Group a and b: 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  deletions and for the LR 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 - 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.
NSCLC patients with EGFR mutant tumors.
For Part : 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  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  insertion
EGFR mutation (LR and /or exdel)
Has documented evidence of an activating EGFR mutation in the tumor tissue determined by either sequencing or PCR-based technique (Part ).
For Part  only: subjects with a positive TM mutation are preferred, but not required. Confirmation of TM 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 , subjects must have a confirmed, positive TM EGFR mutation (acquired TM EGFR mutation or \de novo\ TM EGFR mutation).
Known TM EGFR mutation (not applicable for Part C Period ).
Partial Inclusion criteria:\n\n        Evidence of histologically or cytologically confirmed diagnosis of locally advanced or\n        metastatic EGFRm (del  or LR) NSCLC:\n\n          . 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          . TM disease as follows:\n\n             Phase  If a repeat biopsy was performed on the tumor following prior EGFR TKI\n             therapy, then TM positive disease must be present. Patients of unknown TM 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 CYPA effects, patients with EGFRm\n             (del  or LR) with any TM status are eligible to enroll.\n\n             Studies at RPD Cohort : Patients may have de novo TM mutation, but it is not\n             required. Cohort  and Cohort : Patients must have EGRFm (del  AND TM or LR\n             AND TM) 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  AND TM or LR AND TM) NSCLC in\n             plasma detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR\n             Plasma RGQ kit, Roche cobas EGFR mutation test v (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          . Prior treatment for EGFRm NSCLC as follows:\n\n        Phase  Has progressed after at least  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 RPD Cohort : no prior treatment for locally advanced or metastatic EGFRm\n        NSCLC. Cohorts  and : must have had disease progression on treatment with an approved st\n        or nd generation EGFR TKI. Patients who have been treated with a rd 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  weeks prior to study registration.\n\n        Patients must have at least one measurable lesion as defined by RECIST version . that has\n        not been previously irradiated.\n\n        Tumor tissue available. Requesting formalin fixed paraffin embedded (FFPE) block or \n        unstained sections ( micron). If a lesser amount of tissue is available, contact the\n        sponsor. An archival specimen is acceptable for Phase ; a de novo specimen is required for\n        Cohorts , and  if the TM 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  weeks prior to registration.\n\n        Radiation therapy, excluding stereotactic radiosurgery (SRS), within  week prior to\n        registration.\n\n        Systemic anti cancer therapy within  weeks or  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          -   days prior to registration for erlotinib or afatinib, or  days for gefitinib if\n             they will be part of the lead-in single dose PF- PK study (Phase  Dose\n             Escalation Single and Multiple dose PK and ECG Assessments; Phase  Sildenafil at MTD;\n             and Phase b/ First-Line Single Agent). Please contact the Sponsor for direction for\n             any other EGFR TKI.\n\n          -   half-lives or  days (whichever is longer) prior to registration if they will be\n             starting on continuous PF- dosing directly (Phase  PK sub-studies at RPD;\n             Phase b/ Combination with Palbociclib; Phase b Combination with Avelumab).\n\n        Partial Exclusions for Cohort A and B (Palbociclib combo):\n\n        Prior treatment with a CDK / inhibitor.\n\n        Partial Exclusions for Cohort  (Avelumab combo):\n\n        Prior therapy with an anti PD , anti PD L, anti PD L, anti CD, or anti cytotoxic T\n        lymphocyte associated antigen  (CTLA ) 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
Participants must have a lung cancer harboring an EGFR mutation
EGFR amplifications in the absence of EGFR-activating mutations
Previous treatment with erlotinib or any other EGFR inhibitor
For the dose expansion and extension cohorts, patients also must have confirmation of tumor TM+ 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 TM mutation status must be obtained.
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
EGFR-mutation positive patients must have progressed on or had intolerance to an EGFR small molecule tyrosine kinase inhibitor
Activating mutation in EGFR
Confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity OR
Dose Expansion cohort(s): subjects in the dose expansion cohorts must also have confirmation of tumor TM mutation status (confirmed positive) by cobas EGFR Mutation Test v 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).
Patients must have one of the following: \r\n* NSCLC which harbors EGFR exon  deletion or LR mutation. This subset of patients must be TKI naive; OR\r\n* NSCLC which harbors an EGFR TM 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
For the dose expansion portion only, patient must: ) have a tumor which is EGFR-TM positive and ) be treatment naive to TM-directed EGFR TKI (e.g. AZD, rociletinib, etc); TM testing may be done locally or centrally on study, but if done locally, tissue must be available for central confirmation
Demonstrates absence of EGFR TM.
