD-L2 agent or an antibody targeting other immune-regulatory receptors or mechanisms; examples of such antibodies include (but are not limited to) antibodies against indoleamine 2, 3-dioxygenase (IDO), PD-L1, interleukin-2 receptor (IL-2R), glucocorticoid-induced TNFR family related gene (GITR); prior ipilimumab, interleukin-2 (IL2), bevacizumab and adoptive cell therapy is allowedXx_NEWLINE_xXPart 1b: Must have documented confirmed disease progression on a prior programmed cell death-1 (PD-1) pathway targeted agent or must be PD-1 pathway-targeted treatment naïve.Xx_NEWLINE_xXPhase II PD-1/PD-L1 refractory subsets: Patients with confirmed disease progression within 1 year following initiation of PD-1/PD-L1 inhibitor therapy (patients must have received at least 2 doses of the PD-1/PD-L1 inhibitor). No prior cytotoxic therapy in the advanced setting is permitted. BRAF inhibition therapy is acceptable before immunotherapy where clinically indicated. CTLA-4-inhibition therapy is acceptable as a prior line of therapy or in combination with anti-PD-1 therapy.Xx_NEWLINE_xXPrior treatment with anti-Programmed Cell Death (PD-1)/PD-L1 therapyXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXReceived or ineligible for platinum-based therapy and Programmed death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapyXx_NEWLINE_xXPrior history of or active interstitial lung disease or pneumonitis, encephalitis, seizures, severe immune related adverse events with prior PD-1/PD-L1 containing treatments;Xx_NEWLINE_xXReceived prior therapies targeting PD-1 or PD-L1Xx_NEWLINE_xXNewly diagnosed, metastatic NSCLC with a PD-L1 TPS ? 50% (as determined by central lab using the PD-L1 IHC 22C3 pharmDx kit) NOTE: Subjects with documentation of PD-L1 TPS ? 50% by IHC analysis using the 22C3 pharmDx kit will not require repeat PD-L1 testing by central laboratory; andXx_NEWLINE_xXSubjects with progression on or after first-line platinum-based chemotherapy who have a PD-L1 TPS ? 1% (as determined by central laboratory using the PD-L1 IHC 22C2 pharmDx kit). Subjects with EGFR or ALK genomic tumor aberrations with progression on FDA-approved therapy for these aberrations are eligible NOTE: Subjects with documentation of PD-L1 TPS ? 1% by IHC analysis using the 22C3 pharmDx kit will not require repeat PD-L1 testing by central laboratory;Xx_NEWLINE_xXPatients who discontinued prior anti-PD-1/PD-L1 therapy due to an anti-PD-1/PD-L1-related toxicity.Xx_NEWLINE_xXPrior exposure to immune-mediated therapy, including anti-PD-1, anti-PD-L1 (including durvalumab) or anti-CTLA-4 directed therapy (including tremelimumab); therapeutic anticancer vaccines are not included in this category; exposure to other investigational agents may be permitted after discussion with the study principal investigator (PI)Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPrior chemotherapy, immunotherapy, radiotherapy or major surgery (including radiation therapy or surgery for treatment of brain metastases) must be completed at least 3 weeks before study entry; prior PD-1 or PD-L1 therapy is acceptableXx_NEWLINE_xXPatients whose tumors have PD-L1 expression in >= 50% of tumor cells must have demonstrated progression on or intolerance to pembrolizumab; otherwise, patients who are eligible to receive an FDA-approved anti-PD-1/anti-PD-L1 agent as second-line therapy must also have demonstrated progression on or intolerance to the drugXx_NEWLINE_xXPrior exposure to any agent (approved or investigational) that blocks the programmed cell death-1 (PD-1)/PD-L1 pathway.Xx_NEWLINE_xXPD on first-line therapy.Xx_NEWLINE_xXPrevious therapy with any PD1 or PD-L1 inhibitor (including durvalumab) for any malignancy.Xx_NEWLINE_xXEither known PD-L1 expression at the time of treatment (measured using any FDA approved test) or PD-L1 expression demonstrated using the Ventana SP142 assay in a biopsy taken prior to the start of treatmentXx_NEWLINE_xXHas received prior therapy with anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXSubject has received previous treatment with any anti-PD-1 (Programmed death 1) or anti-PD-L1 (PD-1 ligand receptor) antibodyXx_NEWLINE_xXHas received prior treatment with PD-616 or low-dose cytarabine.Xx_NEWLINE_xXWith the exception of CRPC and mBC patients, patients should have received prior PD-1 / PD-L1-containing checkpoint inhibitor therapy administered as their most recent therapy and have failed to achieve a PR or CR within four (4) months of starting that therapy;Xx_NEWLINE_xXPD-1 / PD-L1 checkpoint inhibitor therapy is permitted;Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T cell receptorXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or blinatumomabXx_NEWLINE_xXPrior PD-1 or PD-L1 inhibitor therapy, or prior therapy with anti-PD-L2 or anti-CTLA-4 inhibitor, or any other drug specifically targeting T-cell co-stimulation or immune checkpoint pathwaysXx_NEWLINE_xXApproved PD-1/PD-L1 inhibitors, CTLA4 checkpoint inhibitors, or other immunotherapy ? 