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    Clinical Trial Results:
    Estudio abierto fase II de ultra-selección de pacientes mediante tecnología de genotipado de nueva generación para el esquema FOLFIRI + Panitumumab en pacientes con cáncer colorrectal estadio IV resistentes a irinotecán sin mutaciones detectables utilizando técnicas de alta sensibilidad para la detección de mutaciones en los genes KRAS, PIK3Ca, BRAF y NRAS

    Summary
    EudraCT number
    		 2012-001955-38
    Trial protocol
    		 ES  
    Global end of trial date
    30 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jul 2020
    First version publication date
    02 Jul 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TTD-12-03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01704703
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Grupo de Tratamiento de los Tumores Digestivos (TTD)
    Sponsor organisation address
    C/ Téllez Nº 30 posterior 1º oficina 4.2, Madrid, Spain, 28007
    Public contact
    TTD, Grupo de Tratamiento de los Tumores Digestivos (TTD), 0034 91 378 82 75, ttd@ttdgroup.org
    Scientific contact
    TTD, Grupo de Tratamiento de los Tumores Digestivos (TTD), 0034 91 378 82 75, ttd@ttdgroup.org
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To estimate the effect of the combination of panitumumab with FOLFIRI on objective response rate defined as complete and partial response according RECIST criteria 1.1, in patients with metastatic colorectal cancer (mCRC) refractory to irinotecan-based chemotherapy without any mutation associated to resistance on KRAS, PIK3Ca (exon 20), BRAF and NRAS genes detected with hypersensitive techniques (Digital PCR in Fluidigm nanofluidic dPCR plataform), named as molecular ultra-selected subgroup.
    Protection of trial subjects
    All patients have been treated according to GCP criteria. Patients were entitled to withdraw from the study at any time and for any reason without prejudice of their future medical care on the part of the doctor or the center. Doses of panitumumab and FOLFIRI could be reduced/delayed in case of adverse events (AEs) as per protocol. Any medication that patients needed for their correct clinical control (except prohibited therapies), according to investigator’s criteria were allowed.
    Background therapy
    		 None.
    Evidence for comparator
    		 Not applicable.
    Actual start date of recruitment
    13 Nov 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 72
    Worldwide total number of subjects
    72
    EEA total number of subjects
    72
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    38
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Ninety-six patients were recruited from November 2012 to July 2015, 24 of whom were screening failures. Thus, 72 patients were finally included in the study. This was a national study conducted in the Departments of Medical Oncology at 12 Spanish hospitals.

    Pre-assignment
    Screening details
    		 Patients aged ≥18 years with histologically confirmed colorectal adenocarcinoma, wild-type KRAS exon 2 (KRAS and NRAS exons 2/3/4 after protocol amendment on 25 July 2013), with ≥1 initially measurable and unresectable metastatic lesion, Karnofsky performance status ≥70% and adequate bone marrow, renal, hepatic and metabolic functions.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Arm title
    		 Panitumumab + FOLFIRI
    Arm description
    		 Patients were treated with panitumumab plus FOLFIRI.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Panitumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received panitumumab 6mg/kg over a 60-min intravenous infusion on day 1 in 2-weeks cycles.

    Investigational medicinal product name
    FOLFIRI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FOLFIRI was intravenously administered on day 1 in 2-week cycles according to the following schema: irinotecan 180mg/m2 over 30-90-min infusion, leucovorin 400 mg/m2 over 120-min infusion, 5-fluorouracil 400mg/m2 bolus, 5-fluorouracil 2400 mg/m2 over 46-h infusion.

    Number of subjects in period 1
    		Panitumumab + FOLFIRI
    Started
    72
    Completed
    71
    Not completed
    1
         Consent withdrawn by subject
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall period
    Reporting group description
    		 -

    Reporting group values
    		 Overall period Total
    Number of subjects
    		 72 72
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 38 38
        From 65-84 years
    		 34 34
    Age continuous
    Units: years
        median (full range (min-max))
    		 62 (38 to 83) -
    Gender categorical
    Units: Subjects
        Female
    		 21 21
        Male
    		 51 51
    Tumour stage at initial diagnosis
    Units: Subjects
        II
    		 4 4
        III
    		 16 16
        IV
    		 52 52
    Karnofsky performance status
    Units: Subjects
        70-80
    		 18 18
        90-100
    		 54 54
    Primary tumour site
    Units: Subjects
        Right colon
    		 10 10
        Left colon
    		 31 31
        Rectum
    		 31 31
    Primary tumour surgery
    Units: Subjects
        Yes
    		 53 53
        No
    		 19 19
    Number of metastatic sites
    Units: Subjects
        <3
    		 49 49
        ≥3
    		 23 23
    Previous chemotherapy for colorectal cancer: adjuvant
    Units: Subjects
        Yes
    		 26 26
        No
    		 46 46
    Previous chemotherapy for colorectal cancer: palliative
    Units: Subjects
        Yes
    		 72 72
        No
    		 0 0
    Subject analysis sets

    Subject analysis set title
    RAS wild-type by qPCR
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    RAS wild-type population by qPCR. This analysis set will be used for reporting efficacy results.

