Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   38529   clinical trials with a EudraCT protocol, of which   6333   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2017-004188-11
    Sponsor's Protocol Code Number:MK-3475-789
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-04-23
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2017-004188-11
    A.3Full title of the trial
    A Randomized, Double-Blind, Phase 3 Study of Pemetrexed + Platinum Chemotherapy with or without Pembrolizumab (MK-3475) in TKI-resistant EGFR-mutated Tumors in Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) Participants (KEYNOTE-789).
    Estudio de fase 3, aleatorizado y doble ciego de quimioterapia con pemetrexed + platino con o sin pembrolizumab (MK-3475) en pacientes con cáncer de pulmón no microcítico (CPNM) no epidermoide, metastásico, con mutación de EGFR y resistente a inhibidores de la tirosina cinasa (KEYNOTE-789).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 3 Study of Pemetrexed + Platinum Chemotherapy with or without Pembrolizumab (MK-3475) in TKI-resistant EGFR-mutated Tumors in Metastatic Non-Squamous NSCLC.
    Estudio de fase 3 de quimioterapia con pemetrexed + platino con o sin pembrolizumab (MK-3475) en pacientes con CPNM no epidermoide, metastásico, con mutación de EGFR y resistente a ITC.
    A.3.2Name or abbreviated title of the trial where available
    Pemetrexed+Platinum Chemotherapy with/ without MK-3475 in TKI-resistant EGFR-mutated Tumors in NSCLC
    Quimioterapia pemetrexed+platino con/sin MK-3475 pacientes con CPNM, mutación EGFR ,resistente ITC.
    A.4.1Sponsor's protocol code numberMK-3475-789
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck Sharp & Dohme de España S.A.
    B.5.2Functional name of contact pointInvestigación Clínica
    B.5.3 Address:
    B.5.3.1Street AddressCalle Josefa Valcárcel, 38
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28027
    B.5.3.4CountrySpain
    B.5.4Telephone number+34913210600
    B.5.5Fax number+34913210590
    B.5.6E-mailensayos_clinicos@merck.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePembrolizumab
    D.3.2Product code MK-3475
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEMBROLIZUMAB
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name ALIMTA (PEMETREXED DISODIUM)
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly Nederland B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEMETREXED DISODIUM
    D.3.9.1CAS number 150399-23-8
    D.3.9.3Other descriptive namePEMETREXED DISODIUM
    D.3.9.4EV Substance CodeSUB03669MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name ALIMTA (PEMETREXED DISODIUM)
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly Australia Pty Limited
    D.2.1.2Country which granted the Marketing AuthorisationAustralia
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Lyophilisate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEMETREXED DISODIUM
    D.3.9.1CAS number 150399-23-8
    D.3.9.3Other descriptive namePEMETREXED DISODIUM
    D.3.9.4EV Substance CodeSUB03669MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Cisplatin
    D.2.1.1.2Name of the Marketing Authorisation holderTEVA GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCISPLATIN
    D.3.9.1CAS number 15663-27-1
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Carboplatin-Actavis
    D.2.1.1.2Name of the Marketing Authorisation holderActavis Group PTC ehf.
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCARBOPLATIN
    D.3.9.3Other descriptive nameCARBOPLATIN
    D.3.9.4EV Substance CodeSUB06614MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Metastatic Non-squamous Non-small Cell Lung Cancer
    Cáncer de pulmón no microcítico, no epidermoide, metastásico
    E.1.1.1Medical condition in easily understood language
    Lung cancer (non-small cell lung cancer)
    Cáncer de pulmón (cáncer de pulmón no microcítico)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029522
    E.1.2Term Non-small cell lung cancer stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To compare PFS per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) based on blinded independent central review (BICR) of the combinations of pembrolizumab + chemotherapy versus saline placebo + chemotherapy
    - To compare overall survival (OS) of the combinations of pembrolizumab + chemotherapy versus saline placebo + chemotherapy
    •Comparar la SSP conforme a los Criterios de evaluación de la respuesta en tumores sólidos 1.1 (RECIST 1.1), según una revisión central independiente y enmascarada (RCIE), entre las combinaciones de pembrolizumab + quimioterapia y placebo salino +quimioterapia.