Patients with a known activating mutation in EGFR (exon  deletion, GA, SI, VL, TM, LF, LR, LQ), 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 TM mutation must also have progressed or been intolerable to treatment with osimertinib
eGFR> % of mean age adjusted normal values
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  mutation is confirmed using an FDA approved device: cobas EGFR mutation test v or therascreen EGFR RGQ polymerase chain reaction (PCR) Kit prior to study enrollment
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
Non-small cell lung cancer: ) 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 TM mutation; we will allow patients with positive EGFR TM mutation if they have progressed on third generation anti-EGFR therapy (e.g. CO- or AZD) 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 .) after at least two months of therapy
Phase  patients must have confirmed EGFR TM mutation-positive NSCLC
Have an EGFR mutation (sensitizing or non-sensitizing)
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 v/ at an outside institution, advanced lung adenocarcinoma with EGFR-sensitizing somatic mutations or a germline TM mutation (detected histologically or via ctDNA analysis using a CLIA assay) with:\r\n* No prior EGFR tyrosine kinase inhibitor (TKI) therapy (cohort )\r\nOR\r\n* Progressive disease after st or nd generation EGFR TKI therapy harboring somatic TM mutation (cohort )\r\nOR\r\n* Progressive disease after treatment with osimertinib who are eligible for local ablative therapy (cohort )
Patients whose tumor harbors EGFR gene mutation that sensitizes tumors to Tyrosine-Kinase Inhibitor (TKI) (EGFR exon -) or Anaplastic Lymphoma Kinase (ALK) rearrangement.
Pathology consistent with EGFR-amplification of tumor (i.e. greater than % of cells exhibiting >  copies of EGFR loci); archival tissue may be tested for EGFR status in a separate consent
Confirmation by the central laboratory that the tumour harbours one of the  common EGFR mutations known to be associated with EGFR-TKI sensitivity (Exdel, LR), either alone or in combination with other EGFR mutations including TM.
Subjects must have evidence of a TM mutation in tumor tissue or plasma obtained after disease progression during or after treatment with an EGFR TKI. TM mutation status from a local laboratory is acceptable; however, a tumor tissue sample or plasma sample suitable for centralized TM mutation analysis must be available.
Patients whose tumors are positive for the sensitizing EGFR mutation
Tumor tissue for determination and/or confirmation of genetic pre-requisites (i.e. EGFR TM positivity post progression on EGFR TKI for Group ; cMet status for Group ) must be provided for analysis Group  patients:
Patients with EGFR TM NSCLC (adenocarcinoma)
Patients with EGFR wild-type NSCLC
Patients who previously received agents targeting c-MET and/or EGFR TM Note: Previous treatment with afatinib may be allowable after discussions between Novartis and Investigator.
The presence of an EGFR TM mutation after progression on a first- or second-generation EGFR TKI; presence of an EGFR TM 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), TM positivity is not required
For patients with a documented EGFR TM mutation: have not received a TKI with activity against the EGFR TM 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 with an EGFR deletion or mutation known (from tumour biopsy or plasma) to be associated with EGFR TKI sensitivity
eGFR >  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 TM mutation, must also have demonstrated progression on or intolerance to osimertinib
Treatment with third generation EGFR inhibitors
Patients with known and documented EGFR mutation who have not received an EGFR inhibitor.
\Acquired\ resistance to commercially available anti-EGFR mAbs approved for the treatment of mCRC must have:
Received treatment with an anti-EGFR for ? weeks
Skin rash > Grade  from prior anti-EGFR therapy at the time of randomization.
Documentation of tumor activating EGFR mutation, specifically either DEL or LR.
For study cohort A, has not had prior treatment with cetuximab, panitumumab, or other anti-EGFR therapy
The washout period for an EGFR inhibitor is a minimum of  days
Prior treatment with rociletinib, or other drugs that target TM positive mutant\n             EGFR with sparing of wild type EGFR
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  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 TM 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
Documented evidence of TM mutation in EGFR following disease progression on the\n             first single agent EGFR TKI.