4 weeksXx_NEWLINE_xXExperienced PD during participation in another Valor studyXx_NEWLINE_xXREGISTRATION TO TREATMENT (STEP 1): Patient must not have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPrior exposure to anti-PD-1, anti-PD-L1, CCR2/5, or anti-CTLA4 antibodiesXx_NEWLINE_xXEnrolled patients may be candidates for standard of care therapy with trabectedin or second line/subsequent line treatment for advanced disease with PD-1/PD-L1 inhibitor monotherapy; otherwise they should have no standard of care option available or be felt appropriate for a phase I clinical trial in the opinion of the treating investigator; prior PD-1/PD-L1 exposure is not an exclusion criteriaXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPrior treatment with an agent that blocks PD-1/PD-L1 pathway or other immune modulating agents within fewer than 4 weeks of 4 half-livesXx_NEWLINE_xXPrior treatment with an anti-CTLA-4, including tremelimumab PD-1 or PD-L1 inhibitor, including durvalumabXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent for dose expansion; (patients in dose escalation may have received an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent)Xx_NEWLINE_xXAny number of prior systemic therapeutic regimens including chemotherapy, pathway inhibitors, biochemotherapy, investigational agents, and immunotherapies other than ipilimumab, nivolumab or other CTLA-4, PD-1 or PD-L1 inhibitorsXx_NEWLINE_xXPatients are excluded if they have a history of prior treatment with ipilimumab, CTLA-4 inhibitor or agonist, nivolumab, PD-1 or PD-L1 inhibitorXx_NEWLINE_xXPrior therapy with anti-PD-1, PD-L1, or PD-L2 agent.Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPrior PD-1- or PD-L1-directed therapy.Xx_NEWLINE_xXReceived prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or other immune checkpoint inhibitor (e.g. anti-CTLA4)Xx_NEWLINE_xXPrior treatment with an investigational compound being tested in this study (e.g., poly ADP ribose polymerase [PARP] inhibitor, anti-PD-1, anti-PD-L1, or anti-PD-L2)Xx_NEWLINE_xXPatients are not eligible who have received prior immunotherapy including interleukin-2 and immune checkpoint antagonists and/or agonists (including but not limited to PD-1, PD-L1, CD137, or OX40)\r\n* NOTE: Single agent anti-CTLA4 monoclonal antibody treatments are permitted; cancer vaccine therapies are permittedXx_NEWLINE_xXPatients may not have had any prior ipilimumab and/or anti-PD-1/PD-L1 agent in the metastatic settingXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPatients must have received or be ineligible for platinum based chemotherapy and must have received at least one line of therapy with a PD-L1 or PD-1 targeting agentXx_NEWLINE_xXDOSE ESCALATION COHORT: Subjects who have received an IDO inhibitor; subjects who have received other immune checkpoint inhibitors (e.g. anti-PD-1, anti-PD-L1, and any other treatment targeting T-cell) will be permitted; subjects who have received experimental vaccines or other immune therapies should be discussed with the principal investigator (PI) to confirm eligibilityXx_NEWLINE_xXDOSE EXPANSION COHORT: Subjects who have received an IDO inhibitor; subjects who have received other immune checkpoint inhibitors (e.g. anti-PD-1, anti-PD-L1, and any other treatment targeting T-cell) will be permitted; subjects who have received experimental vaccines or other immune therapies should be discussed with the PI to confirm eligibilityXx_NEWLINE_xXSubjects must have had clinical benefit while on a PD-1 or PD-L1 inhibitor defined as at least a 3 month PFS, and now have disease progression.Xx_NEWLINE_xXPrevious discontinuation from PD-1 or PD-L1 due to an adverse event.Xx_NEWLINE_xXAny previous treatment with a PD1 or PD-L1 inhibitor, including durvalumabXx_NEWLINE_xXPatient with strong PD-L1 expression (>= 50% of tumor cells expressing PD-L1 ot or tu or TPS >= 50% ) will be excluded; patient’s with unknown PD-L1 expression or when PD-L1 expression can’t be determineXx_NEWLINE_xXHave provided tissue from an archival or newly obtained tissue sample of a tumor lesion, sufficient for analysis of programmed cell death 1 ligand 1 (PD-L1) and other biomarkers; patients who have had PD-L1 analysis previously performed at Merck can substitute earlier analysis results and are not required to submit additional tissue for PD-L1 testing; expression of PD-L1 is NOT required for study entryXx_NEWLINE_xXNSCLC patients who have received prior therapy with an agent directed at PD-1, PD-L1, or programmed cell death 1 ligand 2 (PD-L2)Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti- programmed cell death 1 ligand 2 (PD-L2) agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)Xx_NEWLINE_xXPrior treatment with a PD-1, PD-L1, or PD-L2 blocking therapyXx_NEWLINE_xXReceived prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPatients must be candidates for PD-L1 antibody (Ab) as determined by the treating physicianXx_NEWLINE_xXPrior treatment with anti?PD-1, or anti?PD-L1 therapeutic antibody or pathway targeting agentsXx_NEWLINE_xXCurrent or history of systemic autoimmune disease requiring systemic therapy, including