    •Comparar la SG entre las combinaciones de pembrolizumab +quimioterapia y placebo salino + quimioterapia
    E.2.2Secondary objectives of the trial
    - To compare objective response rate (ORR) per RECIST 1.1 based on BICR of the combinations of pembrolizumab + chemotherapy versus saline placebo + chemotherapy
    - To compare duration of response (DOR) of the combinations of pembrolizumab + chemotherapy versus saline placebo + chemotherapy
    - To evaluate the patient reported outcomes (PROs) mean score changes from baseline to weeks 12 and 27 in global health status and quality of life scale between pembrolizumab + chemotherapy versus saline placebo + chemotherapy
    - To evaluate the PROs time to true deterioration (TTD) in the composite endpoint of cough, chest pain or dyspnea between pembrolizumab + chemotherapy versus saline placebo + chemotherapy
    - To evaluate the safety and tolerability of the combination of pembrolizumab + chemotherapy and saline placebo + chemotherapy
    -Comparar la tasa de respuestas objetivas (TRO) conforme a los criterios RECIST 1.1, según una RCIE, entre las combinaciones de pembrolizumab + quimioterapia y placebo salino + quimioterapia.
    -Comparar la DR entre las combinaciones de pembrolizumab + quimioterapia y placebo salino + quimioterapia.
    -Evaluar las variaciones entre el momento basal y las semanas 12 y 27 de las puntuaciones medias en resultados comunicados por los pacientes (RCP; estado de salud general y escala de calidad de vida) con pembrolizumab + quimioterapia y placebo salino + quimioterapia.
    -Evaluar el tiempo transcurrido hasta un deterioro real (TDR) del criterio de valoración combinado de tos, dolor torácico y disnea con pembrolizumab + quimioterapia y placebo salino + quimioterapia.
    -Evaluar la seguridad y la tolerabilidad de las combinaciones de pembrolizumab + quimioterapia y placebo salino + quimioterapia.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Merck will conduct Future Biomedical Research on DNA (Blood, serum/plasma and tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time
    Merck realizará investigaciones biomédicas futuras con las muestras obtenidas (Sangre, suero / plasma y tejido) para tal finalidad durante este ensayo clínico. Estas investigaciones tendrán por objeto el análisis de biomarcadores con el fin de abordar aspectos nuevos que no se describen en otras partes del protocolo (como parte del ensayo principal) y solo se llevarán a cabo en muestras de los pacientes que hayan otorgado el consentimiento correspondiente. El objetivo de la obtención de muestras para investigaciones biomédicas futuras es estudiar e identificar biomarcadores que proporcionen información a los científicos sobre las enfermedades y sus tratamientos. El objetivo último es utilizar tal información para desarrollar fármacos más seguros y eficaces o para garantizar que los sujetos reciban la dosis correcta del fármaco en el momento preciso.
    E.3Principal inclusion criteria
    1. Have histologically or cytologically confirmed diagnosis of Stage IV (AJCC Version 8 or current version as applicable) non-squamous NSCLC
    2. Have documentation of tumor activating EGFR mutation, specifically either DEL19 or L858R
    3. Have 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 (eg, 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 (eg, 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
    4. Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
    5. Have provided archival tumor tissue sample or newly obtained (no anti-neoplastic therapy since biopsy) core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archival tissue
    6. Be ≥18 years of age on the day of signing informed consent
    7. Have a life expectancy of at least 3 months
    8. Have an ECOG performance status of 0 or 1 within 7 days prior to the first dose of study treatment but before randomization
    9. A male participant must agree to use contraception as detailed in protocol Section 10.3 during the treatment period and for at least 120 days after the last dose of pembrolizumab and up to 180 days after last dose of chemotherapeutic agents
    10. A female participant is eligible to participate if she is not pregnant (see protocol Section 10.3), not breastfeeding, and at least one of the following conditions applies:
    a. Not a woman of childbearing potential (WOCBP) as defined in protocol Appendix 3
    OR
    b. A WOCBP who agrees to follow the contraceptive guidance in protocol Section 10.3 during the treatment period and for at least 120 days after the last dose of pembrolizumab and up to 180 days after the last dose of chemotherapeutic agents
    11. The participant provides written informed consent for the study
    12. Have adequate organ function as defined in the protocol. Specimens must be collected within 10 days prior to the start of trial treatment
    1. Diagnóstico con confirmación histológica o citológica de CPNM no epidermoide en estadio IV (versión 8 del AJCC o versión vigente según proceda).