    Subject analysis sets values
    		 RAS wild-type by qPCR
    Number of subjects
    65
    Age categorical
    Units: Subjects
        Adults (18-64 years)
        From 65-84 years
    Age continuous
    Units: years
        median (full range (min-max))
    62 (38 to 83)
    Gender categorical
    Units: Subjects
        Female
    19
        Male
    46
    Tumour stage at initial diagnosis
    Units: Subjects
        II
    4
        III
    14
        IV
    47
    Karnofsky performance status
    Units: Subjects
        70-80
    14
        90-100
    51
    Primary tumour site
    Units: Subjects
        Right colon
    9
        Left colon
    31
        Rectum
    25
    Primary tumour surgery
    Units: Subjects
        Yes
    49
        No
    16
    Number of metastatic sites
    Units: Subjects
        <3
    45
        ≥3
    20
    Previous chemotherapy for colorectal cancer: adjuvant
    Units: Subjects
        Yes
    25
        No
    40
    Previous chemotherapy for colorectal cancer: palliative
    Units: Subjects
        Yes
    65
        No
    0

    End points

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    End points reporting groups
    Reporting group title
    Panitumumab + FOLFIRI
    Reporting group description
    		 Patients were treated with panitumumab plus FOLFIRI.

    Subject analysis set title
    RAS wild-type by qPCR
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    RAS wild-type population by qPCR. This analysis set will be used for reporting efficacy results.

    Primary: Tumor response in the RAS wild-type population by q-PCR (N=65): RAS (KRAS + NRAS)

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    End point title
    		 Tumor response in the RAS wild-type population by q-PCR (N=65): RAS (KRAS + NRAS) [1]
    End point description
    CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
    End point type
    Primary
    End point timeframe
    Tumor response at the end of the study
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses (Fisher exact) within a single analysis set (N=65) for Nanofluidic dPCR results: Cut-off 0%, p=0.843; Cut-off 0.1%, p=0.745; Cut-off 1%, p=0.624; Cut-off 2%, p= 0.362; Cut-off 3%, p= 0.850; Cut-off 4%, p= 0.850; Cut-off 5%, p= 0.549.
    End point values
    		 RAS wild-type by qPCR
    Number of subjects analysed
    65
    Units: percent
    number (not applicable)
        CR: Conventional qPCR, wild-type
    0.0
        CR: Conventional qPCR, mutation
    0.0
        CR: Nanofluidic dPCR, Cut-off 0%, wild-type
    0.0
        CR: Nanofluidic dPCR, Cut-off 0%, mutation
    0.0
        CR: Nanofluidic dPCR, Cut-off 0.1%, wild-type
    0.0
        CR: Nanofluidic dPCR, Cut-off 0.1%, mutation
    0.0
        CR: Nanofluidic dPCR, Cut-off 1%, wild-type
    0.0
        CR: Nanofluidic dPCR, Cut-off 1%, mutation
    0.0
        CR: Nanofluidic dPCR, Cut-off 2%, wild-type
    0.0
        CR: Nanofluidic dPCR, Cut-off 2%, mutation
    0.0
        CR: Nanofluidic dPCR, Cut-off 3%, wild-type
    0.0
        CR: Nanofluidic dPCR, Cut-off 3%, mutation
    0.0
        CR: Nanofluidic dPCR, Cut-off 4%, wild-type
    0.0
        CR: Nanofluidic dPCR, Cut-off 4%, mutation
    0.0
        CR: Nanofluidic dPCR, Cut-off 5%, wild-type
    0.0
        CR: Nanofluidic dPCR, Cut-off 5%, mutation
    0.0
        PR: Conventional qPCR, wild-type
    47.7
        PR: Conventional qPCR, mutation
    0.0
        PR: Nanofluidic dPCR, Cut-off 0%, wild-type
    49.0
        PR: Nanofluidic dPCR, Cut-off 0%, mutation
    43.8
        PR: Nanofluidic dPCR, Cut-off 0.1%, wild-type
    50.0
        PR: Nanofluidic dPCR, Cut-off 0.1%, mutation
    40.0
        PR: Nanofluidic dPCR, Cut-off 1%, wild-type
    50.0
        PR: Nanofluidic dPCR, Cut-off 1%, mutation
    33.3
        PR: Nanofluidic dPCR, Cut-off 2%, wild-type
    50.0
        PR: Nanofluidic dPCR, Cut-off 2%, mutation
    28.6
        PR: Nanofluidic dPCR, Cut-off 3%, wild-type
    48.3
        PR: Nanofluidic dPCR, Cut-off 3%, mutation
    40.0
        PR: Nanofluidic dPCR, Cut-off 4%, wild-type
    48.3
        PR: Nanofluidic dPCR, Cut-off 4%, mutation
    40.0
        PR: Nanofluidic dPCR, Cut-off 5%, wild-type
    48.4
        PR: Nanofluidic dPCR, Cut-off 5%, mutation
    33.3
        SD: Conventional qPCR, wild-type
    36.9
        SD: Conventional qPCR, mutation
    0.0
        SD: Nanofluidic dPCR, Cut-off 0%, wild-type
    36.7
        SD: Nanofluidic dPCR, Cut-off 0%, mutation
    37.5
        SD: Nanofluidic dPCR, Cut-off 0.1%, wild-type
    36.0
        SD: Nanofluidic dPCR, Cut-off 0.1%, mutation
    40.0
        SD: Nanofluidic dPCR, Cut-off 1%, wild-type
    35.7
        SD: Nanofluidic dPCR, Cut-off 1%, mutation
    44.4
        SD: Nanofluidic dPCR, Cut-off 2%, wild-type
    36.2
        SD: Nanofluidic dPCR, Cut-off 2%, mutation
    42.9
        SD: Nanofluidic dPCR, Cut-off 3%, wild-type
    36.7
        SD: Nanofluidic dPCR, Cut-off 3%, mutation
    40.0
        SD: Nanofluidic dPCR, Cut-off 4%, wild-type
    36.7
        SD: Nanofluidic dPCR, Cut-off 4%, mutation
    40.0
        SD: Nanofluidic dPCR, Cut-off 5%, wild-type
    37.1
        SD: Nanofluidic dPCR, Cut-off 5%, mutation
    33.3
        PD: Conventional qPCR, wild-type
    13.8
        PD: Conventional qPCR, mutation
    0.0
        PD: Nanofluidic dPCR, Cut-off 0%, wild-type
    12.2
        PD: Nanofluidic dPCR, Cut-off 0%, mutation
    18.8
        PD: Nanofluidic dPCR, Cut-off 0.1%, wild-type
    12.0
        PD: Nanofluidic dPCR, Cut-off 0.1%, mutation
    20.0
        PD: Nanofluidic dPCR, Cut-off 1%, wild-type
    12.5
        PD: Nanofluidic dPCR, Cut-off 1%, mutation
    22.2
        PD: Nanofluidic dPCR, Cut-off 2%, wild-type
    12.1
        PD: Nanofluidic dPCR, Cut-off 2%, mutation
    28.6
        PD: Nanofluidic dPCR, Cut-off 3%, wild-type
    13.3
        PD: Nanofluidic dPCR, Cut-off 3%, mutation
    20.0
        PD: Nanofluidic dPCR, Cut-off 4%, wild-type
    13.3
        PD: Nanofluidic dPCR, Cut-off 4%, mutation
    20.0
        PD: Nanofluidic dPCR, Cut-off 5%, wild-type
    12.9
        PD: Nanofluidic dPCR, Cut-off 5%, mutation
    33.3
    No statistical analyses for this end point