significant autoimmunity associated with prior ipilimumab therapy or therapy with antibodies to PD-1 or PD-L1Xx_NEWLINE_xXSubjects must have a tumor sample that is adequate for PD-L1 assessment prior to randomization.Xx_NEWLINE_xXSubjects may not have been previously treated with talimogene laherparepvec, any other oncolytic virus, pembrolizumab, or any other inhibitor of PD-1, PD-L1, or PD-L2.Xx_NEWLINE_xXHas received prior immunotherapy including anti-programmed cell death-1 (anti-PD-1), anti-PD-ligand-1 (anti-PD-L1), or anti-PD-L2 agents, or if the participant has previously participated in Merck pembrolizumab (MK-3475) studies.Xx_NEWLINE_xXPrior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 antibody.Xx_NEWLINE_xXHas previously participated in any other pembrolizumab (MK-3475) trial, or received prior therapy with an anti-programmed cell death 1 (anti-PD-1), anti-PD ligand 1 [anti-PD-L1], and anti-PD-L2Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or if the patient has previously participated in MK-3475 clinical trials.Xx_NEWLINE_xXPrior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPrior treatment with an agent that blocks the programmed death-1/ programmed death-ligand 1 (PD-1/PD-L1 pathway) (certain exceptions may apply)Xx_NEWLINE_xXPrimary refractory melanoma: Subjects must have received prior treatment with anti-PD-1 or anti-PD-L1 therapy (alone or as part of a combination) in the advanced or metastatic setting and have progressive disease as their best response to treatment that is confirmed 4 weeks later.Xx_NEWLINE_xXRelapsed melanoma: Subjects must have received prior anti?PD-1 or anti?PD-L1 therapy (alone or as part of a combination) in the advanced or metastatic setting and achieved partial response ore complete response but later have confirmed progressive disease.Xx_NEWLINE_xXPrior PD-1 or CTLA-4 targeted therapies are excludedXx_NEWLINE_xXPrior PD-1 or CTLA-4 targeted therapies are excluded.Xx_NEWLINE_xXPrior PD-1 or CTLA-4 targeted therapies are excluded.Xx_NEWLINE_xXPrior PD-1 or CTLA-4 targeted therapies are excluded.Xx_NEWLINE_xXPrior PD-1 or CTLA-4 targeted therapies are excluded.Xx_NEWLINE_xXSubjects must not have received prior immunotherapy with anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy.Xx_NEWLINE_xXPrior PD-1 or CTLA-4 targeted therapies are excluded.Xx_NEWLINE_xXPrior PD-1 or CTLA-4 targeted therapies are excluded.Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, or anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX-40, CD137).Xx_NEWLINE_xXPrior treatment with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXCentral determination of programmed cell death ligand 1 (PD-L1) tumor statusXx_NEWLINE_xXPatients must not have received neoadjuvant treatment for their melanoma; patients must not have had prior immunotherapy including, but not limited to ipilimumab, interferon alfa-2b, high dose IL-2, pegylated (PEG)-IFN, anti-PD-1, anti-PD-L1 intra-tumoral, or vaccine therapies; patients must not be planning to receive any of the prohibited therapies during the screening or treatment phases of the studyXx_NEWLINE_xXNo prior treatment with anti-PD-1 or anti-PD-L1Xx_NEWLINE_xXUnless unavailable, must have received at least one of cabozantinib or nivolumab (or other active anti-PD-1/PD-L1 therapy)Xx_NEWLINE_xXMust have disease progression on a prior PD-1-pathway targeted agent.Xx_NEWLINE_xXMust have had documented disease progression while on a prior PD-1 pathway-targeted agent.Xx_NEWLINE_xXHad prior treatment with any other anti-programmed cell death-1 (PD-1), or PD-ligand 1 (PD-L1) or PD-L2 agent or an antibody targeting other immuno-regulatory receptors or mechanisms. Has participated in any other pembrolizumab study and has been treated with pembrolizumab.Xx_NEWLINE_xXb. In Part 2SA, patients with an inadequate response to anti-PD-1 mAb therapy, defined as SD or PD using RECIST v1.1 criteria following at least 2 months of therapy. Patients with PD have a tumor measurement increase of < 2 fold from the time of starting anti-PD-1 therapy, must not have worsening of Eastern Cooperative Oncology Group (ECOG) performance status due to their disease progression, and cannot have new CNS lesion. Patients must also meet the lactic acid dehydrogenase (LDH) or ECOG status. No tumor size criteria are used in Part 2SA.Xx_NEWLINE_xXIf enrolled in Part 2SA, new, growing, or previously untreated lesions since the start of anti-PD-1 therapy.Xx_NEWLINE_xXParticipant has received prior treatment with any anti-programmed cell death protein-1 (anti-PD-1), or PD Ligand-1 (PD-L1) or PD Ligand-2 (PD-L2) agent or an antibody targeting other immunoregulatory receptors or mechanisms.Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or if the patient has previously participated in Merck MK-3475 clinical trials.Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or if the subject has previously participated in Merck MK-3475 clinical trials.Xx_NEWLINE_xXPrior treatment with any other anti-programmed cell death protein-1 (anti-PD-1), or PD Ligand-1 (PD-L1) or PD Ligand-2 (PD-L2) agent or an antibody targeting other immuno-regulatory receptors or mechanismsXx_NEWLINE_xXPrior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent, or agents targeting other checkpoint pathways (e.g. CTLA-4)Xx_NEWLINE_xXParticipants without a PD-L1 test result are eligible for the studyXx_NEWLINE_xXSubject who received any prior monoclonal antibodies against PD-1 or PD-L1 and/or any prior:Xx_NEWLINE_xXPrior exposure to tremelimumab or durvalumab or other anti-CTLA-4, anti-PD-1, anti-PD-L1 antibodiesXx_NEWLINE_xXHas received prior immunotherapy including anti-programmed death-1 (anti-PD-1), anti-PD-ligand-1 (anti-PD-L1), or anti-PD-L2 agents, or if the participant has previously participated in clinical studies with pembrolizumab (MK-3475)Xx_NEWLINE_xXFor the expansion stage, evaluable for PD-L1 expressionXx_NEWLINE_xXAnti PD-1/PD-L1 relapsed cohorts (I and II), participants whose most recent anti-cancer therapy consisted of single-agent PD-1/PD-L1 blockade will be enrolledXx_NEWLINE_xXPrior therapies targeting PD-1 or PD-L1.Xx_NEWLINE_xXSubjects who fail to meet enrollment criteria for other PD-1 or PD-L1 trials solely due to low or negative predictive biomarkers.Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or if the patient has previously participated in a Merck MK-3475 clinical trial.Xx_NEWLINE_xXTumor specimen is not evaluable for PD-L1 expression by the central laboratoryXx_NEWLINE_xXNo prior CTLA-4 or PD-1/PD-L1 therapy for the treatment of metastatic diseaseXx_NEWLINE_xXPrior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway targeting agentsXx_NEWLINE_xXPrior treatment with anti-PD-1, and CTLA-4, or anti-PD-L1 therapeutic antibody or pathway-targeting agentsXx_NEWLINE_xXAnti-programmed cell death protein-1 (anti-PD-1), PD ligand-1 (PD-L1), PD ligand-2 (PD-L2) agent, an antibody targeting other immuno-regulatory receptors or mechanismsXx_NEWLINE_xXThe patient may not have received treatment with immune checkpoint inhibitors (e.g., products that target PD-L1, PD-1, or CTLA-4).Xx_NEWLINE_xXThe patient must have received treatment with an immune checkpoint inhibitor or combination (e.g., products that target PD-1, PD-L1, or CTLA-4) or be intolerant to, or refuse such treatment.Xx_NEWLINE_xXThe patient may have received treatment with an immune checkpoint inhibitor (e.g., products that target PD-L1, PD-1, or CTLA-4).Xx_NEWLINE_xXThe patient may not have received treatment with an immune checkpoint inhibitor (e.g., products that target PD-L1, PD-1, or CTLA-4).Xx_NEWLINE_xXThe patient may have been treated with an immune checkpoint inhibitor (e.g., products that target PD-L1, PD-1, or CTLA-4).Xx_NEWLINE_xXThe patient may have been treated with an immune checkpoint inhibitor (e.g., products that target PD-L1, PD-1, or CTLA-4).Xx_NEWLINE_xXThe patient may not have received treatment with immune checkpoint inhibitors (e.g., products that target PD-L1, PD-1, or CTLA-4).Xx_NEWLINE_xXPrior therapy with PD-1/PDL-1 inhibitors is allowed provided any toxicity attributed to prior PD-1- or PD-L1-directed therapy did not lead to discontinuation of therapy.Xx_NEWLINE_xXPreviously received pembrolizumab or other anti-programmed cell death-1 (PD-1) or anti-PD-L1 immunotherapyXx_NEWLINE_xXIntolerance to prior anti-PD-1/PD-L1 therapyXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPrior treatment with an anti PD-1, anti PD-L1, or anti CTLA-4 agent; participants who entered clinical remission with one of those agents and proceeded to ASCT without intervening relapse may be eligible after discussion with the study chair; note that for patients who enter remission with checkpoint blockade therapy, this will not count towards the 3 lines of prior therapyXx_NEWLINE_xXPatients who have received prior anti-cancer therapy (e.g., biologic or other targeted therapy, chemotherapy) within 2 weeks prior to registration; hormone therapy is permitted until registration\r\n* Note: patients who received prior anti-PD-1, PD-L1 or PD-L2 agents are still eligible; a wash-out period of 2 weeks prior to registration is requiredXx_NEWLINE_xXPrior immunotherapies including but not limited to CD137, anti-PD-1, anti-PD-L1, and CTLA4.Xx_NEWLINE_xXCD137 agonists, immune checkpoint inhibitors including but not limited to CTLA-4, anti-PD-1, and anti-PD-L1 therapiesXx_NEWLINE_xXPrior use of lenalidomide, or monoclonal antibodies against CTLA-4, PD-1, or PD-L1.Xx_NEWLINE_xXPrior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agentsXx_NEWLINE_xXPrior treatment with anti-PD-1, PD-L1, or CTLA4, or ensartinib (X-396).Xx_NEWLINE_xXPrior treatment with atezolizumab or another PD-L1/PD-1 therapyXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXAny previous treatment with a PD-1 or PD-L1 inhibitor, including durvalumabXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or has participated in another Merck pembrolizumab clinical trialXx_NEWLINE_xXHas received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-programmed death ligand 2 (PD-L2) agentXx_NEWLINE_xXHas received one