    2. Documentación de mutación de EGFR activadora en el tumor, en concreto DEL19 o L858R.
    3. Progresión radiológica de la enfermedad determinada por el investigador conforme a los criterios RECIST 1.1 después del tratamiento con un ITC de EGFR:
    a) En los participantes tratados previamente con un ITC de EGFR de primera o segunda generación (p. ej., erlotinib, afatinib o gefitinib) tendrá que confirmarse la ausencia documentada de la mutación T790M en EGFR.
    b) Los participantes con una mutación T790M adquirida confirmada después del tratamiento con ITC de EGFR de primera o segunda generación (p. ej., erlotinib, afatinib o gefitinib) tendrán que haber tenido un fracaso del tratamiento con el ITC osimertinib antes de la inclusión.
    c) Los participantes que no hayan respondido previamente al tratamiento con el ITC osimertinib como primera línea serán elegibles con independencia del estado relativo a la mutación T790M en EGFR.
    4. Presencia de enfermedad medibleconforme a los criterios RECIST 1.1, según la evaluación del investigador/radiólogo del centro. Las lesiones ubicadas en una zona previamente irradiada se considerarán medibles siempre que se haya constatado progresión en dichas lesiones.
    5. Disponibilidad de una muestra de tejido tumoral de archivo o de una biopsia reciente (sin tratamiento antineoplásico desde la biopsia), con aguja gruesa o por escisión, de una lesión tumoral no irradiada previamente. Se prefiere el uso de bloques de tejido fijados en formol e incluidos en parafina (FFIP) a los cortes para microscopio. Se prefiere el uso de biopsias recientes al tejido de archivo.
    6. Edad mínima de 18 años el día de firma del consentimiento informado.
    7. Esperanza de vida mínima de tres meses.
    8. Estado funcional del ECOG de 0 o 1 en los 7 días previos a la primera dosis de tratamiento del estudio pero antes de la aleatorización.
    9. Los varones deben comprometerse a utilizar métodos anticonceptivos tal como se detalla en la sección 10.3 de este protocolo durante el período de tratamiento y hasta, como mínimo, 120 días después de la última dosis de pembrolizumab, así como hasta 180 días después de la última dosis de agentes quimioterápicos.
    10. Una mujer podrá participar en el estudio si no está embarazada (véase la sección 10.3 del protocolo), no está amamantando y cumple al menos una de las condiciones siguientes:
    a. No ser una mujer en edad fértil (MEF) según se define en el apéndice 3. del protocolo.
    O
    b. Es una MEF que se compromete a seguir las normas sobre métodos anticonceptivos que se detallan en el apéndice 10.3 del protocolo durante el período de tratamiento y hasta, como mínimo, 120 días después de la última dosis de pembrolizumab, así como hasta 180 días después de la última dosis de agentes quimioterápicos.
    11. El participante otorga su consentimiento informado por escrito para el estudio.
    12. Presencia de una función orgánica adecuada, que se define en el protocolo. Las muestras se obtendrán en los 10 días previos al comienzo del tratamiento del estudio
    E.4Principal exclusion criteria
    1. Has predominantly squamous cell histology NSCLC. Mixed tumors will be categorized by the predominant cell type; if small cell elements are present, the participant is ineligible.
    2. Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions is eligible.
    3. A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization (see Section 10.3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
    4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
    5. Has received prior systemic cytotoxic chemotherapy or investigational agent(s), excluding EGFR TKIs, for metastatic NSCLC.
    6. Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous
    system (CNS) disease.