    Primary: Tumor response in the RAS wild-type population by q-PCR (N=65): RAS + BRAF

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    End point title
    		 Tumor response in the RAS wild-type population by q-PCR (N=65): RAS + BRAF [2]
    End point description
    CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
    End point type
    Primary
    End point timeframe
    Tumor response at the end of the study
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses (Fisher exact) within a single analysis set (N=65): Conventional qPCR, p= 0.067; Nanofluidic dPCR Cut-off 0%, p=0.773; Cut-off 0.1%, p=0.604; Cut-off 1%, p=0.241; Cut-off 2%, p= 0.130; Cut-off 3%, p= 0.164; Cut-off 4%, p= 0.164; Cut-off 5%, p= 0.076.
    End point values
    		 RAS wild-type by qPCR
    Number of subjects analysed
    65
    Units: percent
    number (not applicable)
        CR: Conventional qPCR, wild-type
    0.0
        CR: Conventional qPCR, mutation
    0.0
        CR: Nanofluidic dPCR, Cut-off 0%, wild-type
    0.0
        CR: Nanofluidic dPCR, Cut-off 0%, mutation
    0.0
        CR: Nanofluidic dPCR, Cut-off 0.1%, wild-type
    0.0
        CR: Nanofluidic dPCR, Cut-off 0.1%, mutation
    0.0
        CR: Nanofluidic dPCR, Cut-off 1%, wild-type
    0.0
        CR: Nanofluidic dPCR, Cut-off 1%, mutation
    0.0
        CR: Nanofluidic dPCR, Cut-off 2%, wild-type
    0.0
        CR: Nanofluidic dPCR, Cut-off 2%, mutation
    0.0
        CR: Nanofluidic dPCR, Cut-off 3%, wild-type
    0.0
        CR: Nanofluidic dPCR, Cut-off 3%, mutation
    0.0
        CR: Nanofluidic dPCR, Cut-off 4%, wild-type
    0.0
        CR: Nanofluidic dPCR, Cut-off 4%, mutation
    0.0
        CR: Nanofluidic dPCR, Cut-off 5%, wild-type
    0.0
        CR: Nanofluidic dPCR, Cut-off 5%, mutation
    0.0
        PR: Conventional qPCR, wild-type
    50.8
        PR: Conventional qPCR, mutation
    0.0
        PR: Nanofluidic dPCR, Cut-off 0%, wild-type
    51.1
        PR: Nanofluidic dPCR, Cut-off 0%, mutation
    38.9
        PR: Nanofluidic dPCR, Cut-off 0.1%, wild-type
    52.1
        PR: Nanofluidic dPCR, Cut-off 0.1%, mutation
    35.3
        PR: Nanofluidic dPCR, Cut-off 1%, wild-type
    52.8
        PR: Nanofluidic dPCR, Cut-off 1%, mutation
    25.0
        PR: Nanofluidic dPCR, Cut-off 2%, wild-type
    52.7
        PR: Nanofluidic dPCR, Cut-off 2%, mutation
    20.0
        PR: Nanofluidic dPCR, Cut-off 3%, wild-type
    51.8
        PR: Nanofluidic dPCR, Cut-off 3%, mutation
    22.2
        PR: Nanofluidic dPCR, Cut-off 4%, wild-type
    51.8
        PR: Nanofluidic dPCR, Cut-off 4%, mutation
    22.2
        PR: Nanofluidic dPCR, Cut-off 5%, wild-type
    51.7
        PR: Nanofluidic dPCR, Cut-off 5%, mutation
    14.3
        SD: Conventional qPCR, wild-type
    36.1
        SD: Conventional qPCR, mutation
    50.0
        SD: Nanofluidic dPCR, Cut-off 0%, wild-type
    34.0
        SD: Nanofluidic dPCR, Cut-off 0%, mutation
    44.4
        SD: Nanofluidic dPCR, Cut-off 0.1%, wild-type
    33.3
        SD: Nanofluidic dPCR, Cut-off 0.1%, mutation
    47.1
        SD: Nanofluidic dPCR, Cut-off 1%, wild-type
    34.0