prior systemic therapy regimen for metastatic renal cell carcinoma (mRCC) directed against PD-1 and/or PD-L1 which must have been the most recent regimen\r\n* Prior high-dose interleukin-2 therapy is permitted in addition to anti-PD(L)1 therapy, but is not required\r\n* Prior bevacizumab or vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) is permitted either in combination with anti-PD(L)1 therapy OR as monotherapy when given PRIOR to anti-PD(L)1 therapy\r\n* Prior treatment with combined ipilimumab and nivolumab is permitted\r\n* Prior axitinib in any setting is not permittedXx_NEWLINE_xXPrior therapy with a PD-1, anti-PD-Ligand 1 (PD-L1), or anti-PD-L2 agent, or previously participated in a Merck pembrolizumab (MK-3475) studyXx_NEWLINE_xXParticpant has received prior therapy with any other anti-PD-1, or PD-L1 or PD-L2 agent or an antibody targeting other immuno-regulatory receptors or mechanism, including participation in any other pembrolizumab trial and treatment with pembrolizumab. a. Examples of such antibodies include (but are not limited to) antibodies against indoleamine 2,3-dioxygenase (IDO), PD-L1, IL-2R, glucocorticoid-induced tumor necrosis factor receptor (GITR).Xx_NEWLINE_xXAll patients must undergo a baseline tumor biopsy for programmed cell death ligand 1 (PD-L1) testing (PD-L1 positivity is determined by greater than or equal to 1% of cells staining in the membrane by immunohistochemistry); for patients with stage IV disease, site of tumor biopsy will preferably be from non-lymph node disease site; the 28-8 clone for PD-L1 testing is required for assessment of PD-L1 status; for PD-L1 testing, the biopsy should contain sufficient tumor content (>= 100 tumor cells/4-micron tissue section); if a sample contains insufficient tumor content, a re-biopsy will be required to obtain a sample with sufficient tumor content prior to treatmentXx_NEWLINE_xXPart B: Anti-PD-1 non-responders are defined as those showing disease progression according to RECIST v1.1 after at least 12 weeks of therapy with a PD-1 antibody either alone or in combination with approved checkpoint inhibitor or targeted therapies according to their label; there is no serological requirementXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, OR other immune check point agonist/inhibitor.Xx_NEWLINE_xXPrior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2 monoclonal antibody.Xx_NEWLINE_xXFor patients in the pazopanib hydrochloride (pazopanib) cohort, no prior systemic therapy for mRCC is allowed, with the exception of prior cytokine therapy (such as interleukin-2, IFN-a), immunotherapy (such as anti-PD-1 or anti-PD-L1), or supportive therapies (such as zoledronic acid, denosumab)Xx_NEWLINE_xXONLY FOR PART B – PD-L1 selection should a PD-L1 expression threshold have been defined in Part A and potentially additional mesothelioma trial data; there will be no PD-L1/biomarker selection for Part AXx_NEWLINE_xXWilling to provide tumor tissue for PD-L1 biomarker analysis (new or archived specimens with agreement of Sponsor). As of 20 March 2016, participants must be PD-L1 positive to be enrolled.Xx_NEWLINE_xXPrior immunotherapy including anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or previously participated in Merck pembrolizumab (MK-3475) clinical trialXx_NEWLINE_xXPrior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or previously participated in Merck MK-3475 clinical trialXx_NEWLINE_xXPrior exposure to any anti-PD-1 or anti-PD-L1 antibody or anti CTLA4Xx_NEWLINE_xXPrior therapy with a PD-1, PD-L1, or CTLA-4 inhibitor or a lung cancer-specific vaccine therapyXx_NEWLINE_xXPrior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed to another co-inhibitory T-cell receptorXx_NEWLINE_xXConfirmed PD-L1-negative SCCHN by Ventana SP263;Xx_NEWLINE_xXPrior therapy with an anti-PD-1 or anti-PD1-L1 or -L2 therapy or previously participated in a Merck pembrolizumab (MK-3475) trialXx_NEWLINE_xXConfirmed PD-L1-positive SCCHN by Ventana SP263 assayXx_NEWLINE_xXPrior exposure to any anti-PD-1 or anti-PD-L1 antibody.Xx_NEWLINE_xXPrior exposure to any anti-PD-1 or anti-PD-L1 antibodyXx_NEWLINE_xXPD-L1+ on immunohistochemistry testing performed by central labXx_NEWLINE_xXOcular melanoma; and have received no more than one line of systemic therapy for metastatic disease. Patients must not have received immune modifying agents (eg. anti PD-L1, anti PD-1, anti CTLA4, TNF agonist, etc.) for metastatic disease, orXx_NEWLINE_xXCutaneous/acral melanoma; and have 1) only previously received systemic therapy for advanced/metastatic disease with the following therapies: BRAF and MEK inhibitors, anti PD-L1, anti PD-1, or anti-CTLA4 and 2) have received checkpoint inhibitor (anti PD-L1, anti PD-1, or anti-CTLA4) based treatment as most recent line of therapy on which disease progressed, as long as progression did not occur in the first 3 months of receiving checkpoint inhibitor treatment. Arm 2 only:Xx_NEWLINE_xXHistological or cytological diagnosis of NSCLC. Patients must have 1) previously received prior anti-PD-L1 or