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+Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria:\r\na) Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory\r\nb) By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results\r\n* Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible\r\n* Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105
+Non-squamous tumors must not be positive for epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R mutation and anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement (results ascertained in centrally as part of ALCHEMIST-SCREEN protocol)
+Patients must not have a known epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) fusion; EGFR/ALK testing is not required prior to registration and is included in the Foundation Medicine Incorporated (FMI) testing for screening/prescreening
+Patients whose biomarker profiling results indicate the presence of an EGFR mutation or echinoderm microtubule-associated protein-like 4 (EML4)/ALK fusion are not eligible
+Tumors must be tested and known negative for EGFR tyrosine kinase inhibitor (TKI) sensitizing mutations (EGFR exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements by routine Clinical Laboratory Improvement Act (CLIA)-certified clinical testing methods; negative circulating tumor DNA results alone are not acceptable; prior testing for tumor PD-L1 status is not required
+An EGFR exon 20 insertion mutation must be detected in the tumor tissue; patients may be enrolled in the study based on an exon 20 insertion EGFR mutation detected by any Clinical Laboratory Improvement Act (CLIA)-certified tissue assay\r\n* NOTE: Testing results are to be submitted via Medidata Rave and the study chair or delegate will review the reports
+Patients receiving targeted therapy (non-cytotoxic, non-immunotherapy based systemic therapy) for NSCLC in the first-line setting. Such designations would include but not be limited to treatments targeting EGFR mutant positive or ALK positive NSCLC in the first-line setting.
+Patient must be eligible for treatment with nivolumab; patients previously treated with nivolumab, pembrolizumab or atezolizumab and who have progressed are eligible; patients with targetable with EGFR or ALK mutations are eligible after disease recurrence or progression after at least one targeted therapy for advanced or metastatic disease
+Group 1a and 1b: NSCLC: Patients with NSCLC must have had disease recurrence or progression during or after no more than one prior systemic chemotherapy regimen (platinum doublet-based) for advanced or metastatic disease. Prior maintenance therapy is allowed (e.g. pemetrexed, erlotinib, bevacizumab). Only patients with EGFR mutation-negative tumor are eligible (defined as negative for exon 19 deletions and for the L858R mutation in EGFR at a minimum; however, if more extensive EGFR mutation testing has been performed, the tumor must not harbor any known activating EGFR mutations in Exons 18-21 in order to be considered EGFR mutation-negative). All patients must be tested for EGFR mutational status and, for ALK translocation status if no mutation is detected in EGFR. Patients with ALK translocation-positive NSCLC must have had disease progression following treatment with a corresponding inhibitor and no more than one systemic chemotherapy regimen (platinum doublet-based), in any sequence.
+Non-squamous NSCLC histology with activating ALK and EGFR mutation
+Tumors must harbor an alteration in ALK using a CLIA-certified laboratory, including, but not limited to, ALK^ATI, ALK fusions, or ALK mutations (for treatment phase)
+For Arm A: must have received 1 prior line of therapy with an EGFR TKI and confirmed T790M negative
+Receipt of an EGFR TKI within 14 days of the first dose of study treatment.
+Patients with nonsquamous NSCLC having functionally significant anaplastic lymphoma kinase (ALK) translocations or epidermal growth factor receptor (EGFR) mutations who have not received prior treatment with ALK or EGFR inhibitor.
+Histologically or cytologically confirmed diagnosis of stage IV NSCLC without epidermal growth factor receptor (EGFR)-sensitizing mutation, ROS1 and/or anaplastic lymphoma kinase (ALK) translocation
+Cohort A1: Non-squamous NSCLC, with no activating EGFR mutations, ALK or ROS1 translocations/rearrangements. If monotherapy pembrolizumab is available as a standard of care treatment option, patients must have a tumor proportion score (TPS) <50% for PD L1 (via the 22C3 pharmDx or the Ventana (SP263) PD L1 IHC assay).
+Tumors lack activating epidermal growth factor receptor (EGFR) mutations or ALK rearrangement (no EGFR or ALK testing is required if a subject has a KRAS mutation or squamous cell histology).
+Histologically or cytologically confirmed advanced (stage IIIB or IV) non-small-cell lung cancer (NSCLC)\r\n* ALK-rearranged NSCLC: ALK rearrangement as assessed by ALK fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), or next-generation sequencing (NGS); for ALK FISH, rearrangements must be detected in > 15% of tumor cells\r\n* EGFR-mutant NSCLC: EGFR activating gene mutation (e.g., L858R, exon 19 deletion) as well as a T790M mutation per local testing
+Prior treatment with appropriate tyrosine kinase inhibitors (TKIs) as follows:\r\n* ALK-positive NSCLC (Cohorts B and D): Participants must have progressed on or after 1 or more next-generation ALK-TKI(s)\r\n* EGFR-mutant NSCLC (Cohorts A and C): Participants must have progressed on or after 1 or more third-generation, T790M mutant-selective EGFR-TKI(s)
+Presence of targetable EGFR mutations or ALK re-arrangements\r\n* All patients with adenocarcinoma histology must be tested for EGFR and ALK status, unless a KRAS mutation is detected in which case EGFR/ALK testing is not required
+Participants with known epidermal growth factor receptor (EGFR) mutations which are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19 and exon 21 [L858R] substitution mutations) are excluded
+Patients must have high PD-L1 expression (Tumor Proportion Score [TPS] ? 50%) as determined by FDA-approved test, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. First- or Second-line UROTHELIAL CARCINOMA (atezolizumab only)
+Histologically or cytologically confirmed immunotherapy naïve, metastatic or locally advanced non-small cell lung cancer not amenable to curative treatment. Subjects may be treatment naive or could have received one prior platinum based chemotherapy for non-small cell lung cancer and subjects with a documented activating mutation (e.g., EGFR, ALK, ROS) must also have received the appropriate therapy and progressed
+An ALK activating mutation;
+NSCLC with EGFR or ALK mutation
+NSCLC patients with EGFR mutant tumors.
+Histologically confirmed non-squamous NSCLC; patients with adenocarcinoma must have had epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutational testing; those with an actionable mutations/rearrangements are excluded
+Inclusion Criteria:\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1\n\n          -  Histologically or cytologically confirmed, Stage IV non-squamous NSCLC. Participants\n             with tumors of mixed non-small cell histology (i.e., squamous and non-squamous) are\n             eligible if the major histological component appears to be non-squamous\n\n          -  No prior treatment for Stage IV non-squamous NSCLC. Participants with a sensitizing\n             mutation in the epidermal growth factor receptor (EGFR) gene or with an anaplastic\n             lymphoma kinase (ALK) fusion oncogene are excluded. Participants with unknown EGFR and\n             ALK status require test results at screening from a local or central laboratory\n\n          -  Participants who have received prior neo-adjuvant, radiotherapy, adjuvant\n             chemotherapy, or chemoradiotherapy with curative intent for non-metastatic disease\n             must have experienced a treatment-free interval of at least 6 months from\n             randomization since the last dose of chemotherapy and/or radiotherapy\n\n          -  Participants should submit a pre-treatment tumor tissue sample if available before or\n             within 4 weeks after enrollment. If tumor tissue is not available, participants are\n             still eligible\n\n          -  For participants enrolled in the extended China enrollment phase: current resident of\n             mainland China, Hong Kong, or Taiwan and of Chinese ancestry\n\n          -  Measurable disease, as defined by RECIST v1.1\n\n          -  Adequate hematologic and end organ function\n\n          -  For women of childbearing potential: agreement to remain abstinent or use\n             contraceptive methods that result in a failure rate of less than (<) 1 percent (%) per\n             year during the treatment period and for at least 5 months after the last dose of\n             atezolizumab or 6 months after the last dose of cisplatin\n\n          -  For men: agreement to remain abstinent or use contraceptive measures and agreement to\n             refrain from donating sperm\n\n        Exclusion Criteria:\n\n        Cancer-Specific Exclusions\n\n          -  Participants with a sensitizing mutation in the EGFR gene or an ALK fusion oncogene\n\n          -  Active or untreated central nervous system (CNS) metastases as determined by computed\n             tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening and\n             prior radiographic assessments\n\n          -  Spinal cord compression not definitively treated with surgery and/or radiation or\n             previously diagnosed and treated spinal cord compression without evidence that disease\n             has been clinically stable for greater than or equal to (>= 2) weeks prior to\n             randomization\n\n          -  Leptomeningeal disease\n\n          -  Uncontrolled tumor-related pain\n\n          -  Uncontrolled or symptomatic hypercalcemia (greater than [>] 1.5 millimole/Liter\n             ionized calcium or calcium >12 milligrams/deciliter or corrected serum calcium >upper\n             limit of normal)\n\n          -  Malignancies other than NSCLC within 5 years prior to randomization\n\n          -  Known tumor programmed death-ligand 1 (PD-L1) expression status from other clinical\n             studies (e.g., participants whose PD-L1 expression status was determined during\n             screening for entry into a study with anti-PD-1 or anti-PD L1 antibodies but were not\n             eligible are excluded)\n\n        General Medical Exclusions:\n\n          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to\n             chimeric or humanized antibodies or fusion proteins\n\n          -  History of certain autoimmune disease\n\n          -  History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced\n             pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis\n\n          -  All participants will be tested for human immunodeficiency virus (HIV) prior to the\n             inclusion into the study and HIV-positive participants will be excluded from the\n             clinical study\n\n          -  Severe infections within 4 weeks prior to randomization\n\n          -  Significant cardiovascular disease, such as New York Heart Association cardiac disease\n             (Class II or greater), myocardial infarction or cerebrovascular accident within 3\n             months prior to randomization, unstable arrhythmias, or unstable angina\n\n          -  Illness or condition that may interfere with a participant's capacity to understand,\n             follow, and/or comply with study procedures\n\n        Exclusion Criteria Related to Medications and Chemotherapy:\n\n          -  Prior treatment with EGFR inhibitors or ALK inhibitors\n\n          -  Any approved anti-cancer therapy, including hormonal therapy within 21 days prior to\n             initiation of study treatment\n\n          -  Prior treatment with cluster of differentiation 137 (CD137) agonists or immune\n             checkpoint blockade therapies, anti-PD-1, and anti-PD-L1 therapeutic antibodies\n\n          -  Treatment with systemic immunostimulatory agents within 4 weeks prior to randomization\n\n          -  Treatment with systemic immunosuppressive medications\n\n        Exclusion Criteria Related to Chemotherapy:\n\n          -  History of allergic reactions to cisplatin, carboplatin, or other platinum-containing\n             compounds\n\n          -  Participants with hearing impairment (cisplatin)\n\n          -  Grade >=2 peripheral neuropathy as defined by National Cancer Institute Common\n             Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria (cisplatin)\n\n          -  Creatinine clearance (CRCL) <60 milliliters/minute (mL/min) for cisplatin or <45\n             mL/min for carboplatin
+For Part 2 only: Participants must also have disease with a previously diagnosed activating epidermal growth factor receptor (EGFR) mutation (includes both inhibitor sensitive primary mutations such as Exon 19 deletion and L858R, as well as marketed tyrosine kinase inhibitor [TKI] -resistant mutations such as Exon 20 insertion). Documentation of EGFR mutation eligibility by CLIA-certified laboratory (or equivalent) testing is required
+For Part 2: Cohort A and B: Participants disease must have most recently progressed following treatment with a marketed EGFR inhibitor. Exception: In participants diagnosed with mutations associated with de novo EGFR inhibitor resistance (for example, exon 20 insertions), only previous treatment with combination platinum-based chemotherapy is required. Cohort C: Participants must have been previously treated with a third generation EGFR TKI (eg, osimertinib). Cohort D: Participants must have been previously diagnosed with an EGFR Exon 20 insertion
+Participant has had prior chemotherapy, targeted cancer therapy, immunotherapy, or treatment with an investigational anticancer agent within 2 weeks or 4 half-lives whichever is longer, before the first administration of JNJ-61186372. For agents with long half-lives, the maximum required time since last dose is 4 weeks. Toxicities from previous anticancer therapies should have resolved to baseline levels or to Grade 1 or less, (except for alopecia [any grade] and Grade less than or equal to [=<] 2 peripheral neuropathy). For Part 2 only: Cohorts A and B: Prior treatment with chemotherapy for metastatic disease is not allowed unless the tumor mutation carries de-novo resistance to EGFR tyrosine kinase inhibitor (TKI) (eg, exon 20 insertions). Cohort C: Prior treatment with more than 2 lines of cytotoxic chemotherapy for metastatic disease (maintenance therapy is not included). Cohort D: Previous treatment with an investigational third generation EGFR TKI with activity against EGFR Exon 20 insertions (such as poziotinib)
+EGFR mutation (L858R and /or ex19del)
+Acquired resistance to EGFR TKI (1st or 2nd génération)
+Has documented evidence of an activating EGFR mutation in the tumor tissue determined by either sequencing or PCR-based technique (Part 1).
+For Part 1 only: subjects with a positive T790M mutation are preferred, but not required. Confirmation of T790M mutation status will be determined from an archived tumor tissue sample or fresh tumor tissue sample obtained via biopsy if archived tissue is not available. In Part 2, subjects must have a confirmed, positive T790M EGFR mutation (acquired T790M EGFR mutation or \de novo\ T790M EGFR mutation).
+Has documented disease progression while receiving at least 30 days of treatment with a currently approved EGFR tyrosine kinase inhibitor (TKI) (e.g., erlotinib, gefitinib or afatinib) with intervening treatment after most recent EGFR TKI therapy (not required for \de novo\ T790M EGFR mutation).
+Eligible for first-line treatment with erlotinib based on documented evidence of tumor harboring an activating EGFR mutation [exon 19 deletion or exon 21 (L858R) substitution mutation].
+Known T790M EGFR mutation (not applicable for Part C Period 2).
+Partial Inclusion criteria:\n\n        Evidence of histologically or cytologically confirmed diagnosis of locally advanced or\n        metastatic EGFRm (del 19 or L858R) NSCLC:\n\n          1. As detected by local EGFR mutation test that includes QIAGEN therascreen EGFR RGQ PCR\n             kit, Roche cobas® EGFR Mutation Test or a sponsor-approved laboratory developed test\n             that is validated in a CLIA laboratory (with tissue submitted for central laboratory\n             confirmation via FDA approved QIAGEN therascreen RCQ PCR kit).\n\n          2. T790M disease as follows:\n\n             Phase 1 If a repeat biopsy was performed on the tumor following prior EGFR TKI\n             therapy, then T790M positive disease must be present. Patients of unknown T790M status\n             following EGFR TKI progression (ie, no post EGFR TKI progression biopsy was performed)\n             are eligible.\n\n             In the PK sub-studies involving food/antacid and CYP3A4 effects, patients with EGFRm\n             (del 19 or L858R) with any T790M status are eligible to enroll.\n\n             Studies at RP2D Cohort 1: Patients may have de novo T790M mutation, but it is not\n             required. Cohort 2 and Cohort 3: Patients must have EGRFm (del 19 AND T790M or L858R\n             AND T790M) NSCLC tumors as detected by local EGFR mutation test that includes QIAGEN\n             Therascreen EGFR RGQ PCR kit, Roche cobas® EGFR Mutation Test or a sponsor-approved\n             laboratory developed test that is validated in a CLIA laboratory, which will then be\n             retrospectively confirmed by the central validated Thermo Fisher Scientific Oncomine\n             Next Generation Sequencing (NGS) cancer panel test. Patients will also be enrolled if\n             they solely test positive for EGFR (del 19 AND T790M or L858R AND T790M) NSCLC in\n             plasma detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR\n             Plasma RGQ kit, Roche cobas® EGFR mutation test v2 (US-IVD) or Sysmex Inostic's\n             OncoBEAMTM EGFR test or a sponsor-approved laboratory developed test that is validated\n             in a CLIA laboratory, which will then be retrospectively confirmed by a validated\n             cfDNA test as determined by the Sponsor.\n\n          3. Prior treatment for EGFRm NSCLC as follows:\n\n        Phase 1 Has progressed after at least 1 prior line of therapy including and EGFR TKI.\n        Patients may have also received other lines of therapy before or after the EGFR TKI.\n\n        Studies at RP2D Cohort 1: no prior treatment for locally advanced or metastatic EGFRm\n        NSCLC. Cohorts 2 and 3: must have had disease progression on treatment with an approved 1st\n        or 2nd generation EGFR TKI. Patients who have been treated with a 3rd generation EGFR TKI\n        are ineligible for this study. Patients may have had multiple lines of therapy; however,\n        the last therapy prior to study treatment must have been an approved EGFR TKI and received\n        within 6 weeks prior to study registration.\n\n        Patients must have at least one measurable lesion as defined by RECIST version 1.1 that has\n        not been previously irradiated.\n\n        Tumor tissue available. Requesting formalin fixed paraffin embedded (FFPE) block or 15\n        unstained sections (5 micron). If a lesser amount of tissue is available, contact the\n        sponsor. An archival specimen is acceptable for Phase 1; a de novo specimen is required for\n        Cohorts 2, and 3 if the T790M status was confirmed by tissue biopsy.\n\n        Partial Exclusion Criteria:\n\n        For All Phases/Cohorts Previously diagnosed brain metastases, unless the patient has\n        completed the treatment that is clinically indicated, if any, and has recovered from the\n        acute effects of any treatment that was delivered prior to study registration, have\n        discontinued corticosteroid treatment for these metastases prior to registration, and are\n        neurologically stable.\n\n        Major surgery within 2 weeks prior to registration.\n\n        Radiation therapy, excluding stereotactic radiosurgery (SRS), within 1 week prior to\n        registration.\n\n        Systemic anti cancer therapy within 2 weeks or 5 half-lives (whichever is longer) of\n        registration excluding EGFR TKIs. Patients on EGFR TKIs must discontinue the agent for a\n        minimum of:\n\n          -  2 days prior to registration for erlotinib or afatinib, or 3 days for gefitinib if\n             they will be part of the lead-in single dose PF-06747775 PK study (Phase 1 Dose\n             Escalation Single and Multiple dose PK and ECG Assessments; Phase 1 Sildenafil at MTD;\n             and Phase 1b/2 First-Line Single Agent). Please contact the Sponsor for direction for\n             any other EGFR TKI.\n\n          -  5 half-lives or 5 days (whichever is longer) prior to registration if they will be\n             starting on continuous PF-06747775 dosing directly (Phase 1 PK sub-studies at RP2D;\n             Phase 1b/2 Combination with Palbociclib; Phase 1b Combination with Avelumab).\n\n        Partial Exclusions for Cohort 2A and 2B (Palbociclib combo):\n\n        Prior treatment with a CDK 4/6 inhibitor.\n\n        Partial Exclusions for Cohort 3 (Avelumab combo):\n\n        Prior therapy with an anti PD 1, anti PD L1, anti PD L2, anti CD137, or anti cytotoxic T\n        lymphocyte associated antigen 4 (CTLA 4) antibody (including ipilimumab, tremelimumab or\n        any other antibody or drug specifically targeting T cell co stimulation or immune\n        checkpoint pathways).\n\n        Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent.\n        Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not\n        requiring immunosuppressive treatment are eligible\n\n        Use of immunosuppressive medication at time of randomization
+Study participants must have had prior epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) testing; participants with sensitizing mutations in EGFR or ALK rearrangements will be excluded
+Participants must have a lung cancer harboring an EGFR mutation
+Prior EGFR tyrosine kinase inhibitor therapy (including gefitinib, erlotinib, or any experimental EGFR tyrosine kinase inhibitor [TKI] agent)
+Participants with known EGFR mutations or ALK rearrangements; all subjects must have been tested for EGFR mutation and ALK rearrangement prior to study entry, unless they are known to have a KRAS mutation\r\n* Note: molecular testing is not required for squamous NSCLC
+Prior or ongoing treatment with any of the following:\r\n* EGFR targeted therapy (TKI or antibody) or any other targeted therapies targeting the ERBB family\r\n* Any cytotoxic chemotherapy, investigational agents, or anticancer drugs for the treatment of advanced NSCLC
+Non-small cell lung cancer (subjects in Part B must either lack EGFR sensitizing mutation or ALK translocation per local test results, or must have progressed on approved standard of care treatment for EGFR or ALK positive NSCLC)
+Has a tumor that harbors an epidermal growth factor receptor (EGFR)-sensitizing (activating) mutation or an anaplastic lymphoma kinase (ALK) translocation
+Prior or ongoing treatment with any of the following:\r\n* EGFR targeted therapy (TKI or antibody) or any other targeted therapies targeting the ERBB family\r\n* Any cytotoxic chemotherapy, investigational agents, or anticancer drugs for the treatment of metastatic NSCLC
+Progression on a first generation EGFR TKI (T790M negative), or progression on a third generation TKI (if T790M positive at time of progression on a first or second generation TKI)
+Prior treatment against NSCLC with an EGFR monoclonal antibody
+Prior afatinib therapy, unless patient received an intervening third generation EGFR TKI after concluding prior afatinib and before enrollment on this clinical study
+Phase II: Subjects with an EGFR or ALK mutation who are no longer candidates for TKI therapy and have progressed on standard systemic therapy (either platinum-based chemotherapy with or without immune checkpoint inhibitor or immune checkpoint inhibitor as first line therapy).