        SD: Nanofluidic dPCR, Cut-off 1%, mutation
    50.0
        SD: Nanofluidic dPCR, Cut-off 2%, wild-type
    34.5
        SD: Nanofluidic dPCR, Cut-off 2%, mutation
    50.0
        SD: Nanofluidic dPCR, Cut-off 3%, wild-type
    35.7
        SD: Nanofluidic dPCR, Cut-off 3%, mutation
    44.4
        SD: Nanofluidic dPCR, Cut-off 4%, wild-type
    35.7
        SD: Nanofluidic dPCR, Cut-off 4%, mutation
    44.4
        SD: Nanofluidic dPCR, Cut-off 5%, wild-type
    36.2
        SD: Nanofluidic dPCR, Cut-off 5%, mutation
    42.9
        PD: Conventional qPCR, wild-type
    11.5
        PD: Conventional qPCR, mutation
    50.0
        PD: Nanofluidic dPCR, Cut-off 0%, wild-type
    12.8
        PD: Nanofluidic dPCR, Cut-off 0%, mutation
    16.7
        PD: Nanofluidic dPCR, Cut-off 0.1%, wild-type
    12.5
        PD: Nanofluidic dPCR, Cut-off 0.1%, mutation
    17.6
        PD: Nanofluidic dPCR, Cut-off 1%, wild-type
    11.3
        PD: Nanofluidic dPCR, Cut-off 1%, mutation
    25.0
        PD: Nanofluidic dPCR, Cut-off 2%, wild-type
    10.9
        PD: Nanofluidic dPCR, Cut-off 2%, mutation
    30.0
        PD: Nanofluidic dPCR, Cut-off 3%, wild-type
    10.7
        PD: Nanofluidic dPCR, Cut-off 3%, mutation
    33.3
        PD: Nanofluidic dPCR, Cut-off 4%, wild-type
    10.7
        PD: Nanofluidic dPCR, Cut-off 4%, mutation
    33.3
        PD: Nanofluidic dPCR, Cut-off 5%, wild-type
    10.3
        PD: Nanofluidic dPCR, Cut-off 5%, mutation
    42.9
    No statistical analyses for this end point

    Secondary: KRAS mutation distribution

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    End point title
    		 KRAS mutation distribution
    End point description
    End point type
    Secondary
    End point timeframe
    Mutations calculated in the population of patients included in the study
    End point values
    		 Panitumumab + FOLFIRI
    Number of subjects analysed
    72
    Units: Subjects
        KRAS: Conventional qPCR, wild-type
    67
        KRAS: Conventional qPCR, mutation
    5
        KRAS: Nanofluidic dPCR, wild-type
    52
        KRAS: Nanofluidic dPCR, mutation
    20
        Exon 2-codon 12–13: Conventional qPCR, wild-type
    71
        Exon 2-codon 12–13: Conventional qPCR, mutation
    1
        Exon 2-codon 12–13: Nanofluidic dPCR, wild-type
    62
        Exon 2-codon 12–13: Nanofluidic dPCR, mutation
    10
        Exon 3-codon 58–61: Conventional qPCR, wild-type
    70
        Exon 3-codon 58–61: Conventional qPCR, mutatiion
    2
        Exon 3-codon 58–61: Nanofluidic dPCR, wild-type
    65
        Exon 3-codon 58–61: Nanofluidic dPCR, mutation
    7
        Exon 4-codon 117: Conventional qPCR, wild-type
    72
        Exon 4-codon 117: Conventional qPCR, mutation
    0
        Exon 4-codon 117: Nanofluidic dPCR, wild-type
    71
        Exon 4-codon 117: Nanofluidic dPCR, mutation
    1
        Exon 4-codon 146: Conventional qPCR, wild-type
    70
        Exon 4-codon 146: Conventional qPCR, mutation
    2
        Exon 4-codon 146: Nanofluidic dPCR, wild-type
    69
        Exon 4-codon 146: Nanofluidic dPCR, mutation
    3
    No statistical analyses for this end point

    Secondary: NRAS mutation distribution

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    End point title
    		 NRAS mutation distribution
    End point description
    End point type
    Secondary
    End point timeframe
    Mutations calculated in the population of patients included in the study
    End point values
    		 Panitumumab + FOLFIRI
    Number of subjects analysed
    72
    Units: Subjects
        NRAS: Conventional qPCR, wild-type
    70
        NRAS: Conventional qPCR, mutation
    2
        NRAS: Nanofluidic dPCR, wild-type
    67
        NRAS: Nanofluidic dPCR, mutation
    5
        Exon 2-codon 12–13: Conventional qPCR, wild-type
    71
        Exon 2-codon 12–13: Conventional qPCR, mutation
    1
        Exon 2-codon 12–13: Nanofluidic dPCR, wild-type
    69
        Exon 2-codon 12–13: Nanofluidic dPCR, mutation
    3
        Exon 3-codon 59–61: Conventional qPCR, wild-type
    71
        Exon 3-codon 59–61: Conventional qPCR, mutation
    1
        Exon 3-codon 59–61: Nanofluidic dPCR, wild-type
    69
        Exon 3-codon 59–61: Nanofluidic dPCR, mutation
    3
        Exon 4-codon 117: Conventional qPCR, wild-type
    72
        Exon 4-codon 117: Conventional qPCR, mutation
    0
        Exon 4-codon 117: Nanofluidic dPCR, wild-type
    72
        Exon 4-codon 117: Nanofluidic dPCR, mutation
    0
        Exon 4-codon 146: Conventional qPCR, wild-type
    72
        Exon 4-codon 146: Conventional qPCR, mutation
    0
        Exon 4-codon 146: Nanofluidic dPCR, wild-type
    71
        Exon 4-codon 146: Nanofluidic dPCR, mutation
    1
    No statistical analyses for this end point

    Secondary: BRAF mutation distribution

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    End point title
    		 BRAF mutation distribution
    End point description
    BRAF mutational status according to Exon 15-codon 600.
    End point type
    Secondary
    End point timeframe
    Mutations calculated in the population of patients included in the study
    End point values
    		 Panitumumab + FOLFIRI
    Number of subjects analysed
    72
    Units: Subjects
        BRAF: Conventional qPCR, wild-type
    68
        BRAF: Conventional qPCR, mutation
    4
        BRAF: Nanofluidic dPCR, wild-type
    68
        BRAF: Nanofluidic dPCR, mutation
    4
    No statistical analyses for this end point

    Secondary: PIK3CA mutation distribution

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    End point title
    		 PIK3CA mutation distribution
    End point description
    PIK3CA mutational status according to Exon 20-codon 1043–1047
    End point type
    Secondary
    End point timeframe
    Mutations calculated in the population of patients included in the study
    End point values
    		 Panitumumab + FOLFIRI
    Number of subjects analysed
    72
    Units: Subjects
        PIK3CA: Conventional qPCR, wild-type
    71
        PIK3CA: Conventional qPCR, mutation
    1
        PIK3CA: Nanofluidic dPCR, wild-type
    70
        PIK3CA: Nanofluidic dPCR, mutation
    2
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS, months) in the RAS wild-type population: RAS (KRAS/NRAS)

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    End point title
    		 Progression-free survival (PFS, months) in the RAS wild-type population: RAS (KRAS/NRAS)
    End point description
    Statistical analysis (Log-rank test) was performed within a single analysis set (N=65). Find below the HR (95% CIs), p-value for each Nanofluidic dPCR Cut-off: Cut-off 0%, 0.9 (0.5–1.6), p=0.741; Cut-off 0.1%, 0.9 (0.5–1.7), p=0.818; Cut-off 1%, 0.8 (0.4–1.8), p=0.657; Cut-off 2%, 1.3 (0.6–2.9), p= 0.513; Cut-off 3%, 1.0 (0.4–2.5), p= 0.996; Cut-off 4%, 1.0 (0.4–2.5), p= 0.996; Cut-off 5%, 3.3 (1.0–11.0), p= 0.048.
    End point type
    Secondary
    End point timeframe
    Progression-free survival (PFS) was measured from study inclusion to progression or death.
    End point values
    		 RAS wild-type by qPCR
    Number of subjects analysed
    65 [3]
    Units: median
    number (not applicable)
        Conventional qPCR, wild-type
    7.4
        Nanofluidic dPCR, Cut-off 0%, wild-type
    7.2
        Nanofluidic dPCR, Cut-off 0%, mutation
    7.4
        Nanofluidic dPCR, Cut-off 0.1%, wild-type
    7.6
        Nanofluidic dPCR, Cut-off 0.1%, mutation
    7.4
        Nanofluidic dPCR, Cut-off 1%, wild-type
    7.6
        Nanofluidic dPCR, Cut-off 1%, mutation
    7.4
        Nanofluidic dPCR, Cut-off 2%, wild-type
    7.6
        Nanofluidic dPCR, Cut-off 2%, mutation
    6.7
        Nanofluidic dPCR, Cut-off 3%, wild-type
    7.6
        Nanofluidic dPCR, Cut-off 3%, mutation
    7.4
        Nanofluidic dPCR, Cut-off 4%, wild-type
    7.6
        Nanofluidic dPCR, Cut-off 4%, mutation
    7.4
        Nanofluidic dPCR, Cut-off 5%, wild-type
    7.6
        Nanofluidic dPCR, Cut-off 5%, mutation
    4.0
    Notes
    [3] - dPCR Cut-off, n (wt/mut): 0%, 49/16; 0.1%, 50/15; 1%, 56/9; 2%, 58/7; 3%, 60/5; 4% 60/5; 5% 62/3
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS, months) in the RAS wild-type population: RAS/BRAF

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    End point title
    		 Progression-free survival (PFS, months) in the RAS wild-type population: RAS/BRAF
    End point description
    Statistical analysis (Log-rank test) was performed within a single analysis set (N=65). Find below the HR (95% CIs), p-value: Conventional qPCR, 6.0 (2.0–17.7), p= 0.001; Nanofluidic dPCR Cut-off 0%, 1.0 (0.6–1.8), p=0.965; Nanofluidic dPCR Cut-off 0.1%, 1.0 (0.6–1.9), p=0.879; Nanofluidic dPCR Cut-off 1%, 1.1 (0.6–2.2), p=0.732; Nanofluidic dPCR Cut-off 2%, 1.7 (0.9–3.4), p= 0.123; Nanofluidic dPCR Cut-off 3%, 1.7 (0.8–3.4), p= 0.160; Nanofluidic dPCR Cut-off 4%, 1.7 (0.8–3.4), p= 0.160; Nanofluidic dPCR Cut-off 5%, 5 (2.1–11.7), p<0.001.
    End point type
    Secondary
    End point timeframe
    Progression-free survival (PFS) was measured from study inclusion to progression or death
    End point values
    		 RAS wild-type by qPCR
    Number of subjects analysed
    65 [4]
    Units: median
    number (not applicable)
        Conventional qPCR, wild-type
    7.6
        Conventional qPCR, mutation
    1.8
        Nanofluidic dPCR, Cut-off 0%, wild-type
    7.6
        Nanofluidic dPCR, Cut-off 0%, mutation
    6.7
        Nanofluidic dPCR, Cut-off 0.1%, wild-type
    7.6
        Nanofluidic dPCR, Cut-off 0.1%, mutation
    6.7
        Nanofluidic dPCR, Cut-off 1%, wild-type
    7.6
        Nanofluidic dPCR, Cut-off 1%, mutation
    5.5
        Nanofluidic dPCR, Cut-off 2%, wild-type
    8.1
        Nanofluidic dPCR, Cut-off 2%, mutation
    4.6
        Nanofluidic dPCR, Cut-off 3%, wild-type
    8.1
        Nanofluidic dPCR, Cut-off 3%, mutation
    4.6
        Nanofluidic dPCR, Cut-off 4%, wild-type
    8.1
        Nanofluidic dPCR, Cut-off 4%, mutation
    4.6
        Nanofluidic dPCR, Cut-off 5%, wild-type
    8.8
        Nanofluidic dPCR, Cut-off 5%, mutation
    4.0
    Notes
    [4] - q/dPCR Cut-off, n(wt/mut): 61/4; 0%, 47/18; 0.1%, 48/17; 1%, 53/12; 2%, 55/10; 3&4%, 56/9; 5% 58/7
    No statistical analyses for this end point

    Secondary: Overall survival (OS, months) in the RAS wild-type population: RAS (KRAS/NRAS)