anti-PD-1 mAb as most recent therapy, AND 2) did not have progressive disease as best overall response on recent PD-L1/PD-1 therapy (ie, stable disease 3 months, PR, or CR), AND 3) who subsequently progressed on anti-PD-L1 or anti-PD-1 mAb.Xx_NEWLINE_xXPrior systemic therapy targeting PD-1: PD-L1 axis.Xx_NEWLINE_xXHas received prior therapy with compounds targeting programmed death (PD)-1, PD-L1, PD-L2, or a mitogen-activated protein kinase (MAPK) pathway inhibitorXx_NEWLINE_xXPrior exposure to any anti-PD-1 or anti-PD-L1 antibodyXx_NEWLINE_xXExpansion Cohort 7: Subjects with Stage IV non-squamous NSCLC who have radiographically progressed on or after treatment with one prior immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1) as the most recent therapy for metastatic disease.Xx_NEWLINE_xXExpansion Cohort 8: Subjects with Stage IV non-squamous NSCLC who have not received prior immune checkpoint inhibitor therapy (anti-PD-1 or anti-PD-L1).Xx_NEWLINE_xXPrior treatment with cabozantinib or immune checkpoint inhibitors including anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy except in Expansion Cohorts 5 and 7 in which prior anti-PD-1 or anti-PD-L1 therapy is required for eligibility. Other restrictions regarding prior therapy may apply.Xx_NEWLINE_xXAny previous treatment with a PD-1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA-4, including tremelimumabXx_NEWLINE_xXPatients who received prior anti-PD-1 therapy are eligible for cohort 1 only and patients who have not received prior anti-PD-1 therapy are eligible for cohort 2 onlyXx_NEWLINE_xXPrior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXAny previous treatment with a PD-1 or PD-L1 inhibitor, including durvalumab or any anti-CTLA4, including tremelimumabXx_NEWLINE_xXHave documented objective radiographic or clinical disease progression after PD-1/PD-L1 +/- anti-CTLA-4 inhibitor therapy (melanoma) or after at least 1 line of chemotherapy for metastatic disease (TNBC)Xx_NEWLINE_xXWith TNBC has received prior therapy with an anti-PD-1, anti-PD-L1, anti-CTLA-4, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXTumor for which standard therapy, including approved anti-PD-1 or anti-PD-L1 therapy, when applicable, does not exist or is no longer effective.Xx_NEWLINE_xXPrevious treatment with anti-PD-1, anti-PD-L1 or anti-PD-L2 therapy.Xx_NEWLINE_xXHas received prior therapy with PD-1, PD-L1, or CTLA-4 inhibitorXx_NEWLINE_xXParticipants in the Combination Expansion Cohorts must have one of the following advanced or recurrent malignancies: non-small cell lung adenocarcinoma or cutaneous melanoma showing primary progression following treatment with an anti-PD1 or anti-PD-L1 regimen; or anti-PD1 or anti-PD-L1 treatment-naïve colorectal or gastric cancer, including gastroesophageal junction cancer of Siewert Type II and Type III.Xx_NEWLINE_xXHas received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXAny previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4, including tremelimumabXx_NEWLINE_xXTen patients with a diagnosis of NSCLC who have disease progression per investigator's assessment who are on anti PD-1 or PD-L1 therapies will be allowed to enroll in the phase II part of this study but must be switched to treatment per this protocolXx_NEWLINE_xXPatients who have had chemotherapy or radiotherapy within14 days prior to entering the study; patients may not be currently receiving any other investigational agents or immunomodulatory agents (e.g. ipilimumab); patients treated with prior PD-1 or PD-L1 directed therapies are ineligible for the phase I portionXx_NEWLINE_xXMust have received either nivolumab or pembrolizumab or a different IND-approved anti-PD1 or anti-PD-L1 therapy, unless medically contraindicatedXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-programmed death-ligand (PD-L)1, or anti-PD-L2 agentXx_NEWLINE_xXFor Part 1b: Must have documented confirmed disease progression on a prior PD-1 pathway targeted agent or must be PD-1 pathway-targeted treatment naïve.Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or CTLA-4 antibody.Xx_NEWLINE_xXPrevious treatment with eribulin mesylate or any anti-programmed death receptor-1 (anti-PD-1), programmed death receptor ligand-1 (PD-L1), or PD-L2 agent.Xx_NEWLINE_xXSubjects who have received prior therapy with regimens containing CTLA-4, PD-L1, or PD-1 antagonists may be permitted to enroll under certain conditionsXx_NEWLINE_xXPreviously treated with a histone deacetylase inhibitor (i.e., vorinostat, belinostat, romidepsin, panobinostat), PD-1/PD-L1-blocking antibody (i.e., atezolizumab, nivolumab, pembrolizumab), or a cytotoxic T-lymphocyte associated protein-4 (CTLA-4) agentXx_NEWLINE_xXPrior therapy with single agent nivolumab, pembrolizumab or other PD-1/PD-L1 antibody or prior therapy with ipilimumab/CTLA-4 antibody for metastatic/unresectable disease is allowed unless they have received it as combination immunotherapy. Patients who received these agents in the adjuvant setting may be enrolled, provided it has been at least 3 months since receiving