    7. Has received a live vaccine within 30 days prior to the first dose of study treatment. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines are live attenuated vaccines and are not allowed.
    8. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
    9. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment.
    10. Has a known additional malignancy that is progressing or has required active treatment within the past 5 years.
    11. Has known active untreated CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, ie, without evidence of progression for at least 4 weeks by repeat imaging, clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
    12. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
    13. Has a known sensitivity to any component of cisplatin, carboplatin, or pemetrexed.
    14. Has an active autoimmune disease that has required systemic treatment in past 2 years. Replacement therapy is not considered a form of systemic treatment and is allowed.
    15. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
    16. Has an active infection requiring systemic therapy.
    17. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
    18. Has a known history of Hepatitis B or known active Hepatitis C virus infection.
    19. Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
    20. Has a history or current evidence of any condition, therapy, or laboratory abnormality. That might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the investigator.
    21. Has known psychiatric or substance abuse disorder that would interfere with cooperating with the requirements of the study.
    22. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of pembrolizumab and up to 180 days after the last dose of chemotherapeutic agents.
    1.CPNM de histología predominantemente epidermoide. Los tumores mixtos se clasificarán por el tipo de célula predominante; si hay elementos microcíticos presentes, el participante no será elegible.
    2.Presencia de ascitis o derrame pleural sintomático. Podrán participar sujetos que se encuentren clínicamente estables tras recibir tratamiento por estos procesos
    3.Mujer en edad fértil que dé positivo en una prueba de embarazo en orina realizada en las 72 horas previas a la aleatorización (véase la sección 10.3). Si el resultado de la prueba en orina es positivo o no puede confirmarse que es negativo, será necesario hacer una prueba de embarazo en suero.
    4.Tratamiento previo con un fármaco anti-PD-1, anti-PD-L1 o anti-PD-L2 o con un fármaco dirigido contra otro receptor de los linfocitos T estimulador o coinhibidor (como CTLA-4, OX-40 o CD137).
    5.Tratamiento previo con quimioterapia citotóxica sistémica o fármacos en investigación, excluidos los ITC de EGFR, para el CPNM metastásico.
    6.Recepción de radioterapia en las dos semanas previas al comienzo del tratamiento del estudio. Los participantes deberán haberse recuperado de toda la toxicidad relacionada con la radiación, no precisar corticoides y no haber sufrido una neumonitis por radiación. Se permite un lavado de una semana en caso de radioterapia paliativa (≤ 2 semanas de radioterapia) por enfermedad que no afecta al sistema nervioso central (SNC).
    7.Recepción de una vacuna de microorganismos vivos en los 30 días previos a la administración de la primera dosis del tratamiento del estudio. Las vacunas inyectables contra la gripe estacional contienen, por lo general, virus muertos y están permitidas; en cambio, las vacunas antigripales intranasales son vacunas de virus vivos atenuados y no están permitidas.
    8.Participación activa o pasada en un estudio de un fármaco en investigación o uso de un dispositivo en investigación en las cuatro semanas previas a la administración de la primera dosis del tratamiento del estudio.
    9.Diagnóstico de inmunodeficiencia o recepción de tratamiento sistémico crónico con esteroides (en dosis superiores a 10 mg diarios de un equivalente de prednisona) o cualquier otra forma de tratamiento inmunodepresor en los siete días previos a la primera dosis del tratamiento del estudio.
    10.Presencia de otra neoplasia maligna conocida que está en progresión o que ha necesitado tratamiento activo en los últimos 5 años.
    11.Presencia de metástasis activas no tratadas en el SNC y/o de meningitis carcinomatosa. Los participantes con metástasis cerebrales tratadas anteriormente podrán participar siempre que se encuentren radiológicamente estables, es decir, sin signos de progresión durante al menos cuatro semanas en estudios de imagen repetidos, clínicamente estables y sin necesidad de tratamiento con esteroides durante al menos 14 días antes de la primera dosis del tratamiento del estudio.
    12.Presencia de hipersensibilidad grave (grado ≥ 3) a pembrolizumab y/o a cualquiera de sus excipientes.