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  months duration of response in patients who do not have a confirmed EGFR mutation
For Dose Expansion Cohort A: patient must ) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, ) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-TM negative confirmed by central testing prior to treatment (if EGFR-TM status is unknown, patients may consent for trial and for biopsy and testing for EGFR TM will be performed as part of initial biopsy for trial), and ) be treatment naive to rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM [HM] and AZD) and EGFR monoclonal antibodies
For Dose Expansion Cohort B: patient must ) have progression of disease on a rd generation EGFR-TKI such as AZD, rociletinib, HM, ) be treatment naive to an EGFR monoclonal antibody, and ) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-TM (EGFR-TM negative) confirmed by central testing prior to treatment (if EGFR-TM status is unknown, patients may consent for trial and for biopsy, and testing for EGFR TM will be performed as part of initial biopsy for trial)
For Dose Expansion Cohort C: patient must ) have progression of disease on a rd generation EGFR-TKI such as AZD, rociletinib, HM, ) be treatment naive to an EGFR monoclonal antibody, ) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-TM post-progression on rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-TM status is unknown, patients may consent for trial and for biopsy, and testing for EGFR TM will be performed as part of initial biopsy for trial
For Dose Expansion Cohort D: patient must ) tumor that harbors an EGFR Exon  insertion by a CLIA certified test, and ) have progressive disease on or after platinum based chemotherapy, and ) be treatment naive to both EGFR-TKI and EGFR monoclonal antibody
Known tumor EGFR, KRAS, and/or Akt mutations or amplification
eGFR ?  mL/min/. m
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.
No clinically significant progression outside of the CNS on most recent EGFR inhibitor therapy
Evidence of common EGFR mutation (Del  and/or LR)
Patients who have had prior therapy that specifically and directly targets the EGFR/HER pathway.
Locally documented EGFR mutation LR and/or exdel, or a characterized de novo EGFR TM mutation (or other rare activating mutations that confer sensitivity to st and nd generation EGFR inhibitors (e.g. LQ, GX, SI)
Phase II Group  (EGFRmut, de novo TM, any c-MET, /L antineoplastic, EGFR TKI nave) only: Advanced NSCLC patients who have not been previously treated with any therapy known to inhibit EGFR and harbor de novo TM mutation .
Phase II Group  (EGFRmut, TM negative, any c-MET, L antineoplastic) only: patients must harbor an EGFR activating mutation and must be nave from any line of systemic antineoplastic therapy in the advanced setting.
Phase II Group  (EGFRmut, any TM, any c-MET, L (treatment-nave), //L antineoplastic): All patients must harbor an EGFR activating mutation and /L patients must have failed (defined as intolerance to treatment or documented disease progression) a maximum of  prior lines of antineoplastic therapy in the advanced setting
Previous treatment with any investigational agent known to inhibit EGFR (mutant or wild-type)
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, AZD, CO-, ASP, EGF) or other anti-EGFR or EGFR monoclonal antibody therapy or dual TKI inhibitors.
De novo EGFR TM mutation identified by central assessment
In Part B-AZD LM expansion (sub-cohort of TM+ LM patients), patients must have central confirmation of TM+ mutation status from a sample taken after documented progression on the last treatment administered prior to enrolling in the study. Patients must have received prior therapy with an EGFR TKI and may also have received additional lines of treatment. Stable extracranial disease is not required.
Response expansion/RPD expansion/ FE Cohort subjects: disease progression on or was intolerant to prior EGFR TKI; activating mutation as above AND TM 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) . Inclusion Criteria for Exon  cohort:
CKD  to  (eGFR > )
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 T mutation develops. Prior molecular therapy for biomarker positive tumors such as (but not limited to) MET, RET and BRAF allowed but not required.
Previous treatment with osimertinib or third generation EGFR TKIs.
Previous treatment with anticancer therapies, EGFR-TKI, HM, or other drugs that target TM-positive mutant EGFR with sparing of wild-type, investigational agent(s) within  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
Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC with known sensitive EGFR mutations; patients with mutations in TM are eligible if they have progressed after treatment with a third generation EGFR tyrosine kinase inhibitor (osimertinib), but otherwise patients must have EGFR TM negative or unknown status; patients previously treated with third generation EGFR tyrosine kinase inhibitor must have achieved a treatment benefit of at least  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 HER 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  common EGFR mutations known to be associated with EGFR-TKI sensitivity (Exdel, LR).