+Patients who are known to have somatic tumor mutations in the following genes, for which targeted agents are available that directly affect the treatment of brain metastasis: Anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), ROS-1 proto-oncogene, and proto-oncogene B-RAF
+Molecular testing results from CLIA-certified laboratories (using tissue and/or blood) demonstrating EGFR-activating mutations Vemurafenib plus Cobimetinib
+Molecular testing results from CLIA-certified laboratories (using tissue and/or blood) demonstrating anaplastic lymphoma kinase (ALK) gene rearrangements, ALK mutations, ALK copy number gain or (for melanoma only) increased ALK expression or presence of ALK-alternative transcription initiation transcript (ALKATI) a) For participants screened using a blood assay: obtain tissue-based testing result confirming study eligibility (within first 4 weeks after enrolment) Atezolizumab
+EGFR amplifications in the absence of EGFR-activating mutations
+Previous treatment with erlotinib or any other EGFR inhibitor
+Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI, e.g., gefitinib or erlotinib. In addition, other lines of therapy may have been given. All patients must have documented radiological progression on the last treatment administered, prior to enrolling in the study.
+Confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria (followed by systemic objective progression (RECIST or World Health Organization [WHO]) while on continuous treatment with an EGFR TKI.
+For the dose expansion and extension cohorts, patients also must have confirmation of tumor T790M+ mutation status from a biopsy sample taken after disease progression on the most recent treatment regimen with an EGFR TKI. Prior to entry, a result from the central analysis of the patient's T790M mutation status must be obtained.
+Previously untreated NSCLC patients. To be eligible for this study, patients must have received and progressed on EGFR TKI therapy.
+Presence of sensitizing EGFR mutations (deletion in exon 19, L858R in exon 21, G719X, and L861Q); patients with the T790M mutation will also be eligible
+No prior treatment with an EGFR TKI for the advanced NSCLC
+Participants enrolling into the MET cohort must have a MET exon 14 mutation as confirmed by targeted next generation (NextGen) sequencing using the Dana-Farber Cancer Institute (DFCI)/Brigham and Women’s Hospital (BWH) OncoPanel or another Clinical Laboratory Improvement Act (CLIA)-certified method; participants whose NSCLC specimens contain actionable genetic mutations/alterations (e.g. ALK/EGFR) should receive appropriate targeted therapies prior to enrollment in the trial
+EGFR and ALK status must be known in all patients with adenocarcinoma histology; patients with activating EGFR mutations or ALK translocations are excluded from this study, unless disease has progressed on all available, approved therapies targeting these alterations
+Patients must have advanced or metastatic NSCLC with histological or cytological confirmation. Patients with known EGFR-activating mutations or ALK rearrangements are excluded.
+Naive to anti-EGFR therapy (cetuximab or panitumumab)
+Prior EGFR inhibitors
+EGFR mutated non-small cell lung cancer (NSCLC) that has previously received a first line platinum doublet and all applicable EGFR TKIs
+PHASE I: Prior treatment with erlotinib, gefitinib or EGFR-blocking monoclonal antibodies (cetuximab and panitumumab) is allowed
+Patients with metastatic colorectal cancer who have progressed on, or are ineligible for standard therapy such as fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab and anti-epidermal growth factor receptor (EGFR) antibodies where appropriate, but are suitable candidates for regorafenib treatment
+EGFR-mutation positive patients must have progressed on or had intolerance to an EGFR small molecule tyrosine kinase inhibitor
+Patients whose tumors harbor an anaplastic lymphoma kinase (ALK) translocation must have progressed on or had intolerance to an ALK inhibitor;
+(Part 2 only) Cohort 1: Have histologically or cytologically confirmed diagnosis of Stage IV squamous NSCLC and have not received prior chemotherapy or immunotherapy for metastatic disease and are not known to be PD-L1 positive (known high PD-L1 expression defined as Tumor Proportion Score [TPS] greater than or equal to 50%). Patients with known sensitizing mutation in the epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) fusion oncogene must have received at least 1 and up to 2 targeted therapies prior to enrollment.
+Activating mutation in EGFR
+No prior epidermal growth factor receptor (EGFR) inhibitor or antiangiogenic agent allowed
+Radiographic documentation of disease progression while on previous continuous treatment with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)
+Confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity OR
+Must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria followed by systemic objective progression while on continuous treatment with EGFR TKI
+Dose Expansion cohort(s): subjects in the dose expansion cohorts must also have confirmation of tumor T790M mutation status (confirmed positive) by cobas® EGFR Mutation Test v2 from formalin-fixed paraffin-embedded tumor tissue (FFPET) or circulating-free tumor DNA (cfDNA) plasma sample taken after disease progression on the most recent treatment regimen (EGFR TKI or chemotherapy or other therapy).
+Cytotoxic chemotherapy, investigational agents, or any anticancer therapy for the treatment of advanced NSCLC (other than EGFR TKI) within 21 days of the first dose of study treatment
+Subjects with epidermal growth factor (EGFR) activating mutations, EGFR T790M or anaplastic lymphoma kinase gene re-arrangement must have received prior standard of care and have evidence of disease progression.
+EGFR mutations as performed on a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory demonstrating EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q. Patients with compound (also referred to as multiple mutations) will be eligible provided the non-small cell lung cancer [NSCLC] demonstrates one of these mutations)
+Prior therapy with EGFR tyrosine kinase inhibitor (TKI) therapy
+Detection of concurrent EGFR mutation with exon 20 T790M, exon 19 deletion, exon 21 L858R mutation or exon 20 insertion. Patients with compound (also referred to as multiple mutations) will be excluded if the molecular testing includes one of these mutations
+Documented activating EGFR mutation (Exon 19 deletion, T790M, or L858R) on tumor samples by Food and Drug Administration (FDA)-approved test
+Prior treatment with osimertinib or other drugs that target EGFR mutant non-small cell lung cancer (including erlotinib, afatinib, gefitinib, rocelitinib)
+Have undergone appropriate standard of care treatment options (in the opinion of the treating investigator); participants with non-small cell lung carcinoma (NSCLC) must have undergone EGFR and ALK testing and have received appropriate initial therapy
+For Part B and Part C, patients with tumors bearing genetic abnormalities for which health authority-approved targeted therapies exist will not be enrolled; e.g, patients with mutations including but not limited to ROS rearrangements, BRAF V600E, EGFR mutations or ALK translocation patients will not be considered eligible
+Patients must have one of the following: \r\n* NSCLC which harbors EGFR exon 19 deletion or L858R mutation. This subset of patients must be TKI naive; OR\r\n* NSCLC which harbors an EGFR T790M mutation that was acquired following progression on erlotinib, gefitinib or afatinib. This subset of patients must have not received prior third generation TKI\r\n* NOTE: EGFR mutation must be documented by a Clinical Laboratory Improvement Amendments (CLIA) certified test
+Previous treatment with osimertinib, or a 3rd generation EGFR TKI. NOTE: Patients who are receiving initial osimertinib (6-12 weeks) outside this study are not excluded
+Prior treatment with, contra-indication to or refusal of a fluoropyrimidine, irinotecan, oxaliplatin and an anti-EGFR targeted therapy (if RAS wild-type [wt])
+Subjects may not have genomic aberrations such as ALK, EGFR, or BRAF for which there are FDA-approved targeted therapies available. Subjects may not have ROS1 aberration in accordance with the pembrolizumab label.
+For lung adenocarcinoma patients, patients must be wild-type for EGFR and ALK. For patients with histologies other than adenocarcinoma, EGFR and ALK status is not required. Adenocarcinoma patients may be consented prior to the EGFR and ALK status being known, but EGFR and ALK status must be determined prior to initiating therapy. EGFR and ALK status may be determined using either tumor- or plasma-based, Clinical Laboratory Improvement Amendments (CLIA)-certified assays. For patients with non-small cell lung cancer (NSCLC), not otherwise specified (NOS), EGFR/ALK testing is not required, as the frequency of alterations is exceedingly rare in this histology. Also, note that patients with ROS1/RET alterations can be enrolled, as tyrosine kinase inhibitors (TKIs)/crizotinib aren’t established as first line therapy for patients with these alterations.
+Histological or cytological diagnosis of advanced/metastatic solid tumor. Measurable disease by RECIST 1.1 with at least 1 measurable lesion that has not been previously irradiated. Availability of tumor specimen taken within 1 year prior to study entry, with no intervening systemic anti-cancer therapy. No prior PD-1/PDL-1 therapy allowed. Combination A: Phase 1b, patients with NSCLC that have progressed on standard therapy or for which no standard therapy is available, and Phase 2, patients with NSCLC, melanoma, SCCHN, TNBC in any line of therapy, SCLC, 1st line NSCLC. 1st line NSCLC must demonstrate to express PD-L1. Activating EGFR mutation, ALK, ROS1 translocation/rearrangements are not permitted. Combination B: Phase 1b, patients with advanced solid tumors (NSCLC, SCCHN, melanoma) that have progressed on standard therapy or for which no standard therapy is available, and Phase 2, patients with NSCLC, melanoma, or SCCHN. Up to 2 lines of prior therapy in advanced/metastatic disease setting allowed. Activating EGFR mutation, ALK, ROS1 translocation/rearrangements are not permitted. Combination C: Ovarian cancer, SCCHN, NSCLC, gastric cancer, platinum resistant ovarian cancer. Up to 2 lines of prior therapy in advanced/metastatic disease setting allowed. TGCT/PVNS that is either inoperable or requires extensive resection. Prior treatment with agents targeting CSF-1/CSF-1R not allowed. NSCLC activating EGFR mutation, ALK, ROS1 translocation/rearrangements are not permitted. Combination D: NSCLC, melanoma, SCCHN, bladder cancer. NSCLC activating EGFR mutation, ALK, ROS1 translocation/rearrangements are not permitted. Up to 2 lines of prior therapy in advanced/metastatic disease setting allowed.
+Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q)
+Progression after prior treatment with an EGFR TKI; in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort
+For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g. AZD9291, rociletinib, etc); T790M testing may be done locally or centrally on study, but if done locally, tissue must be available for central confirmation
+Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment
+Histologically or cytologically confirmed diagnosis of advanced solid tumor malignancy. Patients may be ALK TKI-naive or may have received prior crizotinib and/or second generation ALK TKIs. In addition, patients with a known ALK 1198 mutation will be allowed. -For the expanded cohort portion of the study, patients must have NSCLC with ALK genomic alterations; however, patients will be allowed to enroll based on local FDA-approved ALK results.
+For phase I trial portion, treatment naive or patients previously treated with chemotherapy, immunotherapy or targeted therapy for NSCLC are allowed; patient who underwent curative intent chemotherapy and/or radiation in the neoadjuvant or adjuvant setting are allowed to enroll if tumor recurrence occurred greater than 6 months from completion of that therapy (and will be considered treatment naïve in the stage IV setting); patients with NSCLC tumor known to harbor a genomic aberration for which Food and Drug administration (FDA) approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy
+For phase II trial portion, patients will be enrolled as two parallel cohorts:\r\n* Arm A (treatment naive): patients who are newly diagnosed and treatment naive; patient who underwent curative intent chemotherapy and/radiation in the neoadjuvant or adjuvant setting are allowed to enroll if tumor recurrence occurred greater than 6 months from completion of therapy; patients with NSCLC tumor known to harbor a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy\r\n* Arm B (pre-treated group): patients who have received prior immunotherapy; patients who are primary refractory to immunotherapy (i.e., patients who were previously treated with immunotherapy and did not at least achieve stable disease on first imaging assessment on immunotherapy) or have relapsed disease (i.e., patients that were treated with immunotherapy, achieved at least stable disease on first imaging assessment and subsequently developed disease progression or relapse); patients with NSCLC tumor known to harbor a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy
+EGFR or ALK activating alteration
+Patients with recent (within 15 days preoperatively) history deteriorate kidney function (creatinine serum concentrations > 2.5 mg/dL or epidermal growth factor receptor [eGFR] < 30 mL/kg/min)
+Subjects with EGFR or ALK genomic tumor aberrations should have documented disease progression on FDA-approved therapy for these aberrations; subjects with EGFR or ALK genomic tumor aberrations who develop isolated brain metastases with good response outside the central nervous system (CNS) while on FDA-approved therapy for these aberrations may be included at the discretion of the treating oncologist
+Histologically or cytologically confirmed diagnosis of stage IV NSCLC without epidermal growth factor receptor (EGFR)-sensitizing mutation, ROS1 and/or anaplastic lymphoma kinase (ALK) translocation.
+An EGFR sensitizing mutation must be detected in tumor tissue; specifically, patients harboring the most common mutations, deletions in exon 19 or the L858R mutation in exon 21 are eligible; other EGFR sensitizing mutations may be eligible after discussion with the principal investigator; patients may be enrolled in the study based on an activating EGFR mutation detected by a Clinical Laboratory Improvement Act (CLIA) certified tissue or plasma-based assay, but will be required to undergo a mandatory tumor biopsy during study screening
+Patients in the six patient safety run-in cohort may have had a prior EGFR TKI in the metastatic setting (to allow for patients who started initial therapy at an outside hospital), but treatment duration must have been less than three months; after the initial six-patient safety run-in, no prior EGFR TKI therapy in the metastatic setting is allowed; an EGFR TKI given in the adjuvant setting (i.e. with no measurable disease at the time of administration) is allowable provided the subject has been off of EGFR TKI therapy for at least six months at the time of enrollment
+Patients must have tumors that lack sensitizing EGFR mutation (e.g. exon 19 deletion or exon 21 L858R) or ALK rearrangement; if a patient has squamous histology, then EGFR and ALK testing is not required
+Patients with a known targetable EGFR mutation or ALK rearrangement
+In dose expansion, patients must have received prior anti-EGFR therapy
+Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011):
+Historical confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q).
+Has experienced clinical benefit from an EGFR TKI, followed by systemic progression (Response Evaluation Criteria in Solid Tumors [RECIST version 1.1] or World Health Organization [WHO]) while on continuous treatment with an EGFR TKI.
+Demonstrates absence of EGFR T790M.
+Has previously documented evidence of ALK fusion, ROS1 fusion, BRAF V600E mutation, RET rearrangement, HER2 mutation, MET amplification, or MET exon 14 skipping mutation. No new testing for these genomic alterations is required for Screening.
+Histologically or cytologically confirmed solid tumor of one of the following types associated with overexpression of Epidermal Growth Factor Receptor (EGFR) or EGFR ligands: Dose Escalation Phase:
+Patients with lung cancers harboring sensitizing EGFR or ALK mutations for whom tyrosine kinase inhibitors (TKIs) are approved for first line therapy
+Patients with a known activating mutation in EGFR (exon 19 deletion, G719A, S768I, V769L, T790M, L833F, L858R, L861Q), must have progressed or been intolerant to treatment with a first-line EGFR TKI (erlotinib, afatinib, gefitinib, or osimertinib); patients whose tumors were found to have an EGFR T790M mutation must also have progressed or been intolerable to treatment with osimertinib
+Patients with a known ALK-rearrangement must have progressed or been intolerant to treatment with at least one ALK TKI: crizotinib, ceritinib, alectinib, brigatinib, or loralatinib
+Patients with PDL1 level of >= 50%, who do not have an ALK-rearrangement or EGFR-mutation, must have progressed or been intolerant to treatment with anti-PD1/PDL1 therapy (pembrolizumab, nivolumab, or atezolizumab)
+Confirmation of the presence or absence of EGFR mutations and ALK gene fusions prior to study enrollment in all subjects. Subjects with known EGFR sensitizing mutational status or ALK fusion must have been treated and progressed on EGFR tyrosine kinase inhibitors (TKIs) or ALK-directed therapy, or with tumors harboring EGFR T790M mutation to have received and progressed on therapy directed at the T790M mutation (e.g. osimertinib). Subjects with known ROS1 translocation must have been treated and progressed on ROS1-directed therapy
+Patients whose tumors known to harbor an exon 19 deletion or exon 21 L858R EGFR mutation must have progressed on or had intolerance to an EGFR TKI; patients whose tumors are known to harbor an ALK translocation must have progressed on or had intolerance to an ALK inhibitor
+Patients with activating EGFR mutation or ALK rearrangement which is expected to be responsive to available tyrosine kinase inhibitor therapy, must have been previously treated with an applicable tyrosine kinase inhibitor
+eGFR> 60% of mean age adjusted normal values
+Patients with an active oncogenic driver (e.g., epidermal growth factor [EGFR], activin-receptor-like kinase 1 [ALK1], or the proto-oncogene tyrosine-protein kinase ROS-1) must have progressed on or after a US Food and Drug Administration (FDA)- approved therapy for that aberration (Note: Previous treatment with a tyrosine kinase inhibitor and platinum-based doublets does not exclude the patient.).
+Histologically/cytologically documented stage IIIB to stage IV unresectable non-small cell lung cancer (either squamous cell carcinoma or non-squamous cell lung cancer or mixed histology; EGFR or ALK mutation excluded unless previously treated with a TKI)\r\n* Patients with adenocarcinoma must have been tested for EGFR and ALK mutations
+Patients whose tumors contain activating EGFR mutations or ALK rearrangement should be excluded from this study, unless disease has progressed on all available, approved therapies targeting the EGFR mutation or ALK rearrangement
+Subjects whose tumors harbor a mutation in EGFR exon 19 or 21 or have gene rearrangements in ALK or ROS1 must have already been treated with standard targeted therapies; NOTE: Subjects must also have progressed on or after platinum containing combination chemotherapy
+Cohort 1 specific inclusion criteria: Documented EGFR exon 20 mutation by one of the following Clinical Laboratory Improvement Act (CLIA) certified tests: OncoMine Comprehensive Assay (OCA), Guardant360 Assay (using plasma), or FoundationOne Assay or by a Food and Drug Administration (FDA) approved device using cobas EGFR mutation test version (v)2 or therascreen EGFR RGQ PCt kit; eligible mutations include D770_N771insSVD, D770_N771insNPG, V769_D770insASV, H773_V774insNPH, or any other exon 20 in-frame insertion or point mutation excluding T790M
+Patients must be previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease; previously untreated patients are eligible only if EGFR Exon 20 mutation is confirmed using an FDA approved device: cobas EGFR mutation test v2 or therascreen EGFR RGQ polymerase chain reaction (PCR) Kit prior to study enrollment
+EGFR T790M mutation or any other acquired EGFR exon 20 mutation; patients with coexisting primary EGFR exon 20 and T790M mutations are eligible
+Subjects must have one of the following: a. somatic mutations in human epidermal growth factor receptor (EGFR, HER2, HER3, and HER4); b. EGFR gene amplification (patients with 3+ results on immunohistochemistry testing for EGFR may be allowed to enroll if gene amplification results are unavailable); c. HER2 gene amplification (patients with 3+ results on immunohistochemistry testing for HER-2 may be allowed to enroll if gene amplification results are unavailable).
+Patients who are known to be EGFR- or ALK-positive must have received prior EGFR- or ALK-targeted therapy, respectively\r\n* NOTE: in such cases, documentation of EGFR mutation or ALK translocation status should be provided if available
+Documented EGFR exon 20 insertion mutation
+Documented HER2 exon 20 insertion mutation
+Patient has had previous treatment with poziotinib or any other EGFR or HER2 exon 20 insertion mutation tyrosine kinase inhibitor prior to study participation
+Subjects with known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase receptor (ALK) or ROS1 gene rearrangements must have failed (progressive disease or unacceptable toxicity) at least one prior EGFR or ALK or ROS1 tyrosine kinase inhibitor, respectively. Subject may have received PD-1 or PDL-1 inhibitors and or chemotherapy. There is no limit on lines of prior anti-cancer therapy (a washout period applies for recent anti-cancer treatments).
+Prior erlotinib, gefitinib or lapatinib therapy or prior exposure to any investigational EGFR or panErbB reversible or irreversible inhibitor or any prior panitumumab or investigational EGFR-directed monoclonal antibody
+Patients with advanced (metastatic) NSCLC, whose disease progressed during or after platinum-based chemotherapy; patients with EGFR or ALK genomic tumor aberrations should have disease progression on Food and Drug Administration (FDA)- approved therapy for these aberrations prior to receiving nivolumab
+Patients must have histologically or cytologically confirmed incurable non-small cell lung cancer that harbors an activating mutation in EGFR, MET, BRAF, V600E, RET, HER2, translocation in Alk, or translocation in ROS-1
+Patients with advanced (metastatic) NSCLC, whose disease progressed during or after platinum-based chemotherapy; patients with EGFR or ALK genomic tumor aberrations (testing required for adenocarcinoma patients) should have disease progression on Food and Drug Administration (FDA) approved therapy for these aberrations prior to receiving nivolumab; these patients are eligible regardless of line of therapy
+Non-small cell lung cancer: 1) we will enroll non-small cell lung cancer patients with documented EGFR mutation who failed treatment with anti-EGFR therapy (e.g. erlotinib or afatinib) and tested negative for EGFR T790M mutation; we will allow patients with positive EGFR T790M mutation if they have progressed on third generation anti-EGFR therapy (e.g. CO-1686 or AZD9291) or medically not suitable/candidate for the third generation anti-EGFR therapy; failure from anti-EGFR therapy will be defined as progressive disease by RECIST (version 1.1) after at least two months of therapy
+Prior therapy with any HER2 directed tyrosine kinase inhibitor (TKI) (e.g., lapatinib, afatinib, dacominib, neratinib, capecitabine) or anti-EGFR antibody therapy (e.g., cetuximab)
+Phase 2 patients must have confirmed EGFR T790M mutation-positive NSCLC
+Phase 2 patients are also excluded if they had prior treatment with CK-101 or other third generation TKIs that target EGFR T790M mutation-positive NSCLC, or have evidence that the tumor harbors an exon 20 insertion mutation
+Estimated glomerular filtration rate (eGFR) of at least 50 ml/min; the Cockcroft Gault formula will be utilized to determine eGFR when blood urea nitrogen (BUN) and creatinine testing are performed at baseline. The combination of eGFR serum creatinine and BUN will be used to evaluate patient's renal function for safety assurance.
+Patients with known activating EGFR mutations or ALK rearrangements should have progressed after appropriate targeted treatment in addition to progressing during or after platinum-based doublet chemotherapy
+Have an EGFR mutation (sensitizing or non-sensitizing)
+Has received prior therapy with an EGFR tyrosine kinase inhibitor (such as erlotinib, gefitinib, afatinib, rociletinib, or AZD9291) for NSCLC
+Sensitizing mutations in EGFR or rearrangements in ALK or ROS1
+Subjects must have received prior platinum doublet based treatment\r\n* Up to 2 lines of prior systemic therapy for metastatic disease are permitted\r\n* Adjuvant chemotherapy or concurrent chemoradiation for early stage disease does not count as prior therapy unless subject progressed within 6 months of completion of regimen\r\n* Patients with known activating mutations in epidermal growth factor receptor (EGFR), or known translocation in anaplastic lymphoma kinase (ALK) or ROS-1 are eligible provided they have progressed on or were intolerant to Food and Drug Administration (FDA) approved targeted therapy
+Subjects with histologically or cytologically-confirmed metastatic NSCLC whose disease progressed during/after treatment with at least one platinum-containing chemotherapy regimen; patients whose tumors are known to harbor an exon 19 deletion or exon 21 L858R epidermal growth factor receptor (EGFR) mutation must have progressed on or had intolerance to an EGFR tyrosine kinase inhibitor; patients whose tumors are known to harbor an anaplastic lymphoma kinase (ALK) translocation must have progressed on or had intolerance to an ALK inhibitor
+Patients with histologically confirmed, by the National Cancer Institute (NCI) Laboratory of Pathology or by Clinical Laboratory Improvement Act (CLIA)-certified next generation sequencing or cobas EGFR mutation test v1/2 at an outside institution, advanced lung adenocarcinoma with EGFR-sensitizing somatic mutations or a germline T790M mutation (detected histologically or via ctDNA analysis using a CLIA assay) with:\r\n* No prior EGFR tyrosine kinase inhibitor (TKI) therapy (cohort 1)\r\nOR\r\n* Progressive disease after 1st or 2nd generation EGFR TKI therapy harboring somatic T790M mutation (cohort 2)\r\nOR\r\n* Progressive disease after treatment with osimertinib who are eligible for local ablative therapy (cohort 3)
+INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Patients with known epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations must have been treated on at least one line of molecularly targeted therapy (e.g., erlotinib, crizotinib)
+Tumor exhibits epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) re-arrangement that qualifies the patient for treatment with a systemic agent targeting these mutations
+Patients whose tumor harbors EGFR gene mutation that sensitizes tumors to Tyrosine-Kinase Inhibitor (TKI) (EGFR exon 18-21) or Anaplastic Lymphoma Kinase (ALK) rearrangement.
+Have undergone appropriate standard of care treatment options (in the opinion of the treating investigator); patients with NSCLC must have undergone epidermal growth factor receptor (EGFR) and anaplastic lymphoma receptor tyrosine kinase (ALK) testing and have received appropriate initial therapy
+Patients must have histologically or cytologically confirmed non-small cell lung cancer (NSCLC) that is advanced/metastatic (stage IIIB/IV) or recurrent (progression after surgery or radiation or chemo-radiation treatment for loco-regional disease); patients with epidermal growth factor (EGFR) mutation, anaplastic lymphoma kinase (ALK) gene rearrangement or ROS1 translocation must have received an approved EGFR, ALK, or reactive oxygen species (ROS)1-directed therapy and have signs of disease progression prior to receiving pembrolizumab
+Pathology consistent with EGFR-amplification of tumor (i.e. greater than 15% of cells exhibiting > 5 copies of EGFR loci); archival tissue may be tested for EGFR status in a separate consent
+Prior treatment with EGFR-targeted therapy, including, but not limited to, the following examples: Gilotrif (afatinib),Tarceva (erlotinib), Erbitux (cetuximab), Iressa (gefitinib), Vectibix (panitumumab), Caprelsa (vandetanib), Tykerb (lapatinib), CDX110, D2C7-immunotoxin)
+Confirmation by the central laboratory that the tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations including T790M.
+Patients with characterized EGFR mutations that predict sensitivity to EGFR therapy, including, but not limited to exon 19 deletions and exon 21 mutations
+Documented evidence of somatic activating mutation in EGFR (eg, G719X, exon 19 deletion, L858R, L861Q) in a tumor tissue sample. If a tissue sample is not available, then EGFR mutation status may be determined from circulating tumor DNA obtained from a blood sample using a validated or approved test kit.
+Phase 1: Subjects must have previously received and progressed on or after treatment with an EGFR tyrosine kinase inhibitor (TKI). Additional lines of systemic therapy including investigational agents for locally advanced or metastatic NSCLC are allowed.
+Phase 2: Subjects must not have received more than 1 prior line of therapy for locally advanced or metastatic NSCLC. First-line treatment must include an EGFR TKI, and subjects must have documented disease progression during or following treatment. Subjects with disease that progressed more than 6 months after completion of neoadjuvant/adjuvant chemotherapy or chemoradiation therapy are eligible if they received an EGFR TKI as first-line treatment for advanced NSCLC.
+Subjects must have evidence of a T790M mutation in tumor tissue or plasma obtained after disease progression during or after treatment with an EGFR TKI. T790M mutation status from a local laboratory is acceptable; however, a tumor tissue sample or plasma sample suitable for centralized T790M mutation analysis must be available.
+Any previous use of Janus kinase (JAK) inhibitor, osimertinib, or other EGFR-directed therapy for T790M-mt NSCLC.
+Known ALK mutation
+Presence of exon 19 deletion or exon 21 (L858R) substitution of the EGFR gene
+Known actionable mutations, (e.g. EGFR, ALK, ROS1), against which there is an established effective targeted therapy
+NSCLC subjects with EGFR mutations or ALK translocations should have previously received appropriate Food and Drug Administration (FDA) approved therapies in addition to prior chemotherapy
+PHASE II STUDY NON-SMALL CELL LUNG CANCER (COHORT 2; MEDI+O AND MEDI+C) AND SMALL CELL LUNG CANCER (COHORT 3; MEDI+O ONLY) ELIGIBILITY CRITERIA:\r\nSpecific criteria for the NSCLC cohort:\r\nHistologically or cytologically confirmed advanced NSCLC with at least one prior line of platinum-based chemotherapy (or treatment with epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK] tyrosine kinase inhibitors if tumors harbor an EGFR-sensitizing mutation or ALK translocation respectively)
+Sensitizing epidermal growth factor receptor (EGFR), anaplastic lymphoma receptor tyrosine kinase (ALK) and ROS proto-oncogene 1, receptor tyrosine kinase (ROS-1) mutations are either negative or unknown
+Patients whose tumors are positive for the sensitizing EGFR mutation
+Patients must have histologically or cytologically confirmed diagnosis of stage IIIB or stage IV of non-small cell lung cancer and have received at least two lines of Food and Drug Administration (FDA)-approved or National Comprehensive Cancer Network (NCCN) accepted systemic therapy and progressed through, or not tolerated, such therapy; all subjects which harbor specific mutations, such as endothelial growth factor receptor (EGFR) deletion mutation of anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangements, for which an acceptable targeted therapy exists, at least one of the lines of therapy must be such targeted therapy, unless the subject is not a candidate for the targeted therapy or unable to tolerate that therapy as determined by the treating physician\r\n* Subjects whose tumors harbor an exon 19 deletion or exon 21L858R EGFR mutation must have progressed on or had intolerance to EGFR tyrosine kinase inhibitor\r\n* Subjects whose tumors harbor an AKL translocation must have progressed on or had intolerance to crizotinib (or any FDA approved ALK inhibitor) OR
+Epidermal growth factor receptor (eGFR) < 50 by Mayo or Cockcroft formula
+EGFR mutation with exon 19 deletion or L858R mutation (Exon 21) or ALK rearrangement positive must have failed prior TKI therapy
+Patients with lung cancer whose tumors contain activating epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement should be excluded from this study, unless disease has progressed on all available, approved therapies targeting the EGFR mutation or ALK rearrangement
+Known activating epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation
+Incurable, advanced or metastatic/recurrent non-small cell lung cancer with EGFR activating mutations (exon 19 del, exon 21 L858R, L861Q, G718X); who have radiologic and/or clinically progressive disease on erlotinib at any point during the patient's cancer treatment as determined by the Investigator
+Presence of activating EGFR mutations or ALK re-arrangement unless previously treated with standard TKI therapy; all patients with adenocarcinoma histology must be tested for EGFR and ALK status
+Tumor tissue for determination and/or confirmation of genetic pre-requisites (i.e. EGFR T790M positivity post progression on EGFR TKI for Group 1; cMet status for Group 2) must be provided for analysis Group 1 patients:
+Patients with EGFR T790M NSCLC (adenocarcinoma)
+Patients with EGFR wild-type NSCLC
+Patients who have received more than one prior line of EGFR TKI therapy1 (applies only to Group 1)
+Patients who previously received agents targeting c-MET and/or EGFR T790M Note: Previous treatment with afatinib may be allowable after discussions between Novartis and Investigator.
+Patients with mCRC must have been previously treated with irinotecan and/or oxaliplatin and/or vascular endothelial growth factor (VEGF)/epidermal growth factor receptor (EGFR) therapy or intolerant to these agents
+Participants must have histologically or cytologically confirmed non-small cell lung cancer (NSCLC) with any actionable mutation or translocation in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c-ros oncogene 1 (ROS1)
+Participants must be within 6 months of initiating TKI treatment, which specifically targets the actionable mutation their tumor harbors (i.e., first-line TKI, or a next-line TKI that targets tumors with acquired resistance to first-line TKI)
+Patients with epidermal growth factor receptor (EGFR) or transforming fusion gene EML4-ALK variant 4 (EML4-ALK) mutations
+Patients with EGFR mutations or ALK rearrangements must have disease progression on appropriate Food and Drug Administration (FDA)-approved therapy for these genomic aberrations prior to enrollment
+Histologically confirmed unresectable solid tumor malignancy with at least 1 measurable lesion in dose escalation; in the expansion phase, eligibility limited to metastatic triple negative breast cancer that has received prior taxane and anthracycline therapy; metastatic non-small cell lung cancer (NSCLC) that is not anaplastic lymphoma kinase positive (ALK+) and does not have a epidermal growth factor receptor (EGFR) sensitizing mutation; and metastatic gastric cancer
+Patients must have tumor tissue available for submission that is sufficient to complete c-MET fluorescence in situ hybridization (FISH) studies as well as routine molecular profiling at the University of Pittsburgh Medical Center (UPMC); patients must agree to submission of these specimens\r\n* c-MET amplification will be determined by FISH ratio (c-MET/chromosome 7 centromere probe [CEP7]) > 2.0, based on testing of the primary tumor and/or site of metastatic disease\r\n* Patients’ tumors must undergo testing for epidermal growth factor receptor (EGFR) exon 19 deletion, EGFR exon 21 leucine substitution at position 858 (L858R) substitution, and anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangements; if positive, patients must have been treated with an appropriate tyrosine-kinase inhibitor (TKI) prior to enrolling to the study
+Prior use of MEK162 or concurrent use of other approved anticancer or investigational agents is not allowed; patients treated with prior EGFR tyrosine kinase inhibitor (TKI) therapy (including erlotinib) are allowed to enroll
+Non-small cell lung cancer (NSCLC) with an activating EGFR mutation (exon 19 deletion, L858R point mutation, or any other mutation known to be associated with EGFR TKI sensitivity); presence of an activating EGFR mutation may be documented in tumor tissue or by plasma testing if performed in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory; AND
+The presence of an EGFR T790M mutation after progression on a first- or second-generation EGFR TKI; presence of an EGFR T790M mutation may be documented from biopsy material from any site of disease (intra- or extra-cranial) or from plasma testing if performed in a CLIA-certified laboratory; for patients who have disease progression in the CNS only (with otherwise stable disease systemically), T790M positivity is not required
+Disease progression on a first- or second-generation EGFR TKI (i.e. erlotinib, gefitinib, or afatinib); patient may have also received prior chemotherapy or immunotherapy but this is not required
+Prior treatment with a third-generation EGFR TKI (i.e. rociletinib)
+Have a documented EGFR in-frame exon 20 insertion by a local test, including A763_Y764insFQEA, V769_D770insASV, D770_N771insNPG, D770_N771insSVD, H773_V774insNPH, or any other in-frame exon 20 insertion mutation.
+Have not received a tyrosine kinase inhibitor (TKI) with activity against the specific documented EGFR exon 20 insertion.
+An EGFR exon 20 insertion: A763_Y764insFQEA, V769_D770insASV, D770_N771insNPG, D770_N771insSVD, H773_V774insNPH, or any other in-frame exon 20 insertion mutation.
+For patients with an EGFR exon 20 insertion: have not received a TKI with activity against the specific documented EGFR exon 20 insertion.
+For patients with a HER2 exon 20 insertion or HER2 activating point mutation: have not received a TKI with pan-HER activity (eg, afatinib, neratinib, or dacomitinib).
+Have one of the following documented by a local test: an activating mutation in EGFR including exon 19 deletions or exon 21 L858R substitution (with or without T790M), or an uncommon activating mutation other than exon 20 insertion including, but not limited to, G719X (where X is any other amino acid), S768I, L861Q, or L861R.
+For patients with a documented EGFR exon 19 deletion or exon 21 L858R substitution: resistant to at least one prior EGFR inhibitor (eg, erlotinib, gefitinib, or afatinib).
+For patients with a documented EGFR T790M mutation: have not received a TKI with activity against the EGFR T790M mutation.
+For patients with an uncommon activating mutation in EGFR: have not received a TKI with activity against the specific documented uncommon activating mutation.
+Patients are not required to have HER-2 or epidermal growth factor receptor (EGFR) over-expression to be on this study at the dose escalation cohort; however, patients will be required to have HER-2 overexpression and/or EGFR overexpression for the extension and expansion cohorts\r\n* If the patient has had HER-2 expression measured prior to enrollment, the report alone will be accepted the dose escalation phase of the study\r\n* If the patient has had EGFR expression measured prior to enrollment, the report alone will be accepted on the dose escalation phase of the study.\r\n*If the patient has not had HER-2 or EGFR expression measured prior to enrollment on this study, it would be obligatory for the patient to have the tests performed to justify their status; HER-2 status can be performed by a variety of tests; either immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH) assay are acceptable if breast tumor tissues (previously frozen) are available; the test can be done at Ohio State University (OSU) or elsewhere if the patient is from out of town
+Histologically-confirmed stage 4 NSCLC that: has not been treated with prior chemotherapy for metastatic disease and has high PD-L1 expression (ie, a TPS ? 50%), as determined by an FDA-approved test. Previous neoadjuvant/adjuvant chemotherapy is allowed if completed ? 6 months before diagnosis of metastatic disease.The subject's tumor must not harbor an EGFR sensitizing (activating) mutation or ALK translocation. EGFR sensitizing mutations are those mutations that are amenable to treatment with tyrosine kinase inhibitors including erlotinib, gefitinib, or afatinib. Investigators must be able to produce the source documentation of the EGFR mutation and ALK translocation status in all subjects with non-squamous histologies AND for subjects in whom testing is clinically recommended. If either an EGFR sensitizing mutation of ALK translocation is detected, additional information regarding the mutation status of the other molecule is not required. If unable to test for these molecular changes, formalin fixed paraffin embedded tumor tissue of any age should be submitted to a central laboratory designated by the Sponsor for such testing. Subjects with non-squamous histologies will not be randomized until the EGFR mutation status and/or ALK translocation status is available in source documentation at the site. For patients enrolled who are known to have a tumor of predominantly squamous histology, molecular testing for EGFR and ALK translocation will not be required as this is not standard of care and is not part of current diagnostic guidelines.
+Have an EGFR or ALK genomic tumor aberrations for which targeted therapy with an EGFR or ALK inhibitor is indicated. Additional Exclusion Criteria for Cohort 2:
+Patients with an EGFR deletion or mutation known (from tumour biopsy or plasma) to be associated with EGFR TKI sensitivity
+Patients with an EGFR exon 20 insertion
+Patients who have received prior EGFR treatments for lung cancer
+Patients who have received prior treatment with an EGFR TKI including in the adjuvant setting
+eGFR > 45 mL/min
+Patients whose tumors harbor an EGFR sensitizing mutation must have demonstrated progression on or intolerance to an Food and Drug Administration (FDA)-approved first-line EGFR tyrosine kinase inhibitor (TKI); patients with the EGFR T790M mutation, must also have demonstrated progression on or intolerance to osimertinib
+Part 2: Has a histologically-confirmed adenocarcinoma originating from the colon or rectum (Stage 4 American Joint Committee on Cancer [AJCC] 7th edition). Appendiceal cancer is included. AND Has experienced disease progression or was intolerant to at least 1 and up to 5 systemic chemotherapy regimen(s) for metastatic CRC that must have included fluroropyrimidines and irinotecan or oxaliplatin, ± anti-vascular endothelial growth factor (VEGF) or anti-epidermal growth factor receptor (EGFR)(if indicated by RAS mutational status).
+Treatment with third generation EGFR inhibitors
+Patients with known and documented EGFR mutation who have not received an EGFR inhibitor.
+Absence of an activating mutation (Exon 19 deletion or Exon 21 L858R mutation) in the epidermal growth factor receptor (EGFR) in the pre-treatment biopsy of the tumor. Patients with activating EGFR mutations are eligible if they have progressed following treatment with erlotinib. A pretreatment tumor biopsy must be available for analysis. If a biopsy has not been performed prior to entry, then a biopsy will be required.
+Tumors must demonstrate epidermal growth factor receptor (EGFR) amplification.
+\Acquired\ resistance to commercially available anti-EGFR mAbs approved for the treatment of mCRC must have:
+Received treatment with an anti-EGFR for ?16 weeks
+Progressive disease (PD) documented by imaging or clinical findings less than or equal to 6 calendar months after cessation of previous anti-EGFR mAb treatment
+No more than 6 calendar months from last dose of previous anti-EGFR mAb treatment to date of consent for this trial (regardless of the line of therapy in which it was used)
+Skin rash > Grade 1 from prior anti-EGFR therapy at the time of randomization.
+Patients with sensitizing EGFR mutations and/or ALK gene rearrangements.
+Has confirmation that epidermal growth factor receptor- (EGFR-), anaplastic lymphoma kinase- (ALK-), c-ros oncogene 1- (ROS1-), or B isoform of rapidly accelerated fibrosarcoma- (B-Raf-) directed therapy is not indicated as primary therapy (documentation of absence of tumor activating EGFR or B-Raf mutations AND absence of ALK or ROS1 gene rearrangements)
+Documentation of tumor activating EGFR mutation, specifically either DEL19 or L858R.
+Investigator-determined radiographic disease progression per RECIST 1.1 after treatment with an EGFR TKI therapy: a) Participants previously treated with 1st or 2nd generation EGFR TKI (e.g. erlotinib/afatinib/gefitinib) are required to have confirmed documented absence of EGFR T790M mutation; b) Participants with confirmed acquired T790M mutation after 1st or 2nd generation EGFR TKI (e.g. erlotinib/afatinib/gefitinib) are required to have osimertinib TKI treatment failure prior to enrollment; c) Participants previously failed osimertinib TKI treatment as 1st line therapy are eligible regardless of their EGFR T790M mutation status.
+Patients with tumors tested positive for Epidermal growth factor receptor (EGFR) gene mutations, Anaplastic lymphoma kinase (ALK) gene translocations, or C-ros oncogene receptor tyrosine kinase(ROS1) fusions
+Patients with EGFR, ALK or ROS-1 mutations who are eligible for treatment with a TKI and who have not received such treatment
+Life expectancy greater or equal to 3 months, as determined by the investigator -Patients must have progressed on the standard therapy, including platinum based - chemotherapy. Patients with epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or ROS-1 mutations must have progressed on standard treatment options including EGFR, ALK, or ROS-1-directed therapies.
+Epidermal growth factor receptor (EGFR) mutant and/or anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearranged tumor
+Patients with tumors having actionable genomic alterations should have received prior therapy with Food and Drug Administration (FDA) approved agents targeting these aberrations (ie EGFR, ALK, ROS1, BRAF V600E)
+For study cohort A, has not had prior treatment with cetuximab, panitumumab, or other anti-EGFR therapy
+Have stage IV, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC) with progressive disease after platinum containing chemotherapy (EGFR mutant, ALK, or ROS-1 rearranged NSCLC must have progressed on prior approved tyrosine kinase inhibitor [TKI]’s)
+Patient must have been already tested and have available results of the mutations status of KRAS/NRAS/BRAF and EGFR from the circulating tumor DNA within 10 weeks prior to starting study therapy
+In cohort 1, must have EGFR S492R or other ectodomain mutation detected from circulating tumor DNA from plasma collected after progression to prior cetuximab; may have a concomitant mutation in KRAS, NRAS, or BRAF, if there is at least a 5-fold higher allele frequency of the most prevalent EGFR mutation than the most prevalent KRAS/NRAS/BRAF mutation
+In cohort 2, must have one or more mutations found in KRAS exon 2, 3, or 4; NRAS exon 2, 3, or 4; BRAF codon 600; may have a concomitant EGFR ectodomain mutation, if the most prevalent EGFR ectodomain mutation does not have over a 5-fold higher allele frequency than the most prevalent KRAS/NRAS/BRAF mutation
+In cohort 3, must not have EGFR ectodomain mutation or any mutations in KRAS, NRAS, or BRAF
+Patient has NSCLC with a targetable mutation in EGFR, ALK, or ROS1.
+TREATMENT: Patients with non-small cell lung cancer (NSCLC) must have previously been tested for the presence of epidermal growth factor receptor (EGFR) mutations, and, if detected, should have received and progressed on EGFR tyrosine kinase inhibitor (TKI) therapy
+Prior therapies:\r\n* Patients without activating mutations and gene rearrangements should have received at least one prior chemotherapy regimen; any number of prior therapies is allowed except for immunotherapy (e.g. anti PD-1, PD-L1, vaccines, CTLA-4 etc.)\r\n* Patients with activating mutations and gene rearrangements with known documented benefit from tyrosine kinase inhibitors should have received and demonstrated progression with that inhibitor (e.g. EGFR del 19 mutation should have been treated with gefitinib, erlotinib or afatanib etc); ALK rearrangements should have been treated with an ALK inhibitor; patients who have progressed on these agents should be assessed, if appropriate, for resistance mutations susceptible to approved agents and treated with that agent\r\n* No prior gemcitabine treatment
+DOSE EXPANSION COHORT: Subjects with metastatic or recurrent NSCLC who progressed on at least one line of systemic therapy for metastatic or recurrent disease, which must include anti PD-1 or PD-L1 inhibitor, and must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and accessible tumor for biopsy; molecular status of EGFR and ALK must have been assessed for nonsquamous NSCLC; those with activating EGFR mutation or ALK gene arrangement must have progressed on at least one kinase inhibitor
+Subjects whose tumors express EGFR mutations on exons 19 and 21, ALK rearrangement, or ROS1 rearrangement who still have other Food and Drug Administration (FDA) approved targeted agents available for treatment.
+Patients must have newly diagnosed histologically or cytologically confirmed NSCLC, staged IIIB or IV, for which they have not received first-line cytotoxic chemotherapy (first-line epidermal growth factor receptor [EGFR] inhibitors or anaplastic lymphoma kinase [ALK] inhibitors are allowed given disease progression)
+Known sensitizing EGFR mutations or ALK gene rearrangement; if patient’s biopsy did not allow EGFR or ALK gene analysis (e.g., inconclusive, not enough tissue, etc.), the patient is considered eligible for study; enrollment on this clinical trial after progression on targeted therapy is allowed
+Documented evidence of a tumor with 1 or more EGFR mutations excluding exon 20\n             insertion
+Disease progression confirmed by radiologic assessment while receiving treatment with\n             the first single agent EGFR-TKI
+EGFR TKI treatment discontinued less than or equal to 30 days prior to planned\n             initiation of rociletinib
+The washout period for an EGFR inhibitor is a minimum of 3 days
+No intervening treatment between cessation of single agent EGFR TKI and planned\n             initiation of rociletinib
+-  Documented evidence of an exon 20 insertion activating mutation in the EGFR gene
+Prior treatment with rociletinib, or other drugs that target T790M positive mutant\n             EGFR with sparing of wild type EGFR
+Subjects should have received at least one prior platinum based chemotherapy and an immune checkpoint targeted agent; subjects with epidermal growth factor receptor (EGFR)-mutated and anaplastic lymphoma kinase (ALK)-translocated non-small cell lung cancer (NSCLC) should have received Food and Drug Administration (FDA)-approved targeted therapies as appropriate
+Patients with EGFR/ALK/ROS-1+ lung adenocarcinoma
+For Phase IB Extension Only:\r\n* Either or both of the following:\r\n** A tumor which harbors an activating epidermal growth factor receptor (EGFR)-mutation\r\n** History of objective response, or stable disease for at least 6 months, after treatment with erlotinib, afatinib, or gefitinib\r\n* Either or both of the following:\r\n** Progression or recurrence of disease after receiving prior continuous gefitinib, afatinib, or erlotinib\r\n** A tumor known to harbor a de novo T790M mutation, which is known to confer EGFR TKI resistance\r\n* Participants are allowed to have received systemic chemotherapy or investigational therapy in the intervening period prior to trial enrollment
+Disease progression confirmed by radiologic assessment while on treatment with EGFR-\n             TKI Or
+Disease progression confirmed by radiologic assessment while on treatment with the\n             first single agent EGFR TKI and
+Documented evidence of T790M mutation in EGFR following disease progression on the\n             first single agent EGFR TKI.
+Prior therapy with any agent targeting the HER2 pathway or human epidermal growth factor receptor 1 (HER1) (epidermal growth factor receptor [EGFR]) pathway
+Prior therapy that specifically and directly targets the epidermal growth factor receptor (EGFR) pathway
+* Phase 1 (Part A2) - COMPLETE: Patients with confirmed ALK fusion proteins, ALK mutations, ALK amplification (defined as greater than 4-fold increase in the ALK signal number as compared to reference signal number on chromosome 2q arm) or MET proto-oncogene, receptor tyrosine kinase (MET) mutation or amplification; testing to confirm the presence of ALK fusion proteins, ALK mutations, ALK amplification or evidence of MET mutation or amplification for eligibility purposes must be performed as a Clinical Laboratory Improvement Act (CLIA)-certified assay; ALK immunohistochemistry can be used as a surrogate for fluorescent in situ hybridization (FISH) for patients with inflammatory myofibroblastic tumors (IMT) or ALCL
+* Phase 2 (Part A2): Patients with diagnoses other than neuroblastoma or ALCL with confirmed ALK fusion proteins, ALK mutations, ALK amplification (defined as greater than 4-fold increase in the ALK signal number as compared to reference signal number on chromosome 2q arm) or MET mutation or amplification; testing to confirm the presence of ALK fusion proteins, ALK mutations, ALK amplification or evidence of MET mutation or amplification for eligibility purposes must be performed as a CLIA-certified assay; ALK immunohistochemistry can be used as a surrogate for FISH for patients with IMT
+Patients must have documented presence of an EGFR exon 19 deletion or exon 21 (L858R) substitution mutation; T790M mutation or other molecular abnormality will be allowed as long as it accompanies one of the mutations listed above; EGFR testing must be performed using a Food and Drug Administration (FDA)-approved test or in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.
+Patients must not have received any prior systemic anticancer therapy for advanced or metastatic disease including chemotherapy or EGFR tyrosine kinase inhibitor therapy (including gefitinib, erlotinib, afatinib, or any experimental EGFR tyrosine kinase inhibitors [TKI] agents); prior chemotherapy for non-metastatic disease (i.e. adjuvant therapy or concurrent chemo-radiotherapy) is allowed as long as > 12 months has passed since completion of therapy; adjuvant EGFR-directed therapy is not allowed; local therapy (i.e. palliative radiotherapy) is allowed as long as a period of 7 days has passed since the last dose was received and the patient has recovered from any associated toxicity at the time of registration
+Pathologically confirmed non-small cell lung cancer with documented EGFR mutation in tumor deoxyribonucleic acid (DNA) or complete/partial response to first line EGFR tyrosine kinase inhibitors with > or = to 6 months duration of response in patients who do not have a confirmed EGFR mutation
+Progressive disease with radiographic evidence of disease progression per investigator assessment during therapy with an EGFR tyrosine kinase inhibitor in the metastatic setting; patients may continue EGFR inhibitor therapy throughout the screening period until the day prior to nab-paclitaxel treatment initiation
+Prior positive test for EGFR mutation or ALK gene rearrangement
+Pathologically confirmed diagnosis of non-small cell lung cancer with either EGFR exon 19 deletion mutation, EGFR exon 21 L858R point mutation, exon 18 G719X, and exon 21 L861Q; other rare EGFR mutations may be eligible after discussion with the overall principal investigator; mutations detected at outside laboratories are acceptable for enrollment
+Tumors with epidermal growth factor receptor mutation positive or anaplastic lymphoma kinase fusion oncogene positive treated with a tyrosine kinase inhibitor are permitted; however, subjects should have progressed on or be intolerant to the targeted therapy.
+Participants in Stage 2 (Expansion) receiving erlotinib: i) sensitizing mutation in the EGFR gene and ii) consent to collection of tumor tissue samples before, during, and after treatment for biopsy and PD biomarker analyses.
+For participants receiving erlotinib group: prior treatment with any EGFR mutant-targeting TKI
+Non-small cell lung cancer (NSCLC)\r\n* Metastatic or locally advanced disease that progressed after at least one prior therapy \r\n* Note: patients who have actionable molecular targets (e.g., epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], c-ros oncogene 1[ROS1] mutations) must have received (when indicated) prior appropriate targeted therapy using Food and Drug Administration (FDA)-approved agents
+NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test
+For Dose escalation cohort - progressive disease on at least one prior EGFR-tyrosine kinase inhibitor (TKI) (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation)
+For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies
+For Dose Expansion Cohort B: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial)
+For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial
+For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naive to both EGFR-TKI and EGFR monoclonal antibody
+Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment
+Prior treatment with anti-epidermal growth factor receptor (EGFR) therapy (either panitumumab or cetuximab)
+Has confirmation that epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK)-directed therapy is not indicated.
+Known tumor EGFR, KRAS, and/or Akt2 mutations or amplification
+eGFR ? 50 mL/min/1.73 m2
+History of NSCLC with EGFR mutation or an EGFR activating mutation that has had a clinical response to erlotinib, afatinib, or gefitinib in the patient being enrolled.
+Occurrence or progression of BM while receiving first line therapy (either erlotinib, afatinib, or gefitinib) for at least 14 days. Patients may have received osimertinib (or other agents inhibiting the T790M EGFR mutation) as second line therapy. If BM progression occurs after osimertinib, patient will be eligible.
+Evidence of common EGFR mutation (Del 19 and/or L858R)
+Absence of known epidermal growth factor receptor (EGFR) mutation
+Histologically or cytologically confirmed diagnosis of advanced non-small cell lung cancer (stage IIIB or IV) or recurrent disease. Subjects with known EGFR mutations or ALK or ROS1 gene rearrangements must have also failed prior EGFR or ALK or ROS1 tyrosine kinase inhibitor, respectively (PD or unacceptable toxicity). Subjects may have received PD-1 or PDL-1 inhibitors. There is no limit on lines of prior anti-cancer therapy.
+Patients must be willing to be off EGFR-tyrosine-kinase inhibitor (TKI) therapy for a minimum of one week; (in expansion cohort A patients on erlotinib do not have to discontinue treatment)
+Patients who have had prior therapy that specifically and directly targets the EGFR/HER2 pathway.
+Participants with epidermal growth factor receptor (EGFR) sensitizing mutations and anaplastic lymphoma kinase (ALK) rearrangements
+Have received prior anticancer therapy with monoclonal antibodies, signal transduction inhibitors, or any therapies targeting the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), or VEGF receptor.
+Locally documented EGFR mutation L858R and/or ex19del, or a characterized de novo EGFR T790M mutation (or other rare activating mutations that confer sensitivity to 1st and 2nd generation EGFR inhibitors (e.g. L861Q, G719X, S768I)
+Phase Ib only: documented progression of disease according to RECIST v1.1 while on continuous treatment with EGFR TKI (e.g.: erlotinib, gefitinib or afatinib).
+Phase II Group 1 (EGFRmut, any T790M, any c-MET, 2/4L antineoplastic, EGFR TKI resistant) only: Patients demonstrated a documented clinical benefit (CR (any duration), PR (any duration), or SD for at least 6 months) on prior EGFR TKI (e.g. erlotinib, gefitinib or afatinib, and subsequently demonstrated progression according to RECIST v1.1.
+Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI naïve) only: Advanced NSCLC patients who have not been previously treated with any therapy known to inhibit EGFR and harbor de novo T790M mutation .
+Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic) only: patients must harbor an EGFR activating mutation and must be naïve from any line of systemic antineoplastic therapy in the advanced setting.
+Phase II Group 4 (EGFRmut, any T790M, any c-MET, 1L (treatment-naïve), 2//3L antineoplastic): All patients must harbor an EGFR activating mutation and 2/3L patients must have failed (defined as intolerance to treatment or documented disease progression) a maximum of 2 prior lines of antineoplastic therapy in the advanced setting
+Previous treatment with any investigational agent known to inhibit EGFR (mutant or wild-type)
+Patients who have received more than three prior lines of antineoplastic therapies (including EGFR TKI) in advanced setting.
+Phase II Group 1 (EGFRmut, any T790M, any c-MET, 2/4L antineoplastic, EGFR TKI resistant):
+More than 3 prior lines of systemic antineoplastic therapies (including EGFR TKI) in the advanced setting
+More than 1 previous treatment line with 1st or 2nd generation EGFR TKI (e.g. erlotinib, gefitinib, afatinib) in the advanced setting
+Previous treatment with an investigational or marketed 3rd generation EGFR TKI (e.g. AZD9291, CO-1686, ASP8273, EGF816)
+Previous treatment with an investigational or marketed agent known to inhibit EGFR (e.g. EGF monoclonal antibody therapy, dual TKI inhibitor).
+Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI naïve):
+Previous treatment with an investigational or marketed agent that inhibits EGFR. EGFR inhibitors include (but not limited to) all generations of EGFR TKI (e.g.erlotinib, gefitinib, afatinib, AZD9291, CO-1686, ASP8273, EGF816) or other anti-EGFR or EGFR monoclonal antibody therapy or dual TKI inhibitors.
+De novo EGFR T790M mutation identified by central assessment
+Previous treatment with an investigational or marketed 3rd generation EGFR TKI (e.g. AZD9291, CO-1686, ASP8273, EGF816)
+Previous treatment with an investigational or marketed agent known to inhibit EGFR (e.g. EGF monoclonal antibody therapy, dual TKI inhibitor).
+Inclusion Criteria:\n\n        All patients must meet all of the following inclusion criteria:\n\n          1. Histologically or cytologically confirmed metastatic or unresectable locally advanced\n             NSCLC with radiological progression on the most recent therapy received\n\n          2. Documented evidence of a tumor with 1 or more EGFR activating mutations excluding exon\n             20 insertion\n\n          3. Disease progression confirmed by radiological assessment while receiving treatment\n             with single agent EGFR-TKI (e.g., erlotinib, gefitinib, afatinib, or dacomitinib) or\n             EGFR-TKI in combination with other targeted therapy (e.g. bevacizumab, immunotherapy)\n\n          4. Multiple lines of prior treatment are permitted and there is no specified order of\n             treatment, but in the course of their treatment history, patients must have received\n             and have radiologically documented disease progression following:\n\n             At least 1 line of prior treatment with a single-agent EGFR-TKI (e.g., erlotinib,\n             gefitinib, afatinib, or dacomitinib)\n\n             If EGFR-TKI is a component of the most recent treatment line, the washout period for\n             the EGFR-TKI is a minimum of 3 days before the start of study drug treatment\n\n             AND\n\n             A platinum-containing doublet chemotherapy (either progressed during therapy or\n             completed at least 4 cycles without progression with subsequent progression after a\n             treatment-free interval or after a maintenance treatment).\n\n             If cytotoxic chemotherapy is a component of the most recent treatment line, treatment\n             with chemotherapy should have been completed at least 14 days prior to start of study\n             treatment. When an EGFR-TKI is given in combination with platinum-containing doublet\n             chemotherapy, treatment with the EGFR-TKI may continue until at least 3 days before\n             start of treatment.\n\n          5. Have undergone a biopsy of either primary or metastatic tumor tissue within 60 days\n             prior to start of treatment and have tissue sent to the central laboratory prior to\n             randomization\n\n          6. Measureable disease according to RECIST Version 1.1\n\n          7. Life expectancy of at least 3 months\n\n          8. ECOG performance status of 0 to 1\n\n          9. Age ? 18 years (in certain territories, the minimum age requirement may be higher\n             e.g., age ? 20 years in Japan and Taiwan, age ? 21 years in Singapore)\n\n         10. Patients should have recovered to National Cancer Institute (NCI) Common Terminology\n             Criteria for Adverse Events (CTCAE) Grade ? 1 from any significant\n             chemotherapy-related toxicities\n\n         11. Adequate hematological and biological function\n\n         12. Written consent on an Institutional Review Board (IRB)/Independent Ethics Committee\n             (IEC)-approved ICF before any study specific evaluation\n\n        Exclusion Criteria:\n\n        Any of the following criteria will exclude patients from study participation:\n\n          1. Any other malignancy associated with a high mortality risk within the next 5 years and\n             for which the patients may be (but not necessarily) currently receiving treatment\n\n             Patients with a history of malignancy that has been completely treated, with no\n             evidence of that cancer currently, are permitted to enroll in the trial provided all\n             chemotherapy was completed > 6 months prior and/or bone marrow transplant > 2 years\n             prior\n\n          2. Known pre-existing interstitial lung disease\n\n          3. Tumor small cell transformation by local assessment, irrespective of presence of\n             T790M+ component\n\n          4. Patients with leptomeningeal carcinomatosis are excluded. Other central nervous system\n             (CNS) metastases are only permitted if treated, asymptomatic, and stable (not\n             requiring steroids for at least 2 weeks prior to randomization and the patient is\n             neurologically stable i.e. free from new symptoms of brain metastases)\n\n          5. Patients who are currently receiving treatment with any medications that have the\n             potential to prolong the QT interval and that treatment cannot be either discontinued\n             or switched to a different medication (known to have no effect on QT) before starting\n             protocol-specified treatment (see http://crediblemeds.org/ for a list of QT-prolonging\n             medications)\n\n          6. Prior treatment with rociletinib, or other drugs that target T790M+ mutant EGFR with\n             sparing of WT-EGFR including but not limited to osimertinib, HM61713, and TAS-121\n\n          7. Any contraindications for therapy with pemetrexed, paclitaxel, gemcitabine or\n             docetaxel unless a contraindication with respect to one of these drugs will not affect\n             the use of any of the others as a comparator to rociletinib\n\n          8. Any of the following cardiac abnormalities or history:\n\n               1. Clinically significant abnormal 12-lead ECG, QT interval corrected using\n                  Fridericia's method (QTCF) > 450 msec\n\n               2. Inability to measure QT interval on ECG\n\n               3. Personal or family history of long QT syndrome\n\n               4. Implantable pacemaker or implantable cardioverter defibrillator\n\n               5. Resting bradycardia < 55 beats/min\n\n          9. Non-study related surgical procedures ? 7 days prior to randomization. In all cases,\n             the patient must be sufficiently recovered and stable before treatment administration\n\n         10. Females who are pregnant or breastfeeding\n\n         11. Refusal to use adequate contraception for fertile patients (females and males) while\n             on treatment and for 6 months after the last dose of study treatment (rociletinib and\n             chemotherapy irrespective of single cytotoxic agent used)\n\n         12. Presence of any serious or unstable concomitant systemic disorder incompatible with\n             the clinical study (e.g., substance abuse, uncontrolled intercurrent illness including\n             uncontrolled diabetes, active infection, arterial thrombosis, and symptomatic\n             pulmonary embolism)\n\n         13. Any other reason the investigator considers the patient should not participate in the\n             study\n\n         14. Treatment with live vaccines initiated less than 4 weeks prior to randomization
+In Part A, prior treatment with at least one line of a single agent EGFR TKI and at least 1 line of chemotherapy.
+In Part B-BM expansion, patients must have not received any EGFR TKI and have asymptomatic brain metastasis, either found during screening process which does not require local treatment in the opinion of the investigator or local treatment has been given (surgery or radiation), patient must be stable without corticosteroid and/or anti-convulsants treatment for at least 2 weeks before study enrollment. For Part B-LM expansion, patients who received previous EGFR TKI treatment must have stable extracranial disease;EGFR TKI treatment naïve patients can also be enrolled into AZD9291 cohorts, or AZD3759 cohorts if efficacy signal seen in Part A and agreed by Safety Review Committee.
+Histological or cytological diagnosis of Stage IV NSCLC lacking epidermal growth factor receptor (EGFR)-sensitizing mutation and/or anaplastic lymphoma kinase (ALK) translocation, and received no prior systemic chemotherapy treatment for their metastatic NSCLC
+EGFR sensitizing mutation and/or ALK translocation
+Dose escalation subjects: Epidermal Growth Factor Receptor (EGFR) activating mutation by local testing: exon 18 G719X, exon 19 deletion, exon 21 L861Q, exon 21 L858R or exon 20 insertion; and received prior treatment with EGFR Tyrosine Kinase Inhibitor (TKI)
+Response expansion/RP2D expansion/ FE Cohort subjects: disease progression on or was intolerant to prior EGFR TKI; activating mutation as above AND T790M mutation; tumor sample subsequent to EGFR TKI is available for central testing; at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Inclusion Criteria for Exon 20 cohort:
+Subject on any line of treatment and has an EGFR exon 20 insertion mutation on examination of an NSCLC tissue or cellular specimen. Local testing may determine eligibility and a tumor sample should also be sent for central testing.
+Subjects with non-squamous histology must be tested for Epithelial Growth Factor Receptor (EGFR) mutations (including, but not limited to, deletions in exon 19 and exon 21 [L858R] substitution) and Anaplastic Lymphoma Kinase (ALK) rearrangement if tests have not been previously performed. Subjects with progressive disease during or after EGFR or ALK tyrosine kinase inhibitor (TKI) regimens are eligible. Subjects are eligible if genetic test results are indeterminate or if no tumor tissue is available or accessible for testing as long as they have received one prior systemic therapy
+Known EGFR exon 19 or 21 mutation or ALK rearrangement
+A patient with non-squamous NSCLC must have been tested for relevant EGFR mutations, ALK translocation or other genomic aberrations (e.g. ROS rearrangement, BRAF V600E mutation) for which FDA-approved targeted therapy is available and, if positive, the patient should have received such therapy prior to study entry.
+In the absence of relevant EGFR mutation, ALK translocation, ROS rearrangement or BRAF V600E mutation, the patient must have received first-line therapy with a platinum-based regimen, be intolerant to, or refused such treatment.
+A patient with a tumor with an EGFR mutation, ALK translocation, ROS rearrangement, or BRAF V600E mutation may have received appropriate inhibitors of EGFR, ALK, ROS or BRAF in addition to 3 prior lines of therapy for metastatic disease.
+Patients with NSCLC and known anaplastic lymphoma kinase (ALK) translocations or epidermal growth factor receptor (EGFR) mutations who have not received prior treatment with ALK or EGFR inhibitor.
+Subjects with characterized Epidermal Growth Factor Receptor (EGFR) activating mutations that predict sensitivity to anti-EGFR-therapy, including, but not limited to exon 19 deletions and exon 21 alterations
+Subjects with characterized Anaplastic Lymphoma Kinase (ALK) rearrangements that predict sensitivity to anti-ALK therapy
+There should be a minimum of 4 weeks from any prior investigational drug, chemotherapy, immunotherapy, with the exception of hormonal therapy for prostate and breast cancers, HER2-directed therapy for HER2+ breast or stomach cancer (3+ immunohistochemistry [IHC] or fluorescence in situ hybridization [FISH]+), drugs targeting EGFR, ALK or ROS1 in EGFR, ALK, ROS1-mutated lung cancer, respectively, or standard maintenance therapies for any solid tumor under the condition that subjects are on these therapies for at least two months before start of trial treatment
+CKD 1 to 3 (eGFR > 30)
+EGFR, ALK and ROS biomarker positive tumors are eligible as long as the patient has received at least one standard oral, molecular inhibitor therapy in addition to standard platinum doublet chemotherapy. More than one molecular inhibitor is allowed such as a first generation EGFR inhibitor followed by a next generation EGFR inhibitor when T790 mutation develops. Prior molecular therapy for biomarker positive tumors such as (but not limited to) MET, RET and BRAF allowed but not required.
+Have T790M-positive status using a test validated and performed locally after disease progression on EGFR tyrosine kinase inhibitor (TKI) treatment.
+Previous treatment with osimertinib or third generation EGFR TKIs.
+Subjects must have histologically confirmed, unresectable, locally advanced or metastatic pleural or peritoneal predominantly (>50% of tumor component) epithelial mesothelioma or nonsquamous non-small-cell lung cancer (NSCLC). Both chemotherapy-naive and previously treated subjects will be eligible; however, newly diagnosed NSCLC subjects eligible for FDA-approved therapies should have received the same before enrollment (e.g. subjects with epidermal growth factor receptor [EGFR]-mutated and anaplastic lymphoma kinase [ALK]-translocated NSCLC should have received FDA-approved targeted therapies).
+Participants with non-squamous histology has known or unknown sensitizing epidermal growth factor receptor (EGFR) and/or anaplastic lymphoma kinase positive (ALK) mutation. Note: Participants with squamous histology and unknown EGFR and ALK mutational status are eligible.
+Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI
+At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q)
+Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy
+Confirmation from a previous archival sample that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity
+Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI. Additional other lines of therapy may have been given. All patients must have documented radiological progression on the last treatment administered prior to enrolling in the study.
+The participant must have progressed after 1 platinum-based chemotherapy regimen for Stage IV NSCLC. Prior therapy with VEGF/VEGFR targeting agents is permitted. Prior neoadjuvant/adjuvant therapy is permitted. Prior treatment with EGFR-TKI and ALK inhibitors is mandatory in participants with NSCLC whose tumor has EGFR-activating mutations or ALK translocations, respectively.
+ELIGIBILITY FOR TREATMENT ON ARM 1: NSCLC patients with a mutation in epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) must have demonstrated progression or intolerance to at least one of the corresponding targeted therapies (for example erlotinib or crizotinib)
+Known EGFR TK activating mutations or ALK rearrangements
+Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC with known sensitive EGFR mutations; patients with mutations in T790M are eligible if they have progressed after treatment with a third generation EGFR tyrosine kinase inhibitor (osimertinib), but otherwise patients must have EGFR T790M negative or unknown status; patients previously treated with third generation EGFR tyrosine kinase inhibitor must have achieved a treatment benefit of at least 4 months
+For EGFR mutant cohort, patients must have: a) documented EGFR mutation by Clinical Laboratory Improvement Amendments (CLIA)-certified test b) documented disease progression on treatment with erlotinib, gefitinib, afatinib, or other EGFR-targeted tyrosine kinase inhibitor c) tissue available from a biopsy or surgical procedure performed after progression on an EGFR targeted tyrosine kinase inhibitor; if tissue is not available, the patient must have biopsy accessible disease and must be willing to undergo a biopsy
+For HER2 mutant cohort, patients must have: a) documented EGFR mutation by CLIA-certified test b) documented disease progression on treatment with erlotinib, gefitinib, afatinib, or other EGFR-targeted tyrosine kinase inhibitor c) tissue available following progression on most recent systemic therapy; if tissue is not available, the patient must have biopsy accessible disease and must be willing to undergo a biopsy
+The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R).
+Prior treatment with an EGFR-TKI.
+Patients must be diagnosed with ALK-positive advanced NSCLC. The tumor must be ALK-positive as determined by ALK rearrangement in ?15% of cells (as measured by FISH using the Vysis break-apart ALK probe) or by using the Ventana ALK IHC test. The analysis may be performed locally.
+Inclusion Criteria:\n\n          -  Histologically or cytologically documented diagnosis of Stage IIIB not amenable to\n             radical treatment or Stage IV NSCLC (pathological characterization must determine the\n             non-squamous or squamous histological subtype as well as adenocarcinoma subtype\n             classification)\n\n          -  HER2 status of IHC 2+ or 3+ as determined by a Sponsor-designated central laboratory\n\n          -  Prior treatment with at least one regimen of platinum-based (cisplatin or carboplatin)\n             chemotherapy in the locally advanced or metastatic setting/recurrent NSCLC with\n             documented disease progression by investigator assessment\n\n          -  Participants with a known anaplastic lymphoma kinase (ALK) fusion oncogene (must be\n             documented in the participant's chart) must have also experienced disease progression\n             or intolerance with a first-line ALK Tyrosine Kinase Inhibitor (TKI) approved for the\n             treatment of ALK fusion oncogene NSCLC (for example, crizotinib). Disease progression\n             or intolerance must be documented\n\n          -  Participants with a known mutation in the epidermal growth factor receptor (EGFR) gene\n             (must be documented in the participant's chart) must have also experienced disease\n             progression or intolerance with an EGFR TKI approved for the treatment of EGFR-mutant\n             NSCLC (for example, gefitinib, erlotinib, afatinib). Disease progression or\n             intolerance must be documented\n\n          -  Measurable disease determined as per the RECIST v1.1\n\n          -  Life expectancy of at least (>/=) 12 weeks\n\n          -  Adequate organ function\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1\n\n          -  Left ventricular ejection fraction (LVEF) >/= 50 percent (%) by either echocardiogram\n             (ECHO) or multiple-gated acquisition (MUGA) scan\n\n          -  Use of highly effective contraception\n\n        Exclusion Criteria:\n\n        Cancer-Related Criteria:\n\n          -  Any approved anti-cancer therapy less than or equal to (</=) 21 days (including\n             chemotherapy or hormonal therapy) before the first study treatment; the following\n             exceptions are allowed: (1) TKIs approved for the treatment of NSCLC must be\n             discontinued greater than (>) 7 days prior to the first study treatment on D1C1 (The\n             baseline computed tomography [CT] scan must be completed after discontinuation of\n             TKIs); (2) Hormone-replacement therapy or oral contraceptives; (3) Anti-emetics,\n             Granulocyte-colony stimulating factor (GCS-F), and prophylactic antibiotics according\n             to local standards\n\n          -  Investigational therapy participation in another clinical study with therapeutic\n             intent </= 21 days before first study treatment\n\n          -  Previous irradiation is permitted if >/=14 days since the last fraction of\n             radiotherapy have elapsed before the first study treatment on Day 1 as long as a\n             sufficient number of target lesions remain to allow for measurable disease as per\n             RECIST v1.1\n\n          -  Participants who have untreated brain metastases or are symptomatic; participants with\n             treated brain metastases must have discontinued corticosteroid therapy and not have\n             any neurological symptoms\n\n          -  History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity\n             to trastuzumab or murine proteins or any excipient of the product\n\n          -  History of exposure to the following cumulative doses of anthracyclines: Doxorubicin\n             or liposomal doxorubicin > 500 milligram per meter-square (mg/m^2); Epirubicin > 900\n             mg/m^2; Mitoxantrone > 120 mg/m^2. If another anthracycline, or more than one\n             anthracycline, has been used, the cumulative dose must not exceed the equivalent of\n             500 mg/m^2 doxorubicin\n\n          -  Peripheral neuropathy of Grade >/= 3 per the National Cancer Institute Common Toxicity\n             Criteria for Adverse Events Version 4.0 (NCI CTCAE v. 4.0)\n\n          -  History of other malignancy within the last 5 years, except for appropriately treated\n             carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer,\n             or other cancers with a similar outcome as those mentioned above\n\n        Cardiopulmonary Function Criteria:\n\n          -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent\n             drainage procedures\n\n          -  Severe dyspnea at rest due to complications of advanced malignancy or requiring\n             current continuous oxygen therapy\n\n          -  Clinical history of active hemoptysis\n\n          -  Evidence of active pneumonitis during screening\n\n          -  Current unstable ventricular arrhythmia requiring treatment\n\n          -  History of symptomatic congestive heart failure (CHF) New York Heart Association\n             (NYHA) classes II-IV\n\n          -  History of myocardial infarction or unstable angina within 6 months of enrollment\n\n          -  History of a decrease in LVEF to <50%\n\n        General Criteria:\n\n          -  Current severe, uncontrolled systemic disease (for example, clinically significant\n             cardiovascular, pulmonary, or metabolic disease)\n\n          -  Major surgical procedure or significant traumatic injury within 28 days before\n             enrollment or anticipation of the need for major surgery during the course of study\n             treatment\n\n          -  Current pregnancy or lactation\n\n          -  Current known active infection with human immunodeficiency virus (HIV), hepatitis B\n             virus (HBV), or hepatitis C virus (HCV)
+Subject has squamous NSCLC, or an untreated known EGFR mutation of exon 19 deletion or L858R mutation in exon 21, or a known ALK gene rearrangement.
+Radiological documentation of disease progression following 1st line EGFR TKI Treatment without any further treatment
+Treatment with an approved EGFR-TKI (e.g.,erlotinib, gefitinib, afatinib) within 8 days or approximately 5x half-life of the first dose of study treatment
+Previous treatment with AZD9291, or a 3rd generation EGFR TKI For subjects who cross-over to AZD9291:
+Subject has non-squamous NSCLC, or a known Epidermal Growth Factor Receptor (EGFR) mutation of exon 19 deletion or L858R mutation in exon 21, or a known Anaplastic Lymphoma Kinase (ALK) gene rearrangement.
+Inclusion:\n\n          -  Aged at least 18 years. Japan patients aged at least 20 years.\n\n          -  Locally advanced/metastatic NSCLC not amenable to curative surgery or radiotherapy\n\n          -  Radiological documentation of disease progression:\n\n        following 1st line EGFR TKI treatment but who have not received further treatment OR\n        following prior therapy with an EGFR TKI and a platinum-based doublet chemotherapy.\n        Patients who received prior EGFR TKI and platinum-based doublet chemotherapy may have also\n        received additional lines of treatment. All patients must have documented radiological\n        progression on the last treatment administered prior to enrolling in the study.\n\n          -  Disease progression following 1st line EGFR TKI treatment or following prior EGFR TKI\n             and platinum-containing doublet chemotherapy.\n\n          -  Confirmation that the tumour harbours an EGFR mutation known to be associated with\n             EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). Patients must\n             have central confirmation of tumour T790M mutation positive status from a biopsy\n             sample taken after confirmation of disease progression on the most recent treatment\n             regimen.\n\n          -  World Health Organisation (WHO) performance status 0-1 with no deterioration over the\n             previous 2 weeks and a minimum life expectancy of 12 weeks.\n\n          -  At least one lesion, not previously irradiated and not chosen for biopsy during the\n             study screening period, that can be accurately measured at baseline as ? 10mm in the\n             longest diameter (except lymph nodes which must have short axis ? 15mm) with\n             computerised tomography (CT) or magnetic resonance imaging (MRI) which is suitable for\n             accurate repeated measurements.\n\n          -  Females of child-bearing potential using contraception; negative pregnancy test.\n\n        Exclusion:\n\n          -  Treatment with an EGFR-TKI within 8 days of study entry; any cytotoxic chemotherapy,\n             investigational agents or other anticancer drugs within 14 days of study entry;\n             previous treatment with AZD9291 (or 3rd generation TKIs); major surgery within 4\n             weeks; radiotherapy treatment to more than 30% of the bone marrow or with a wide field\n             of radiation within 4 weeks; current treatment with potent inhibitors of CYP2C8 and\n             potent inhibitors/inducers of CYP3A4.\n\n          -  Unresolved toxicities from prior therapy.\n\n          -  Unstable spinal cord compression/brain metastases.\n\n          -  Severe/uncontrolled systemic diseases, including uncontrolled hypertension, bleeding\n             diatheses or infection.\n\n          -  Refractory nausea/vomiting, chronic gastrointestinal diseases or bowel resection.\n\n          -  Cardiac disease.\n\n          -  Past history of ILD, drug-induced ILD, radiation pneumonitis which required steroid\n             treatment, or any evidence of clinically active interstitial lung disease.\n\n          -  Inadequate bone marrow reserve or organ function.
+Subjects must have a. In the escalation phase, locally advanced or metastatic NSCLC subjects who have either failed to respond or relapsed following any line of standard treatment, were unable to tolerate, or were not eligible for standard treatment b. In the expansion phase, histologically or cytologically confirmed locally advanced or metastatic NSCLC that is EGFR mutation positive, naïve to EGFR TKI therapy, and sensitive to EGFR TKIs therapy
+For Japan Escalation - the same as the global escalation I/E criteria except patients must be EGFR mutation positive
+Patients must have adequate EGFR greater than 30 mL/min per 1.73 m2 (per VA formula and adjusted for gender and race)
+Patients receiving first-line erlotinib, crizotinib for epidermal growth factor receptor (EGFR) mutant-positive or echinoderm microtubule associated protein like 4 (EML4)-anaplastic lymphoma receptor tyrosine kinase (ALK) positive NSCLC will be excluded
+Known epidermal growth factor receptor (EGFR) mutations which are sensitive to available targeted inhibitor therapy
+Histologically proven advanced MPM, advanced peritoneal mesothelioma (for dose escalation cohort only) or non-squamous NSCLC (stage IIIB/IV) who have not been treated with prior chemotherapy or immunotherapy, except that NSCLC subjects with EGFR mutant or ALK positive must have had an EGFR tyrosine kinase inhibitor (TKI) or ALK inhibitor and progressed or been shown to be intolerant of therapy prior to enrolling in this trial, if such ALK inhibitor and EGFR targeted therapy are approved and available in the country in which patients are being enrolled OR Histologically proven metastatic uveal melanoma who have not been treated with prior chemotherapy (MTD cohort only), OR Histologically proven HCC who have failed (PD and/or side effects-been intolerant of) treatment with sorafenib. Failure is defined as having progressed radiographically on, or been intolerant to prior systemic therapy. Intolerance is defined as discontinuation due to an AE(s) on prior systemic therapy that was unacceptable to the treating physician and / or patient, with or without dose interruption and modification. Failure requires at least 14 days of treatment with sorafenib, except for a subject that has had a severe allergic reaction to sorafenib at any time, even less than 14 days of treatment with sorafenib and thus it would be imprudent to re-challenge them with that agent. Cirrhotic status of Child-Pugh grade A-B7 must be present. Child-Pugh status should be determined based on clinical findings and laboratory data during the screening period (Appendix E). Subjects on anti-coagulants are to receive 1 point for their INR status, as they are presumed to have a <1.7 baseline PT/INR.\, OR Histologically proven high-grade glioma who have failed (PD and/or side effects) treatment with radiotherapy ± temozolomide, OR Sarcomatoid cancer of any line.
+Documented presence of EGFR mutation confirmed by MSKCC or a local facility
+No prior treatment with erlotinib, gefitinib, or other EGFR tyrosine kinase inhibitors
+Patients with documented EGFR or ALK mutations must have been treated with prior EGFR or ALK therapy as well as a platinum containing doublet
+All adenocarcinoma patients will be tested for ALK rearrangements and EGFR (exon 19 deletion and exon 21 L8585R substitution) mutations and must have been treated with prior EGFR or ALK therapy as well as a platinum containing doublet
+PART A: Non-small cell lung cancer (NSCLC) with adenocarcinoma histology must have been previously tested for both epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements
+PART A: Known EGFR mutation and/or ALK rearrangement in NSCLC with adenocarcinoma histology
+Participants must have histologically or cytologically confirmed stage IV or recurrent non-small cell lung cancer with a documented exon 20 insertion mutation in EGFR (exon 20 insertion/deletion and deletion mutations will also be allowed)
+Known to be wild-type for mutations in EGFR, KRAS, and ALK
+Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI e.g. gefitinib or erlotinib (with the exception of 1st line expansion cohort). In addition other lines of therapy may have been given. All patients must have documented radiological progression on the last treatment administered prior to enrolling in the study.
+Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR
+Must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria (Jackman et al 2010) followed by systemic objective progression (RECIST or WHO) while on continuous treatment with EGFR TKI.
+Previous treatment with a single-agent EGFR TKI (e.g. gefitinib or erlotinib).
+For dose expansion and extension cohorts, patients must also have confirmation of tumour T790M mutation status (confirmed positive or negative) from a biopsy sample taken after disease progression on the most recent treatment regimen (irrespective of whether this is EGFR TKI or chemotherapy). Prior to entry a result from the central analysis of the patient's T790M mutation status must be obtained.
+Treatment with an EGFR TKI (erlotinib or gefitinib) within 8 days (approximately 5x half-life) of the first dose of study treatment.
+Histologically- or cytologically-confirmed stage IV non-squamous, NSCLC who have progressed after at least one prior line of treatment; in the expansion phase, participants are only eligible if their molecular category has not been fully enrolled (10 participants with epidermal growth factor receptor (EGFR) mutations, 5 participants with anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangement, 5 participants with wild type v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), EGFR and ALK)
+Last chemotherapy or treatment with another systemic anti-cancer agent must have stopped >= 4 weeks prior to enrollment (or >= 5 half-lives for oral tyrosine-kinase inhibitors); participants with EGFR mutations and ALK gene rearrangement who have not received a tyrosine kinase inhibitor targeting their molecular abnormality (e.g., erlotinib or crizotinib respectively); participants must have recovered (CTCAE =< 1) from acute toxicities of any previous therapy (with the exception of alopecia)
+STEP 1 ENROLLMENT: standard induction chemotherapy planned defined as: at least 4 cycles of platinum doublet chemotherapy for metastatic disease (with or without bevacizumab); if the patient is known to be EGFR mutation positive, erlotinib, afatinib, or gefitinib for >= 3 months, or for patients with known EML4-ALK fusions, crizotinib for >= 3 months
+STEP 2 ENROLLMENT AND RANDOMIZATION: completion of standard induction chemotherapy planned defined as: at least 4 cycles of platinum doublet chemotherapy for metastatic disease (with or without bevacizumab); if the patient is known to be EGFR mutation positive, erlotinib, afatinib, or gefitinib for >= 3 months, or for patients with known EML4-ALK fusions, crizotinib; note that it is not mandatory to check EGFR mutation or EML4-ALK status prior to entry, but patients that receive options 2 or 3 should have had these molecular tests performed
+For the expanded cohort only, patient must not have had prior therapy with an EGFR-specific monoclonal antibody or EGFR-specific tyrosine kinase inhibitor (TKI) for treatment of incurable HNSCC; prior therapy with an EGFR-specific monoclonal antibody as part of the definitive treatment of curable HNSCC is acceptable if this occurred more than 3 months prior to study enrollment; for the dose-finding cohorts, prior EGFR-specific therapy in the incurable setting is allowed
+Progression following a single line of prior cytotoxic therapy including a platinum agent plus a standard cytotoxic partner other than a taxane (typically pemetrexed, gemcitabine or vinorelbine):\r\n* Previous treatment with targeted therapy will not count as a prior line of therapy if the patient’s tumor has the relevant molecular change (e.g., epidermal growth factor receptor [EGFR] mutation for erlotinib and echinoderm microtubule associated protein like 4 [EML4]/anaplastic lymphoma receptor tyrosine kinase [ALK] or receptor tyrosine kinase [ROS1] for crizotinib)\r\n* Previous treatment with immune-oncologic agents (such as nivolumab) will not count as a prior line of therapy
+Histologically or cytologically confirmed stage IV EGFR-mutant NSCLC or, in the absence of availability of EGFR testing (for example, inadequate tissue), clinical response overwhelmingly consistent with EGFR mutation (partial response [PR] plus at least 6 months free of progressive disease as a consequence of EGFR-TKI therapy)
+Treatment with any Food and Drug Administration (FDA) approved or experimental cancer treatment following progression on EGFR-TKI (e.g., radiation or chemotherapy; supportive regimens such as denosumab or zoledronic acid will not result in exclusion)
+Histologic documentation of primary lung carcinoma, non-squamous histology with activating epidermal growth factor receptor (defined as deletion 19 or exon 21 L858R mutation); Note: EGFR mutation testing must be performed at a Clinical Laboratory Improvement Amendments (CLIA) certified lab; either institutional or through a commercial laboratory (e.g. Genzyme, Response Genetics, etc); the laboratory report from the commercial laboratories report the specific mutations detected, and the method of detecting the exon 19 and exon 21 L858R point mutations must be available
+Progression on, or intolerance of, or ineligibility for all standard therapies (including regimens containing fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and an anti-epidermal growth factor receptor [EGFR] antibody [where appropriate]); patients who are intolerant of, or ineligible for 5-FU, oxaliplatin, and/or the combination of both will be excluded
+Patients with mutations in the epidermal growth factor receptor (EGFR) gene; the mutational status of all patients with adenocarcinoma and non-squamous histology will be determined prior to study entry
+Documented activating epidermal growth factor receptor mutation (Del19 and/or L858R) with tumour tissues.
+Subject must be chemotherapy naive (except Arm D, K, L and M). Prior use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is acceptable. For Arms D, K, and L, subjects must be non-progressors within 42 days after completion of first-line treatment with ?4 cycles of Platinum Doublet chemotherapy with or without Bevacizumab. See below for Arm M
+Previously tested for presence of EGFR and ALK mutations in lung cancer tissue confirmed in a CLIA-certified laboratory (or equivalent). Subjects with EGFR or ALK mutation are eligible if they have previously received EGFR or ALK inhibitor(s) respectively.
+Confirmation of the presence or absence of EGFR mutations and ALK gene fusions prior to study enrollment in all subjects; subjects with unknown EGFR sensitizing mutational status or ALK fusion must have been treated and progressed on EGFR tyrosine kinase inhibitors (TKIs) or ALK-directed therapy
+positive for ALK activating point mutations
+Somatic activating mutation in EGFR radiographic progression during treatment with erlotinib or any other EGFR tyrosine kinase inhibitor (TKI) therapies
+Any type of systemic therapy (chemotherapy or experimental drugs) within 2 weeks of starting treatment on protocol except for a EGFR TKI
+No prior systemic anticancer therapy (including EGFR and ALK inhibitors)
+Confirmed stage IV or recurrent EGFR Mutation (MT)+ NSCLC with disease progression after 1 prior EGFR TKI therapy
+No evidence of exon 20 T790M mutation after progression on prior EGFR tyrosine kinase inhibitor(TKI) therapy.
+Somatic activating mutation in EGFR
+No prior treatment with an EGFR tyrosine kinase inhibitor (TKI)
+Evidence of either EGFR gene amplification by fluorescence in situ hybridization (FISH) or EGFR activating mutation in the most recent tumor specimen prior to enrollment; results of EGFR gene amplification will be confirmed by Dr. John Lafrate's laboratory at Massachusetts General Hospital (MGH) post hoc; gene amplification is defined as EGFR to Cen7 (centromere 7 copy number control) ratio of at least 2 to 1; for EGFR activating mutation, any one of the following EGFR mutations is eligible: extracellular domain mutation: EGFRvIII, R108K, T263P, A289V, A289D, A289T, G598V; or kinase domain mutation: G719X, T790M, exon19 deletions/insertions (at/near/within codons 744-759), exon 20 insertions/deletions/mutations (insertions/deletions at or near 766-769, S768I, R776C), L858R, L861Q
+Prior investigational therapy with an agent that is known or proposed to be active by action on any component of the EGFR tyrosine kinase, IGF1R, mTOR, or c-MET pathways
+Subject has an EGFR activating mutation (exon 19 deletion or exon 21 L858R), with or without T790M mutation, by local or central testing on examination of a NSCLC FFPE specimen (archival or fresh biopsy). Subjects harboring both exon 19 deletion and exon 21 L858R mutations are not eligible. A tissue sample from the same block used to determine eligibility by local testing should be available to send to the central lab for confirmatory testing. Subjects randomized based on local results indicating presence of EGFR mutation may remain on study if central results are discordant.
+Subject has received a prior treatment with a therapeutic agent targeting EGFR (e.g., afatinib, dacomitinib, ASP8273, etc).
+Tumors with driver mutations (epidermal growth factor receptor mutation positive or anaplastic lymphoma kinase fusion oncogene positive) should have had disease progression or been intolerant to the standard tyrosine-kinase inhibitor (TKI), and should include a second line TKI where such therapy is available and indicated.
+Previously received an EGFR-directed monoclonal antibody within the past 4 weeks.
+eGFR > 30 ml/min/1.73 m^2
+Documented evidence of a tumor with activating EGFR mutations by local testing. Patients with exon 20 insertions are not eligible with the exception of patients with documented evidence of the exon 20 insertion A763_Y764insFQEA in the EGFR gene
+Documented evidence of an exon 20 insertion activating mutation other than A763_Y764insFQEA in the EGFR gene
+Prior treatment with EGFR TKIs (e.g. erlotinib, gefitinib, neratinib, afatinib, AZD9291, or dacomitinib), rociletinib or other drugs that target mutant EGFR
+Patients with known EGFR-activating mutations or ALK rearrangements should have received treatment with a targeted kinase inhibitor (e.g., erlotinib, crizotinib) and no longer be considered as a candidate for such treatment
+Never-smokers if EGFR/ALK testing results are unknown
+Patients with NSCLC that harbors an ALK rearrangement, or sensitizing EGFR mutation
+Subject has an EGFR activating mutation based on local testing.
+Subjects with known EGFR mutations which are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19 and exon 21 [L858R] substitution mutations) are excluded; all subjects with non-squamous histology must have been tested for EGFR mutation status; use of a Food and Drug Administration (FDA)-approved test is strongly encouraged
+Treatment on this protocol may begin as long as the patient has recovered from toxicities of prior therapy at the discretion of the treating physician; patients with non-small cell lung cancer (NSCLC) harboring an EGFR, ALK or ROS-1 alteration must have progressed through at least one prior therapy with appropriate molecularly targeted agents
+Must have progressed following treatment with platinum-based combination chemotherapy for metastatic disease, and patients with an EGFR or ALK/ROS1 genetic aberration must have received appropriately targeted treatment.
+Progression within 6 weeks following their last dose of anti-EGFR therapy
+Treatment with a non-EGFR targeting regimen following progression on anti-EGFR plus irinotecan-based therapy
+History of severe anti-EGFR toxicity requiring drug discontinuation or dose-modification within the first 4 months of prior anti-EGFR therapy
+Subject has a documented exon 19 deletion or exon 21 L858R EGFR activating mutation.
+Intervening anticancer treatment subsequent to the EGFR TKI is allowed (but not required).
+Subject has a NSCLC tissue sample obtained after subject developed resistance to EGFR TKI therapy that is available for central testing.
+Subject's baseline tumor specimen (obtained after subject developed resistance to EGFR TKI therapy) is T790M negative.
+Subject received an EGFR TKI for at least 6 months and progressed on this therapy within the past 28 days.
+Subject has not had any intervening anticancer treatment subsequent to the EGFR TKI with the exception of radiotherapy which is allowed if it occurred at least 14 days prior to the first dose of study drug.
+Key Eligibility Criteria:\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1\n\n          -  Confirmed recurrent Stage IV NSCLC which progressed while on treatment with EGFR TKI\n\n          -  Measurable disease according to Response Evaluation Criteria in Solid Tumors version\n             1.1 (RECIST 1.1)\n\n          -  Documented evidence of an EGFR mutation known to be associated with an EGFR TKI\n             sensitivity\n\n          -  No T790M mutation or small cell transformation including an assessment from tumor\n             biopsy obtained while on or subsequent to the most recent EGFR TKI therapy\n\n          -  Acceptable laboratory results as indicated by protocol\n\n          -  Acceptable cardiac function as indicated by protocol\n\n        Key Exclusion Criteria:\n\n          -  Receiving medication that prolongs QT interval, with a risk of causing Torsades de\n             Pointes (TdP) unless ECG meets inclusion criteria while on a stable dose of the\n             medication\n\n          -  Family history of long QTc syndrome\n\n          -  Symptomatic central nervous system (CNS) lesions\n\n          -  Radiation therapy within 2 weeks prior to the first dose of study medication\n\n          -  Major surgery within 4 weeks or minor surgery within 2 weeks prior to the first dose\n             of study medication\n\n          -  Concurrent active malignancy requiring systemic treatment\n\n          -  Any other serious uncontrolled medical disorders or psychological conditions that may\n             interfere with study conduct including but not limited to: clinically significant\n             active infection (e.g., tuberculosis, viral hepatitis, human immunodeficiency virus\n             [HIV]), recent (within 6 months) myocardial infarction or unstable angina, congestive\n             heart failure, poorly-controlled hypertension or diabetes, concurrent active\n             malignancy, or psychiatric condition that may interfere with the patient's ability to\n             follow study procedures\n\n          -  Pregnant or breast-feeding
+Received prior EGFR TKI therapy for recurrent or metastatic SCC (e.g., oral EGFR TKIs such as erlotinib, gefitinib, or afatinib)
+Subjects that are known to be epidermal growth factor (EGFR)-activating mutation positive must have received an EGFR inhibitor.
+Subjects known to be anaplastic lymphoma kinase (ALK)-fusion/rearrangement mutation positive must have received an ALK inhibitor.
+Patients with tumors that harbor either EGFR sensitizing mutations or ALK rearrangement\r\n* EGFR sensitizing mutations include: \r\n** Exon 19 deletion or insertion\r\n** L858R (c.2573 T>G)\r\n** G719X (c.2156 G>C, G>T, or G>A)\r\n** L861Q (c.2582 T>A)
+Patients known to be positive for activating Epidermal Growth Factor Receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation
+Metastatic NSCLC with documented EGFR exon 19 deletion or exon 21 (L858R) substitution mutation
+Patients must have histologically confirmed recurrent or metastatic gastrointestinal carcinomas, non-squamous non-small cell lung carcinomas, urothelial carcinomas, and sarcomas with disease progression after at least one line of standard therapy; disease should have progressed following all treatments known to prolong survival, unless a given treatment is contraindicated\r\n* Patients with colorectal carcinoma must have progressed through at least two lines of standard chemotherapy in the metastatic setting\r\n* Patients with non-small cell lung cancer with known sensitizing EGFR mutation and/or anaplastic lymphoma kinase (ALK) rearrangement should have received prior erlotinib and/or crizotinib, respectively\r\n* Patients with urothelial carcinoma will have progressed on prior platinum-based therapy or for which platinum-based therapy is contraindicated\r\n* Patients enrolled on the expansion phase of the protocol must demonstrate EGFR expression by immunohistochemistry on archival tumor samples prior to undergoing 89Zr-panitumumab PET/CT scans
+Participants must have known HIV infection and histologically confirmed non-small cell lung cancer that is metastatic or unresectable; patients will be eligible regardless of tumor EGFR mutation status
+Participants who received prior treatment with erlotinib or other EGFR-targeted agents
+Persons with tumors known to have biomarkers predictive of resistance to erlotinib therapy (specifically Kirsten rat sarcoma viral oncogene homolog [KRAS] mutations, anaplastic lymphoma receptor tyrosine kinase [ALK] gene rearrangements, and EGFR T790M mutations) will be ineligible for study participation; if the results of molecular studies are not available or known at the time of study registration and subsequently become available, such participants will be considered eligible and if deriving clinical benefit may continue receiving erlotinib at the discretion of the investigator and study chair
+If tumor histology is adenocarcinoma, must have wild-type EGFR genotype as assessed by a validated assay that includes exon 19 deletion and exon 21 (L858R) substitution.
+Patients with known activating mutations in the epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma receptor tyrosine kinase (ALK) or c-ros oncogene 1, receptor tyrosine kinase (ROS-1) (this test [ROS-1] will be done only on select patients and at the discretion of treating physicians) translocation positive; the mutational status of all patients will be determined prior to study entry
+Subjects with a known EGFR mutation must have received previous treatment with an EGFR tyrosine kinase inhibitor; and subjects with a known ALK translocation must have received previous treatment with an ALK inhibitor.
+Tumor tissue available for epidermal growth factor receptor (EGFR) expression analysis
+In countries where anaplastic lymphoma kinase (ALK) inhibitors are available for the treatment of NSCLC, subjects need to have been screened for ALK fusion gene rearrangements and excluded if positive, unless previously treated and progressed on an appropriate tyrosine kinase inhibitor (TKI) therapy
+In countries where EGFR TKIs are available for the treatment of NSCLC, subjects need to have been screened for EGFR mutations and excluded if positive, unless previously treated and progressed on an appropriate TKI therapy
+Patients with targetable mutation i.e. epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK), must have been treated with at least 1 prior tyrosine kinase inhibitor (TKI)
+Patients must have received at least one platinum-containing regimen for the treatment of advanced or metastatic disease (except for epidermal growth factor receptor [EGFR]-mutant patients); prior maintenance therapy is allowed and will be considered as the same line of therapy when continued without discontinuation after initiation of a treatment regimen; NSCLC with documented EGFR mutation will be eligible after progression on an EGFR-tyrosine-kinase inhibitor (TKI) alone; NSCLC with other molecular targets, such as fusion gene involving the anaplastic lymphoma kinase (ALK) gene (such as echinoderm microtubule associated protein like 4 [EML4]-ALK) or ROS proto-oncogene 1 , receptor tyrosine kinase (ROS-1), will be eligible if they have progressed on targeted agents (ALK inhibitor) and chemotherapy or are not a candidate for chemotherapy
+Patients with unknown status of EGFR mutation (only for patients with adenocarcinoma histology)
+The institution’s pre-enrollment biomarker screening at a Clinical Laboratory Improvement Amendments (CLIA) certified lab documents presence of known “sensitive” mutations in epidermal growth factor receptor tyrosine kinase (EGFR TK) domain (exon 19 deletion, L858) and/or EML4-anaplastic lymphoma kinase (ALK) fusion arrangement; either the primary tumor or the metastatic lymph node tissue may be used for testing of mutations
+The institution’s pre-enrollment biomarker screening at a CLIA certified lab documents absence of T790M mutation in the EGFR TK domain
+Epidermal growth factor receptor (EGFR) mutations
+Patients must have EGFR gene mutation in their tumors. This can be source - documented by one of the following: • Provide a pathology report that indicates the patient's tumor had EGFR activating mutation in the past. Or: • Perform testing (local or central) in an archival tumor or a fresh baseline biopsy tumor tissue to show the presence of EGFR activating mutation.
+Patients must have documented clinical benefit (CR, PR, or patients with SD for 6 months or greater) on prior EGFR TKI (e.g. erlotinib or gefitinib) followed by documented progression according to RECIST.
+For Phase Ib, prior cetuximab or other EGFR-targeted antibody therapy is allowed regardless of the prior treatment settings.
+Documented EGFR activating mutations (if already tested)
+LUNG ADENOCARCINOMA COHORT (COHORT 3 ONLY): Patients must have had at least one prior therapy for advanced disease (platinum-containing chemotherapy or one of the approved targeted therapies [an approved epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for EGFR mutant tumors or crizotinib and ceritinib for anaplastic lymphoma receptor tyrosine kinase (ALK) translocated tumors]); there is no limit to the number of prior chemotherapy regimens received
+Prior treatment with epidermal growth factor receptor (EGFR)-targeted small molecules, EGFR-targeted antibodies, and/or any investigational agents for HNSCC
+Individuals who meet the eligibility criteria for EGFR germline mutation testing but who do not have advanced cancer may enroll for EGFR germline mutation testing only and will not be eligible for the treatment or not otherwise specified (NOS) arms
+ERLOTINIB HYDROCHLORIDE ARM: Patients must have an EGFR tyrosine kinase inhibitor (TKI) sensitizing mutation as determined by analysis of the primary tumor or a metastatic site in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory
+ERLOTINIB HYDROCHLORIDE ARM: Previous anti-EGFR TKI therapy
+ERLOTINIB HYDROCHLORIDE ARM: Patients with a known EGFR TKI resistant mutation
+In patients with non-squamous non-small cell lung cancer, investigators must be able to produce source documentation of the EGFR mutation status or ALK translocation status.
+PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy
+PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib
+PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy
+FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib
+Have histologic or cytologic documentation of solid tumor including EGFR mutated (EGFRm) NSCLC
+NSCLC with known EGFR mutation or anaplastic lymphoma kinase (ALK) gene translocation (such as EML4-ALK)
+Adequate tissue for central immunohistochemical (IHC) assay of Met receptor, and epidermal growth factor receptor (EGFR) testing if EGFR status is unknown
+Patients with tumors confirmed to have EGFR-activating mutations who are suitable for anti-EGFR therapy (e.g. gefitinib or erlotinib), as determined by the investigator, unless that treatment is unavailable or refused by the patient
+Known epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutated disease (molecular testing not required prior to study entry)
+Prior treatment with an EGFR TKI; in Phase 2, prior treatment with a T790M-directed EGFR TKI for patients in Group B. Previous chemotherapy is allowed; in Phase 2, immediate prior therapy must be EGFR TKI
+There will be no limit on number of prior therapies for NSCLC; patients with previously untreated NSCLC will be eligible if they are uninterested in or ineligible for standard first line chemotherapy; patients with NSCLC known to harbor an anaplastic lymphoma kinase (ALK) rearrangement, or epidermal growth factor receptor (EGFR) mutation known to be sensitive to Food and Drug Administration (FDA) approved tyrosine kinase inhibitors (TKI), are only eligible after experiencing disease progression (during or after treatment) or intolerance to an FDA approved EGFR TKI or ALK TKI, respectively
+Patients with activating but not sensitizing mutations (exon 20 insertions, EGFR T790M)
+Subject with a tumor of non-squamous histology must be tested for epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangement. Subject with EGFR activating mutation or ALK rearrangement must have experienced disease progression or unacceptable toxicity/intolerance after receiving at least one EGFR tyrosine kinase inhibitor or ALK inhibitor;
+Activating EGFR mutation (exon 19 deletion, L858R, G719X, L861X)
+Presence of EGFR activating mutation and absence of EGFR T790M in the tumour associated with the latest disease progression. Only applicable in Part B
+Part A: Progression of disease (RECIST 1.1) while on continuous treatment with single EGFR TKI or for histology other than adenocarcinoma and without prior EGFR TKI treatment: progression of disease (RECIST v1.1) on platinum-based chemotherapy. Part B: Progression of disease (RECIST v1.1) while on continuous treatment with single agent of the second generation irreversible EGFR TKI (e.g. afatinib or dacomitinib)
+No intervening systemic therapy between cessation of EGFR TKI and study treatment
+No known potentially targetable mutation other than IGF signaling pathway or EGFR or no available treatment for potentially targetable mutation
+Patient whose disease progressed on insufficient dose of EGFR TKI immediately prior to study in the opinion of the investigator
+More than 2 prior EGFR TKI treatment regimens for Part B
+Chemotherapy, biological therapy or investigational agents (except EGFR TKIs) within 4 weeks
+Use of previous EGFR TKIs except afatinib within 3 days
+Previous treatment with EGFR TKI which cannot be documented as either reversible or irreversible (Part B only)
+Part B only: Prior treatment with third generation irreversible EGFR TKI (e.g. AZD9291 or CO-1686)
+A documented somatic activating mutation in epidermal growth factor receptor (EGFR) (including but not limited to exon 19 deletion or L858R)
+Received erlotinib or other EGFR tyrosine kinase inhibitor (TKI) treatment for at least 2 weeks prior to enrollment
+Any type of systemic therapy (chemotherapy or experimental drugs) within 3 weeks of starting treatment on protocol except for erlotinib or other EGFR TKI
+Prior therapy targeting the epidermal growth factor receptor (EGFR) pathway
+Acquired resistance to marketed anti-EGFR mAbs as defined in the protocol
+Patients with epidermal growth factor receptor (EGFR) overactivity mutations or anaplastic lymphoma kinase (ALK) rearrangements must have received tyrosine-kinase inhibitor (TKI) therapy prior to consideration for enrollment;
+Radiographic disease recurrence or progression during or after front-line platinum-based doublet chemotherapy. For patients with known epidermal growth factor receptor (EGFR) activating mutations or anaplastic lymphoma kinase (ALK) translocations, appropriate targeted treatment should have been used. Mutation testing is not required.
+Non-small cell lung cancer (NSCLC) that is either EGFR or ALK mutated
+For participants with a documented epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement, one additional line of non-cytotoxic prior treatment will be permitted provided the therapy is a targeted agent against the EGFR mutation or ALK rearrangement.
+Presence of an activating EGFR (epidermal growth factor receptor) mutation or ALK (anaplastic lymphoma kinase) translocation in the tumor.
+Known presence of documented sensitizing epidermal growth factor receptor (EGFR) activating mutation or echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) translocation (screening following local standards, but strongly encouraged in non-squamous histology)
+Unknown epidermal growth factor receptor (EGFR)mutation status or previously known EGFR mutated status in patients with adenocarcinoma.
+Patients with any known epidermal growth factor receptor (EGFR) mutation and/or anaplastic lymphoma receptor tyrosine kinase (ALK) translocation
+Prior treatment with an epidermal growth factor receptor (EGFR) inhibitor is allowed if it was administered as part of definitive therapy for locally advanced disease and completed/terminated >/= 3 months before study enrollment
+Exposure to an investigational or marketed agent that can act by EGFR inhibition
+Patients who received prior phosphoinositide-3-kinase (PI3K) inhibitor or anti-receptor tyrosine-protein kinase erbB-3 (ERBB3 or HER3) antibody treatment, including bi-specific antibodies with HER3 as one of the targets (patients with prior exposure to pertuzumab or epidermal growth factor receptor (EGFR)-targeted agents are eligible)
+Subjects must have confirmed EGFR amplification by central lab
+Subjects must have a solid tumor type likely to over-express Epidermal Growth Factor Receptor (EGFR) (Phase 1)
+Eligibility is restricted to subjects with confirmed EGFR amplification in the EGFR amplified cohort
+(summarized due to limitation of characters)\n\n        Inclusion Criteria:\n\n          1. Written informed consent\n\n          2. Aged at least 18 years (20 years for Japan)\n\n          3. Histological or cytological confirmation diagnosis of EGFRm+ NSCLC. Confirmation from\n             a previous archival sample that the tumour harbours an EGFRm+ known to be associated\n             with EGFR TKI sensitivity.\n\n          4. Radiological documentation of disease progression while on a previous continuous\n             treatment with an EGFR TKI (on the last treatment administered prior to enrolling in\n             the study)\n\n             Part B cMET+ve patients:\n\n               -  No prior treatment with a 3rd generation TKI: at least one prior line of therapy\n                  with 1st or 2nd generation EGFR TKI, but not a 3rd generation (T790M-directed)\n                  EGFR TKI.\n\n               -  Prior treatment with a 3rd generation TKI: at least one prior line of therapy\n                  with a 3rd generation (T790M-directed) EGFR TKI for EGFRm or T790M+ NSCLC.\n\n             Part B cMET-ve patients:\n\n               -  T790M directed EGFR TKI patients only: their immediate prior therapy before entry\n                  into this study must be a T790M directed EGFR TKI.\n\n               -  ?2nd line cohort: patients must have progressed while on treatment with an EGFR\n                  TKI (T790M directed EGFR TKIs are permitted). Other prior lines of therapy may\n                  have been given.\n\n             Part D cMET-ve patients:\n\n             No prior treatment with a 3rd generation TKI, T790M negative:\n\n             Patients must have received at least one prior line of therapy with 1st or 2nd\n             generation EGFR TKI, but not a 3rd generation (T790M directed) EGFR TKI.\n\n          5. cMET status: Prior to study entry, local confirmation of tumour cMET status is\n             acceptable, a central result will be confirmed retrospectively. If a local test is not\n             available, central confirmation of tumour cMET status must be obtained prior to study\n             entry.\n\n             T790M status: Local confirmation of tumour T790M status is acceptable, a central\n             result will be confirmed retrospectively. If local testing is performed with the\n             Cobas® EGFR Mutation Test, the central confirmation is not required.\n\n          6. At least one lesion, not previously irradiated, not biopsied during the screening\n             period, that can be accurately measured at baseline as ?10 mm in the longest diameter\n             (except lymph nodes which must have short axis ?15 mm) with CT or MRI which is\n             suitable for accurate repeated measurements\n\n          7. WHO performance status 0-1 with no deterioration over the previous 2 weeks and minimum\n             life expectancy of 12 weeks\n\n          8. Females should be using adequate contraceptive measures, must not be breast feeding\n             and must have a negative pregnancy test prior to start of dosing if of child-bearing\n             potential or must have evidence of non-child-bearing potential.\n\n        Exclusion Criteria (summary):\n\n          -  Treatment with an EGFR TKI within approximately 5x half-life of the first dose of\n             study treatment. Any cytotoxic chemotherapy, investigational agents or other\n             anticancer drugs for the treatment of advanced NSCLC from a previous treatment regimen\n             or clinical study within 14 days of the first dose of study treatment. Patients\n             currently receiving (or unable to stop use) medications or herbal supplements known to\n             be potent inducers of CYP3A4 (at least 3 weeks prior). For AZD6094 patients currently\n             receiving (or unable to stop use at least 2 weeks) prior to receiving the first dose,\n             medications known to be strong inhibitors of CYP1A2. Prior AZD9291 dosing in the\n             present study. Prior or current treatment with AZD6094 or another cMET inhibitor (if\n             allocated to AZD9291 + AZD6094). Radiotherapy with a limited field of radiation for\n             palliation within 1 week of the first dose of study treatment, with the exception of\n             patients receiving radiation to more than 30% of the bone marrow or with a wide field\n             of radiation which must be completed within ?4 weeks of the first dose of study\n             treatment. Major (or anticipated major) surgical procedure (excluding placement of\n             vascular access) or significant traumatic injury within 4 weeks of the first dose of\n             study treatment. Currently receiving treatment with warfarin sodium.\n\n          -  With the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy,\n             any unresolved toxicities from prior therapy and/or pre-study biopsies greater than\n             CTCAE Grade 1 at the time of starting study treatment.\n\n          -  Spinal cord compression or brain metastases unless asymptomatic, stable and not\n             requiring steroids for at least 2 weeks prior to start of study treatment.\n\n          -  Severe or uncontrolled systemic diseases; known serious active infection; active\n             hepatitis B or C; cardiac disease; inadequate bone marrow reserve or organ function or\n             coagulation parameters; inadequate liver or renal function; GI events that would\n             preclude adequate absorption, distribution, metabolism or excretion of AZD9291,\n             AZD6094 or selumetinib; hipersensitivity to IP or similar drugs\n\n          -  Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation\n             pneumonitis which required steroid treatment, or any evidence of clinically active\n             ILD.
+Patients who have had prior anti-epidermal growth factor receptor (EGFR) antibody therapy and who have not responded to this treatment will be excluded; however, patients who have responded to prior anti-EGFR therapy are eligible
+Known EGFR (exon 19 and 21) mutations, ALK translocations, and/or ROS-1 translocations
+A tumor block or 10 unstained slides must be available for determining EGFR mutational status; only those patients who have a mutation of the EGFR tyrosine kinase domain will be able to enroll in this study
+For the MTD expansion cohort, patients will be eligible if they meet one of the following criteria:\r\n* Have an EGFR-sensitive mutation (as G719C in exon 18, E746-A750 in exon 90, L858R in exon 21) and have been previously treated with EGFR inhibitor therapy but have subsequently developed resistance, OR\r\n* Have an EGFR-resistant mutation (as T790M in exon 20), OR\r\n* Do not have an EGFR mutation, but have benefited from EGFR inhibitor therapy (including either >= 4 months of stable disease [SD] OR a >= partial response [PR])
+NSCLC with documented epidermal growth factor receptor (EGFR) mutation associated with response to EGFR inhibitors or documented fusion gene involving anaplastic lymphoma kinase (ALK) gene
+Results of endothelial growth factor receptor (EGFR)-activating mutation testing
+More than 30 days of exposure to an investigational or marketed agent that can act by EGFR inhibition, or a known EGFR-related toxicity resulting in dose modifications (EGFR inhibitors including but not limited to gefitinib, erlotinib and cetuximab)
+Epidermal growth factor receptor (EGFR)-mutation-positive disease according to local laboratory testing
+Prior treatment with epidermal growth factor receptor (EGFR)-targeted small molecules
+Prior treatment of NSCLC with EGFR TKIs or monoclonal antibodies targeting EGFR
+Prior use of any monoclonal antibodies directly targeting the epidermal growth factor receptor (EGFr). Subjects who have received prior tyrosine kinase inhibitors such as gefitinib or erlotinib are eligible.
+Prior or other EGFR inhibiting agents.
+Patients with EGFR- or ALK-positive disease are not eligible for this study
+Prior EGFR tyrosine kinase inhibitor (TKI) therapy with progression, and documented EGFR T790M mutation on tumor biopsy; however, this need not be only second line
+No known presence of known EGFR or EML4-ALK driver mutations in the tumor
+Patient has no unstable renal function, defined as a change in estimated glomerular filtration rate (eGFR) (calculated with the MDRD equation) of > 25% for patients with mild and moderate renal impaired or as a change in eGFR > 30% for patients with severe renal impaired, from screening to enrollment.
+NSCLC must harbor an EGFR activating mutation (Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q)
+Progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including osimertinib [AZD9291] allowed for dose escalation only)
+For the dose expansion portion ONLY, patient must: 1) have progression of disease with erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) tumors must be EGFR T790M negative confirmed by central testing prior to treatment (If EGFR-T790M status is unknown, patient may consent for trial for biopsy and testing for EGFR T790M will be performed as part of the initial biopsy for the trial: patients who test positive for EGFR T790M by central testing will be ineligible for the dose expansion), 3) be treatment naive for 3rd generation EGFR-TKI (CO-1686 and osimertinib [AZD9291]) and mTOR inhibitors
+Known EGFR mutation status
+No prior treatment for Stage IV non-squamous or squamous NSCLC. Participant known to have a sensitizing mutation in the epidermal growth factor receptor (EGFR) gene or an anaplastic lymphoma kinase (ALK) fusion oncogene are excluded from the study
+Known sensitizing mutation in the EGFR gene or ALK fusion oncogene
+Subject is currently on anti-EGFR (human epidermal growth factor receptor) therapy, such as Iressa (gefitinib) or Erbitux (cetuximab, C225)
+Any prior treatment with erlotinib or other agent whose primary mechanism of action is known to inhibit EGFR
+Any prior treatment with erlotinib or other agent whose primary mechanism of action is known to inhibit EGFR
+Histologically or cytologically documented metastatic or unresectable, locally advanced or metastatic NSCLC, with one or more activating EGFR mutation (eg, G719X, exon 19 deletion, L858R, L861Q) and absence of exon 20 insertion
+For Phase 2 Group A, EGFR TKI treatment-naïve and chemotherapy-naïve
+Patients with NSCLC (adenocarcinoma, squamous, or adenosquamous histopathology) must also meet the following criteria: a. Must have disease that is stage IIIB, not curable by surgery or radiotherapy, or stage IV; b. Must have received at least one prior chemotherapy regimen for locally advanced or metastatic disease; c. EGFR-positive or ALK-positive patients must have received at least one line of EGFR-directed or ALK-directed therapy, respectively; d. Must have received prior taxane therapy.
+Patients who have received a non-FDA or non-EMA approved anti-EGFR agent or any other non-FDA or non-EMA approved agent as part of concurrent radiotherapy
+Impaired renal function defined as epidermal growth factor receptor (eGFR) < 50 mL/min/1.73m2
+Chemotherapy naive NSCLC patients; for NSCLC patients with lung adenocarcinoma, tumors must be EGFR and ALK wild-type; if a KRAS mutation is detected, EGFR and ALK testing is not required
+Previous EGFR-directed therapy
+Patients with impaired renal function (eGFR < 30)
+All subjects providing written informed consent will complete the subject history and screening form prior to MR imaging; the form will be reviewed to determine whether the subject is at risk as defined above and the availability of an estimated glomerular filtration rate (eGFR) within six weeks of anticipated MR imaging; an eGFR result greater than six weeks prior to the MRI imaging date will be repeated and evaluated for renal function; subjects with an eGFR of < 30 mL/min/1.73 m^2 will be excluded from the study
+Patients with an estimated GFR (eGFR) > 90 ml/min reported within 30 days, and who have not had intervening chemotherapy or other treatment or condition that might deteriorate renal function, may receive any gadolinium agent
+Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011)
+Historical confirmation that the tumor harbors an epidermal growth factor receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q)
+Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease [Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI
+Demonstrates absence of EGFR T790M mutation if treated with erlotinib, gefitinib, or afatinib. No EGFR mutation testing is required if treated with osimertinib.
+Has previously documented evidence of ALK fusion, ROS1 fusion, BRAF V600E mutation, RET rearrangement, HER2 mutation, MET amplification, or MET exon 14 skipping mutation. No new testing for these genomic alterations is required for Screening.
+Histologically or cytologically confirmed diagnosis of NSCLC that is EGFR Wild-type, ALK-negative rearrangement and ROS1-negative rearrangement
+Patient with known severely impaired renal function (defined as eGFR MDRD< 30 ml/min/1.73m2)
+Patients should have pathologically or cytologically confirmed stage IV non-small cell lung cancer with clinical or radiological evidence that it is not amenable to therapy with curative intent; prior EGFR tyrosine kinase inhibition (TKI) therapy is permitted but not required
+Patients should be potential candidates for therapy with an EGFR tyrosine kinase inhibitor or with an anti-EGFR monoclonal antibody by clinical criteria
+Patients should have clinical characteristics that would suggest an increased probability of benefit from an EGFR inhibitor; specifically, they should have known EGFR mutations or high gene copy number
+Impaired renal function defined as eGFR< 50 mL/min/1.73m2
+Participants with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic alternations should have PD on prior US-FDA approved therapy for these aberrations.
+EGFR genotype must not be known; however, pending EGFR tumor genotyping is allowed\r\n* Participants with positive or pending EGFR mutation on plasma genotyping performed at the central lab are eligible for enrollment, and will not need to repeat initial plasma genotyping on study
+Participants must not have had prior treatment with an EGFR kinase inhibitor, EGFR directed therapy or investigational agent
+Patients with EGFR mutations expected to be sensitive to EGFR inhibitors and patients with EML4/ALK translocations are excluded, unless all available Food and Drug Administration (FDA)-approved targeted therapy options have been utilized; for example, a patient with exon 19 EGFR mutation who has never been treated with an EGFR inhibitor would be excluded; patients with other sensitizing mutations that become actionable with FDA-approved targeted therapies during the course of this trial (e.g., crizotinib for MET deletion 14) will also be expected to have utilized all available FDA-approved targeted therapy options prior to eligibility\r\n* Note: In contrast to the above, a patient with an EGFR mutation who has been treated with a first-generation and third generation tyrosine kinase inhibitors (TKIs) and then with four cycles of carboplatin plus pemetrexed would be eligible
+Patients with EGFR and ALK alterations should have been treated with at least 1 line of targeted tyrosine kinase inhibitor