    13.Sensibilidad conocida a algún componente de cisplatino, carboplatino o pemetrexed.
    14.Presencia de una enfermedad autoinmunitaria activa que ha precisado tratamiento sistémico en los dos últimos años. El tratamiento de reposición no se considera una forma de tratamiento sistémico y se permitirá su uso.
    15.Antecedentes de neumonitis (no infecciosa) que precisó la administración de esteroides o presencia de una neumonitis activa.
    16.Presencia de una infección activa que precisa tratamiento sistémico.
    17.Antecedentes de infección por el virus de la inmunodeficiencia humana (VIH). No es necesario realizar pruebas de VIH a menos que lo exijan las autoridades sanitarias locales.
    18.Antecedentes de infección por el virus de la hepatitis B o infección activa por el virus de la hepatitis C
    19.Antecedentes de tuberculosis activa (Bacillus tuberculosis).
    20.Antecedentes o datos presentes de cualquier proceso, tratamiento o anomalía analítica que, en opinión del investigador, podría confundir los resultados del estudio, dificultar la participación durante la totalidad del estudio o motivar que la participación no sea lo más conveniente para el participante.
    21.Presencia de un trastorno psiquiátrico o por abuso de sustancias que pueda dificultar el cumplimiento de los requisitos del estudio.
    22.Embarazo, en período de lactancia o intención de concebir o engendrar un hijo durante el período previsto del estudio, desde la visita de selección hasta 120 días después de la última dosis de pembrolizumab y hasta 180 días después de la última dosis de los agentes quimioterápicos.
    E.5 End points
    E.5.1Primary end point(s)
    1) Progression-free Survival (PFS) per RECIST 1.1 assessed by BICR
    2) Overall survival (OS)
    1.Supervivencia sin progresión conforme a los criterios RECIST 1.1 verificada mediante una RCIE
    2.Supervivencia Global (SG)
    E.5.1.1Timepoint(s) of evaluation of this end point
    - 34 weeks after the last participant has been randomized (estimated approximately 372 PFS events across two treatment groups have been observed)
    - Final PFS analysis: 12 months after the last participant has been randomized AND at least 414 PFS events have been observed (estimated~32 months after the first participant randomized)
    - Final OS analysis: To be performed every 8 to 9 months until at least 30 months after the last participant has been randomized AND at least ~360 deaths have occurred for the final OS analysis (estimated ~59 months after the first participant randomized)
    - 34 semanas después de que el último participante haya sido incluido (se estiman aproximadamente 372 eventos de supervivencia libre de progresión entre ambos grupos de tratamiento)
    - Análisis final de la supervivencia sin progresión: al menos 12 meses después de que el último sujeto haya sido incluido Y después de que se hayan observado al menos 414 eventos de supervivencia libre de progresión (se calcula que esto sucederá ~32 meses después del primer sujeto incluido)
    - Análisis final de supervivencia global: el análisis final de supervivencia global se realizará cada 8 o 9 meses hasta al menos 30 meses después de que el último sujeto haya sido incluido Y hayan sucedido al menos ~360 fallecimientos (se calcula que sucederá ~59 meses después del primer sujeto incluido)
    E.5.2Secondary end point(s)
    1) Objective response rate (ORR) per RECIST 1.1 assessed by BICR
    1)Tasa de respuesta global (TRG) conforme a los criterios RECIST 1.1 verificada mediante una RCIE
    E.5.2.1Timepoint(s) of evaluation of this end point
    34 weeks after the first 270 participants have been randomized (estimated ~19 months after the first participant randomized)
    34 semanas después de que los primeros 270 pacientes hayan sido incluidos (se estima que esto sucederá ~19 meses después del primer paciente incluido en el ensayo)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Quality of life patient reported outcomes
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Crossover phase to pembrolizumab monotherary
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA51
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Brazil
    Canada
    China
    France
    Germany
    Hong Kong
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    Spain
    Sweden
    Taiwan
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 240
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 240
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 156
    F.4.2.2In the whole clinical trial 480
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    Ninguna
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-06-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-15
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2020 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA