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.
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.
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)
NSCLC patients with EGFR mutant tumors.
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)
Acquired resistance to EGFR TKI (1st or 2nd génération)
Prior treatment with 3rd generation TKI
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).
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
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 afatinib therapy, unless patient received an intervening third generation EGFR TKI after concluding prior afatinib and before enrollment on this clinical study
EGFR amplifications in the absence of EGFR-activating mutations
Previous treatment with erlotinib or any other EGFR inhibitor
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.
An EGFR TKI (e.g., erlotinib, gefitinib, or osimertinib) within 8 days or approximately 5 times the half-life of the specific drug, whichever is longer, of the first dose of study treatment. (If sufficient wash-out time has not occurred due to scheduling or PK properties, an alternative appropriate wash-out time based on known duration and time to reversibility of drug-related adverse events must be agreed upon by Hansoh and the Investigator).
Previously untreated NSCLC patients. To be eligible for this study, patients must have received and progressed on EGFR TKI therapy.
No prior treatment with an EGFR TKI for the advanced NSCLC
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
EGFR-mutation positive patients must have progressed on or had intolerance to an EGFR small molecule tyrosine kinase inhibitor
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
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
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
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
In dose expansion, patients must have received prior anti-EGFR therapy
Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011):
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.
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
eGFR> 60% 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 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
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: 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
Phase 2 patients must have confirmed EGFR T790M mutation-positive NSCLC
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)
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
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.
Prior treatment with neoadjuvant or adjuvant EGFR-TKI at any time
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.
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)
Treatment with an EGFR TKI (i.e. erlotinib, gefitinib or afatinib) within 8 days or approximately 5 x half-life, whichever is longer, of the first dose of study treatment
For patients with a documented EGFR T790M mutation: have not received a TKI with activity against the EGFR T790M mutation.
Patients with an EGFR deletion or mutation known (from tumour biopsy or plasma) to be associated with EGFR TKI sensitivity
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
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 ?16 weeks
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.
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
Prior treatment with rociletinib, or other drugs that target T790M 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 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.
No prior treatment with systemic anti-EGFR inhibitors or pemetrexed is permitted
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
For participants receiving erlotinib group: prior treatment with any EGFR mutant-targeting TKI
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 exposure to EGFR inhibitors.
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.
Patients who have had prior therapy that specifically and directly targets the EGFR/HER2 pathway.
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).
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.
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).
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 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.
In Part B-AZD9291 LM expansion (sub-cohort of T790M+ LM patients), patients must have central confirmation of T790M+ 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.
Treatment with an EGFR TKI (e.g., erlotinib or gefitinib) within 8 days or approximately 5 x half-life, whichever is the longer, of the first dose of study treatment.
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:
CKD 1 to 3 (eGFR > 30)
Previous treatment with osimertinib or third generation EGFR TKIs.
Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI
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
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.
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:
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
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).
Treatment with an EGFR TKI (erlotinib or gefitinib) within 8 days (approximately 5x half-life) of the first dose of study treatment.
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
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)
History of previous response to EGFR-TKI, defined as either a PR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, or at least six months without progressive disease as a result of EGFR-TKI therapy
Progressive disease as measured via RECIST 1.1 following EGFR-TKI therapy (with =< 5 sites of disease amenable to SRS or other locally-ablative treatment)
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)
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
Confirmed stage IV or recurrent EGFR Mutation (MT)+ NSCLC with disease progression after 1 prior EGFR TKI therapy
Subject has received a prior treatment with a therapeutic agent targeting EGFR (e.g., afatinib, dacomitinib, ASP8273, etc).
eGFR > 30 ml/min/1.73 m^2
Prior treatment with EGFR TKIs (e.g. erlotinib, gefitinib, neratinib, afatinib, AZD9291, or dacomitinib), rociletinib or other drugs that target mutant EGFR
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
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)
Prior monotherapy with an EGFR inhibitor except as maintenance 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 previous anti-cancer chemotherapy, immunotherapy or investigational agents =< 3 weeks prior to the first day of study defined treatment; NSCLC patients with EGFR mutation can enroll within 7 days of discontinuing EGFR-TKI; palliative radiation < 1 week before the start of treatment (lesions subjected to radiotherapy may not be used as target lesions); patients who receive gamma knife radiosurgery for brain metastases within 1 week prior to treatment start
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.
Documented EGFR activating mutations (if already tested)
ERLOTINIB HYDROCHLORIDE ARM: Previous anti-EGFR TKI therapy
ERLOTINIB HYDROCHLORIDE ARM: Patients with a known EGFR TKI resistant mutation
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
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
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
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
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
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)
Any type of systemic therapy (chemotherapy or experimental drugs) within 3 weeks of starting treatment on protocol except for erlotinib or other EGFR TKI
Acquired resistance to marketed anti-EGFR mAbs as defined in the protocol
Exposure to an investigational or marketed agent that can act by EGFR inhibition
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.
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)
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 T790M mutation on tumor biopsy; however, this need not be only second line
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
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
For Phase 1 and Phase 2 Group B, progression after prior 1st or 2nd generation EGFR TKI (eg, erlotinib, gefitinib, afatinib). Previous chemotherapy for NSCLC is allowed.
For Phase 2 Group A, EGFR TKI treatment-naïve and chemotherapy-naïve
Previous EGFR-directed therapy
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
Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011)
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.
Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) from a previous cancer treatment regimen or clinical study (other than EGFR TKI), within 14 days of the first dose of study treatment
Prior treatment with a VEGF receptor TKI within a time period equivalent to 5 half-lives of the prior TKI (e.g., there should be no substantial amount of TKI remaining in the patient)
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 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