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    End point title
    		 Overall survival (OS, months) in the RAS wild-type population: RAS (KRAS/NRAS)
    End point description
    Statistical analysis (Log-rank test) was performed within a single analysis set (N=65). Find below the HR (95% CIs), p-value for each Nanofluidic dPCR Cut-off: Cut-off 0%, 0.6 (0.3–1.2), p=0.142; Cut-off 0.1%, 0.7 (0.3–1.4), p=0.294; Cut-off 1%, 0.6 (0.3–1.7), p=0.367; Cut-off 2%, 0.8 (0.3–2.1), p= 0.689; Cut-off 3%, 0.8 (0.3–2.2), p= 0.620; Cut-off 4%, 0.8 (0.3–2.2), p= 0.620; Cut-off 5%, 1.5 (0.4–4.7), p= 0.534.
    End point type
    Secondary
    End point timeframe
    Overall survival (OS) was measured from enrolment to death
    End point values
    		 RAS wild-type by qPCR
    Number of subjects analysed
    65 [5]
    Units: median
    number (not applicable)
        Conventional qPCR, wild-type
    13.9
        Nanofluidic dPCR, Cut-off 0%, wild-type
    11.7
        Nanofluidic dPCR, Cut-off 0%, mutation
    17.4
        Nanofluidic dPCR, Cut-off 0.1%, wild-type
    11.8
        Nanofluidic dPCR, Cut-off 0.1%, mutation
    16.1
        Nanofluidic dPCR, Cut-off 1%, wild-type
    12.5
        Nanofluidic dPCR, Cut-off 1%, mutation
    16.1
        Nanofluidic dPCR, Cut-off 2%, wild-type
    13.9
        Nanofluidic dPCR, Cut-off 2%, mutation
    16.1
        Nanofluidic dPCR, Cut-off 3%, wild-type
    13.9
        Nanofluidic dPCR, Cut-off 3%, mutation
    16.1
        Nanofluidic dPCR, Cut-off 4%, wild-type
    13.9
        Nanofluidic dPCR, Cut-off 4%, mutation
    16.1
        Nanofluidic dPCR, Cut-off 5%, wild-type
    13.9
        Nanofluidic dPCR, Cut-off 5%, mutation
    16.1
    Notes
    [5] - dPCR Cut-off, n (wt/mut): 0%, 49/16; 0.1%, 50/15; 1%, 56/9; 2%, 58/7; 3%, 60/5; 4% 60/5; 5% 62/3
    No statistical analyses for this end point

    Secondary: Overall survival (OS, months) in the RAS wild-type population: RAS/BRAF

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    End point title
    		 Overall survival (OS, months) in the RAS wild-type population: RAS/BRAF
    End point description
    Statistical analysis (Log-rank test) was performed within a single analysis set (N=65). Find below the HR (95% CIs), p-value: Conventional qPCR, 8.1 (2.6–25.5), p< 0.001; Nanofluidic dPCR Cut-off 0%, 0.7 (0.4–1.4), p=0.349; Nanofluidic dPCR Cut-off 0.1%, 0.8 (0.4–1.7), p=0.619; Nanofluidic dPCR Cut-off 1%, 1.0 (0.5–2.2), p=0.951; Nanofluidic dPCR Cut-off 2%, 1.3 (0.6–2.8), p= 0.528; Nanofluidic dPCR Cut-off 3%, 1.5 (0.7–3.3), p= 0.290; Nanofluidic dPCR Cut-off 4%, 1.5 (0.7–3.3), p= 0.290; Nanofluidic dPCR Cut-off 5%, 2.8 (1.3–6.4), p= 0.012.
    End point type
    Secondary
    End point timeframe
    Overall survival (OS) was measured from enrolment to death
    End point values
    		 RAS wild-type by qPCR
    Number of subjects analysed
    65 [6]
    Units: median
    number (not applicable)
        Conventional qPCR, wild-type
    16.1
        Conventional qPCR, mutation
    6.2
        Nanofluidic dPCR, Cut-off 0%, wild-type
    11.8
        Nanofluidic dPCR, Cut-off 0%, mutation
    16.1
        Nanofluidic dPCR, Cut-off 0.1%, wild-type
    12.5
        Nanofluidic dPCR, Cut-off 0.1%, mutation
    16.1
        Nanofluidic dPCR, Cut-off 1%, wild-type
    13.9
        Nanofluidic dPCR, Cut-off 1%, mutation
    13.7
        Nanofluidic dPCR, Cut-off 2%, wild-type
    15.6
        Nanofluidic dPCR, Cut-off 2%, mutation
    8.4
        Nanofluidic dPCR, Cut-off 3%, wild-type
    16.2
        Nanofluidic dPCR, Cut-off 3%, mutation
    8.4
        Nanofluidic dPCR, Cut-off 4%, wild-type
    16.2
        Nanofluidic dPCR, Cut-off 4%, mutation
    8.4
        Nanofluidic dPCR, Cut-off 5%, wild-type
    16.2
        Nanofluidic dPCR, Cut-off 5%, mutation
    7.3
    Notes
    [6] - q/dPCR Cut-off, n(wt/mut): 61/4; 0%, 47/18; 0.1%, 48/17; 1%, 53/12; 2%, 55/10; 3&4%, 56/9; 5% 58/7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Toxicity was assessed at every study visit according to the Common Toxicity Criteria for Adverse Events version 4.0
    Adverse event reporting additional description
    If a patient had more than one event classified with the same preferred term, then the worst case was used
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 -