Central confirmation of TM+ mutation status
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, nave to EGFR TKI therapy, and sensitive to EGFR TKIs therapy
Documented presence of EGFR mutation confirmed by MSKCC or a local facility
For dose expansion and extension cohorts, patients must also have confirmation of tumour TM 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 TM mutation status must be obtained.
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  months prior to study enrollment; for the dose-finding cohorts, prior EGFR-specific therapy in the incurable setting is allowed
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  months free of progressive disease as a consequence of EGFR-TKI therapy)
Somatic activating mutation in EGFR radiographic progression during treatment with erlotinib or any other EGFR tyrosine kinase inhibitor (TKI) therapies
Confirmed stage IV or recurrent EGFR Mutation (MT)+ NSCLC with disease progression after  prior EGFR TKI therapy
No evidence of exon  TM mutation after progression on prior EGFR tyrosine kinase inhibitor(TKI) therapy.
Somatic activating mutation in EGFR
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 Cen (centromere  copy number control) ratio of at least  to ; for EGFR activating mutation, any one of the following EGFR mutations is eligible: extracellular domain mutation: EGFRvIII, RK, TP, AV, AD, AT, GV; or kinase domain mutation: GX, TM, exon deletions/insertions (at/near/within codons -), exon  insertions/deletions/mutations (insertions/deletions at or near -, SI, RC), LR, LQ
Subject has received a prior treatment with a therapeutic agent targeting EGFR (e.g., afatinib, dacomitinib, ASP, etc).
eGFR >  ml/min/. m^
Prior treatment with EGFR TKIs (e.g. erlotinib, gefitinib, neratinib, afatinib, AZD, or dacomitinib), rociletinib or other drugs that target mutant EGFR
Subject has an EGFR activating mutation based on local testing.
Progression within  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  months of prior anti-EGFR therapy
Subjects that are known to be epidermal growth factor (EGFR)-activating mutation positive must have received an EGFR inhibitor.
Prior monotherapy with an EGFR inhibitor except as maintenance therapy
Participants who received prior treatment with erlotinib or other EGFR-targeted agents
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 unknown status of EGFR mutation (only for patients with adenocarcinoma histology)
The institutions pre-enrollment biomarker screening at a CLIA certified lab documents absence of TM mutation in the EGFR TK domain
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.
Documented EGFR activating mutations (if already tested)
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
FOR PHASE II COHORT B: (EGFR exon  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
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
Presence of EGFR activating mutation and absence of EGFR TM in the tumour associated with the latest disease progression. Only applicable in Part B
No known potentially targetable mutation other than IGF signaling pathway or EGFR or no available treatment for potentially targetable mutation
Use of previous EGFR TKIs except afatinib within  days
Acquired resistance to marketed anti-EGFR mAbs as defined in the protocol
Eligibility is restricted to subjects with confirmed EGFR amplification in the EGFR amplified cohort
A tumor block or  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
Prior treatment with an EGFR inhibitor other than cetuximab at any time
More than  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)
Prior treatment of NSCLC with EGFR TKIs or monoclonal antibodies targeting EGFR
Prior or other EGFR inhibiting agents.
Prior EGFR tyrosine kinase inhibitor (TKI) therapy with progression, and documented EGFR TM mutation on tumor biopsy; however, this need not be only second line
For the dose expansion portion ONLY, patient must: ) have progression of disease with erlotinib, gefitinib or afatinib as last previous systemic treatment, ) tumors must be EGFR TM negative confirmed by central testing prior to treatment (If EGFR-TM status is unknown, patient may consent for trial for biopsy and testing for EGFR TM will be performed as part of the initial biopsy for the trial: patients who test positive for EGFR TM by central testing will be ineligible for the dose expansion), ) be treatment naive for rd generation EGFR-TKI (CO- and osimertinib [AZD]) and mTOR inhibitors
Known EGFR mutation status
Any prior treatment with erlotinib or other agent whose primary mechanism of action is known to inhibit EGFR
Non-surgical cohort only: positive phospho-EGFR assessment (>=  stained pixels) from tissue obtained from previous clinical liver biopsy
Any prior treatment with erlotinib or other agent whose primary mechanism of action is known to inhibit EGFR
Previous EGFR-directed therapy
Demonstrates absence of EGFR TM mutation if treated with erlotinib, gefitinib, or afatinib. No EGFR mutation testing is required if treated with osimertinib.
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
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 EML/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  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 ) 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