therapyXx_NEWLINE_xXSubjects who are treatment-naive or pretreated (prior anti-PD-1 or anti-PD-L1 required) in the recurrent/metastatic setting.Xx_NEWLINE_xXSubject eligibility will be based on PD-L1 expression as determined by a specified IHC assay.Xx_NEWLINE_xXAll patients must have received at least one line of systemic therapy in the metastatic setting; prior immunotherapy is allowed, including prior treatment with nivolumab, another PD-1 inhibitor, or a PD-L1 inhibitor, as long as the reason for discontinuation of a prior PD-1 pathway inhibitor was not for drug-related toxicityXx_NEWLINE_xXSubject has received PD-1/PD-L1 blockade or has been informed of the results of relevant positive Phase 3 trials with these agents.Xx_NEWLINE_xXPrior exposure to immunotherapy, such as, but not limited to, other anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodies, excluding therapeutic cancer vaccinesXx_NEWLINE_xXCohort 1 (combination of niraparib and PD-1 inhibitor): patients must have tumors with high PD-L1 expression (TPS ? 50%) per local assessment; with no known EGFR sensitizing mutation and/or ROS-1 or ALK translocations, and no prior systemic chemotherapy or PD-1/PD-L1 inhibitor treatment for metastatic NSCLCXx_NEWLINE_xXCohort 2 (combination of niraparib and PD-1 inhibitor): patients must have tumors with PD-L1 expression (TPS between 1% and 49%) per local assessment, with no known EGFR-sensitizing mutation and/or ROS-1 or ALK translocation, and no prior systemic chemotherapy or PD-1/PD-L1 inhibitor treatment for metastatic NSCLCXx_NEWLINE_xXCohort 3 (single agent niraparib): patients must have metastatic sqNSCLC and have progressed after both prior platinum-based chemotherapy and prior PD-1 or PD-L1 inhibitor treatmentXx_NEWLINE_xXPrior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXNSCLC Cohorts (CIT-Naïve): Participants with histologically confirmed incurable, advanced NSCLC not previously treated with anti-PD?L1/PD-1 and/or with anti-CTLA?4 (investigational or approved), for whom a clinical trial of an investigational agent in combination with an anti-PD?L1/PD-1 antibody is considered an acceptable treatment option (if CIT [including anti-PD?L1/PD-1 agents] is approved as treatment for NSCLC by local regulatory authorities).Xx_NEWLINE_xXNSCLC Cohort (CIT-Treated): Participants with histologically confirmed incurable, advanced NSCLC previously treated with anti-PD-L1/PD-1 with or without anti-CTLA-4 (investigational or approved)Xx_NEWLINE_xXColorectal cancer (CRC) Cohort: Participants with histologically confirmed incurable, advanced adenocarcinoma of the colon or rectum not previously treated with anti-PD-L1/PD-1 and/or anti-CTLA-4 (investigational or approved)Xx_NEWLINE_xXHead and neck squamous cell carcinoma (HNSCC) Cohort: Participants with histologically confirmed inoperable, locally advanced or metastatic, recurrent, or persistent HNSCC (oral cavity, oropharynx, hypopharnyx, or larynx) not amenable to curative therapy not previously treated with anti-PD-L1/PD-1 and/or anti-CTLA-4 (investigational or approved)Xx_NEWLINE_xXUrothelial carcinoma (UC) Cohort (CIT-Naïve): Participants with histologically confirmed incurable, advanced transitional cell carcinoma of the urothelium including renal pelvis, ureters, urinary bladder, and urethra, not previously treated with anti-PD-L1/PD-1 with or without anti-CTLA-4 (investigational or approved), for whom a clinical trial of an investigational agent in combination with an anti-PD?L1 antibody is considered an acceptable treatment option, if CIT (including anti-PD?L1/PD-1 agents) is approved as treatment for UC by local regulatory authoritiesXx_NEWLINE_xXUC Cohort (CIT-Treated): Participants with histologically confirmed incurable advanced transitional cell carcinoma of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra) previously treated with anti-PD-L1/PD-1 with or without anti-CTLA-4 (investigational or approved)Xx_NEWLINE_xXRenal cell carcinoma (RCC) Cohort: Participants with histologically confirmed incurable, advanced RCC with component of clear cell histology and/or component of sarcomatoid histology not previously treated with anti-PD-L1/PD-1 and/or anti-CTLA-4 (investigational or approved)Xx_NEWLINE_xXMelanoma Cohort: Participants with histologically confirmed incurable, advanced melanoma not previously treated with anti-PD-L1/PD-1 and/or anti-CTLA-4 (investigational or approved) in the metastatic setting Additional Inclusion Criteria for Participants in the Serial-Biopsy Expansion Cohort of Phase 1b:Xx_NEWLINE_xXIn the NSCLC CIT-Treated exploration cohort in Phase 1b, the most recent systemic treatment should have been anti-PD?L1/PD-1 and/or anti-CTLA-4 as monotherapy or in combinationXx_NEWLINE_xXIn the NSCLC CIT-Naïve expansion cohort in Phase 1b, prior treatment with anti-PD?L1/PD-1 and/or anti-CTLA-4 (investigational or approved) is not allowedXx_NEWLINE_xXPrior treatment with an agent that blocks the PD-1/PD-L1 pathwayXx_NEWLINE_xXPrior treatment with systemic immune modulating agents (other than anti-PD-1/PD-L1 agents) that was within 28 days prior to enrollment, or within 90 days prior to enrollment if there was an immune related adverse event, or associated with toxicity that resulted in discontinuation of the immune modulating agentXx_NEWLINE_xXCompletion of PD-L1 testing\r\n* Patients will be stratified as PD-L1 >= 5% versus (vs) < 5% OR inevaluable; baseline tumor will be utilized; if this returns inevaluable, efforts should be made to utilize the resected specimenXx_NEWLINE_xXDocumentation of program death ligand-1 (PD-L1) status prior to randomization.Xx_NEWLINE_xXPrior treatment with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXAny previous treatment with a PD1 or PD-L1 inhibitor, including durvalumabXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas had treatment a prior monoclonal antibody targeting PD-1, PD-L1, PD-L2, or CTLA-4Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2Xx_NEWLINE_xXPrevious treatment with eribulin mesylate or any anti-PD-1, PD-L1, or PD-L2 agent or participation in any MK-3475 Merck studiesXx_NEWLINE_xXPatient must have had prior treatment with anti-PD-1 or anti-PD-L1 agents and have documented disease progression on these agents prior to registration; patient must have received anti-PD-1 or PD-L1 based therapy as the immediate previous line of treatment and within 56 days prior to registrationXx_NEWLINE_xXAny previous treatment with a PD1 or PD-L1 inhibitor, including durvalumabXx_NEWLINE_xXPatients must NOT have received any class of drugs targeted to the PD-1/PD-L1 pathwayXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXMelanoma (anti-PD-1/PD-L1 therapy naïve or pre-treated)Xx_NEWLINE_xXNon small cell lung cancer (anti-PD-1/PD-L1 therapy naïve or pre-treated)Xx_NEWLINE_xXRenal Cell Carcinoma (anti-PD-1/PD-L1 therapy naïve or pre-treated)Xx_NEWLINE_xXPrior participation in an interventional, investigational cancer vaccine or immunotherapy study except for an anti-PD-1/PD-L1 study.Xx_NEWLINE_xXChemotherapy, or immunotherapy or any other systemic anticancer therapy =< 3 weeks prior to study drug administration date; patients receiving anti-PD-1 treatment, and continue to receiving this treatment in combination with selinexor (Arms L and M), can start receiving the selinexor and anti-PD-1 combination without washout of the prior anti-PD-1 antibodyXx_NEWLINE_xXNo prior treatment with agents targeting EGFR mutation, ALK rearrangement, and PD-1/PD-L1/CTLA-4Xx_NEWLINE_xXPrevious treatment with rociletinib or MPDL3280A, or other 3rd generation EGFR TKI (eg, AZD-9291, HM61713), or PD 1 axis targeted therapy (eg, anti PD 1 or anti-PD L1)Xx_NEWLINE_xXHaving received any prior MAb (monoclonal antibodies) against CTLA-4 (cytotoxic T lymphocyte-associated antigen), PD-1, or PD-L1 or having received other investigational MAbs (monoclonalantibodies) within 6 monthsXx_NEWLINE_xXAny previous treatment with a PD-1 or PD-L1 inhibitor, including durvalumab or an anti- CTLA-4, including tremelimumabXx_NEWLINE_xXPrior treatment with anti PD-1 or PD-L1 therapy (Arm A)Xx_NEWLINE_xXPatients treated with PD-1 or PD-L1 inhibitors, CDK 4/6 inhibitors, or other immune-based therapy are eligibleXx_NEWLINE_xXPrior exposure to PD-1 or PD-LI treatmentXx_NEWLINE_xXHas received prior treatment with PD-1/PD-L1 pathway inhibitors in the adjuvant settingXx_NEWLINE_xXEligible for with plan to undergo neoadjuvant treatment with atezolizumab followed by surgery as part CC# 14524, or planned to undergo treatment with anti-PD-1 or anti-PD-L1 per standard of careXx_NEWLINE_xXReceived prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPrevious exposure to CD40, PD-1, PD-L1, CTLA-4 antibodies or any other immunomodulatory agentXx_NEWLINE_xXPrior treatment with CD137 agonists, anti?PD-1, or anti?PD-L1 therapeutic antibody or pathway-targeting agentsXx_NEWLINE_xXSubjects who are currently receiving treatment with the anti-PD-1 antibody Pembrolizumab either alone or in combination and are progressing. Subjects must have received at least 4 doses of anti-PD-1/PD-L1 therapy ORXx_NEWLINE_xXSubjects who have previously received any anti-PD-1/PD-L1 therapy, alone or in combination. Subjects must have received at least 4 doses of anti-PD-1/PD-L1 therapyXx_NEWLINE_xXPatients must not have had prior exposure to any immune checkpoint inhibitors including anti-PD-1, anti-PD-L1 gents, anti-PD-L2 agents, or anti-CTLA-4 monoclonal antibodiesXx_NEWLINE_xXReceived prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXPrior therapy with an agent that blocks the PD-1/PD-L1 pathwayXx_NEWLINE_xXPrior treatment with PD-L1 inhibitor, PD-1 inhibitor, anti-CTLA4, anti-CD137, anti-OX40 or other immune checkpoint blockade or activator therapy with the exception of subjects who received atezolizumab in this study and are eligible for re-treatmentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXNo evidence of PD for ?3 months before the first dose of study drug.Xx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xXHas received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agentXx_NEWLINE_xX