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 72 (38.89%)
         number of deaths (all causes)
    52
         number of deaths resulting from adverse events
    4
    Vascular disorders
    Ictus minor
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Confusional syndrome
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar pain
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Febrile syndrome
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Intestinal subocclusion
         subjects affected / exposed
    5 / 72 (6.94%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 1
    Gastrointestinal toxicity
         subjects affected / exposed
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 72 (5.56%)
         occurrences causally related to treatment / all
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    Digestive toxicity
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Mucositis
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary thromboembolism
         subjects affected / exposed
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Bilateral pneumonia
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Bronchoaspiration
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Obstructive jaundice
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Urinary sepsis
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle deterioration
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Urine infection
         subjects affected / exposed
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    E.Coli sepsis
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Catheter infection
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory infection
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    72 / 72 (100.00%)
    Vascular disorders
    Epistaxis
         subjects affected / exposed
    4 / 72 (5.56%)
         occurrences all number
    4
    Thrombosis
         subjects affected / exposed
    4 / 72 (5.56%)
         occurrences all number
    5
    General disorders and administration site conditions
    Xerosis
         subjects affected / exposed
    8 / 72 (11.11%)
         occurrences all number
    11
    Asthenia
         subjects affected / exposed
    47 / 72 (65.28%)
         occurrences all number
    129
    Fever
         subjects affected / exposed
    8 / 72 (11.11%)
         occurrences all number
    10
    Blood and lymphatic system disorders
    Edema of lower extremities
         subjects affected / exposed
    4 / 72 (5.56%)
         occurrences all number
    4
    Anaemia
         subjects affected / exposed
    17 / 72 (23.61%)
         occurrences all number
    32
    Leukopenia
         subjects affected / exposed
    7 / 72 (9.72%)
         occurrences all number
    22
    Neutropenia
         subjects affected / exposed
    27 / 72 (37.50%)
         occurrences all number
    64
    Thrombocytopenia
         subjects affected / exposed
    5 / 72 (6.94%)
         occurrences all number
    13
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    15 / 72 (20.83%)
         occurrences all number
    23
    Diarrhoea
         subjects affected / exposed
    53 / 72 (73.61%)
         occurrences all number
    165
    Dysphagia
         subjects affected / exposed
    5 / 72 (6.94%)
         occurrences all number
    6
    Stomatitis
         subjects affected / exposed
    4 / 72 (5.56%)
         occurrences all number
    8
    Constipation
         subjects affected / exposed
    17 / 72 (23.61%)
         occurrences all number
    24
    Mucositis
         subjects affected / exposed
    30 / 72 (41.67%)
         occurrences all number
    114
    Nausea
         subjects affected / exposed
    30 / 72 (41.67%)
         occurrences all number
    59
    Intestinal subocclusion
         subjects affected / exposed
    5 / 72 (6.94%)
         occurrences all number
    9
    Vomiting
         subjects affected / exposed
    18 / 72 (25.00%)
         occurrences all number
    28
    Xerostomia
         subjects affected / exposed
    8 / 72 (11.11%)
         occurrences all number
    14
    Respiratory, thoracic and mediastinal disorders
    Tracheal dryness
         subjects affected / exposed
    7 / 72 (9.72%)
         occurrences all number
    14
    Common cold
         subjects affected / exposed
    5 / 72 (6.94%)
         occurrences all number
    5
    Dyspnoea
         subjects affected / exposed
    8 / 72 (11.11%)
         occurrences all number
    12
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    12 / 72 (16.67%)
         occurrences all number
    33
    Alopecia
         subjects affected / exposed
    9 / 72 (12.50%)
         occurrences all number
    12
    Cutaneous
         subjects affected / exposed
    26 / 72 (36.11%)
         occurrences all number
    53
    Dermatitis
         subjects affected / exposed
    6 / 72 (8.33%)
         occurrences all number
    16
    Erythema
         subjects affected / exposed
    7 / 72 (9.72%)
         occurrences all number
    8
    Finger fissure
         subjects affected / exposed
    11 / 72 (15.28%)
         occurrences all number
    16
    Skin hyperpigmentation
         subjects affected / exposed
    5 / 72 (6.94%)
         occurrences all number
    5
    Hypertrichosis
         subjects affected / exposed
    6 / 72 (8.33%)
         occurrences all number
    9
    Paronychia
         subjects affected / exposed
    16 / 72 (22.22%)
         occurrences all number
    27
    Pruritus
         subjects affected / exposed
    7 / 72 (9.72%)
         occurrences all number
    12
    Rash
         subjects affected / exposed
    43 / 72 (59.72%)
         occurrences all number
    141
    Hand and foot syndrome
         subjects affected / exposed
    5 / 72 (6.94%)
         occurrences all number
    7
    Cutaneous xerosis
         subjects affected / exposed
    7 / 72 (9.72%)
         occurrences all number
    8
    Periungual fissure
         subjects affected / exposed
    4 / 72 (5.56%)
         occurrences all number
    6
    Onycholysis
         subjects affected / exposed
    4 / 72 (5.56%)
         occurrences all number
    4
    Trichomalacia
         subjects affected / exposed
    4 / 72 (5.56%)
         occurrences all number
    8
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    6 / 72 (8.33%)
         occurrences all number
    9
    Musculoskeletal and connective tissue disorders
    Lumbar pain
         subjects affected / exposed
    8 / 72 (11.11%)
         occurrences all number
    10
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    20 / 72 (27.78%)
         occurrences all number
    26
    Urine infection
         subjects affected / exposed
    6 / 72 (8.33%)
         occurrences all number
    8
    Respiratory infection
         subjects affected / exposed
    4 / 72 (5.56%)
         occurrences all number
    5
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    20 / 72 (27.78%)
         occurrences all number
    33
    Iron deficiency
         subjects affected / exposed
    5 / 72 (6.94%)
         occurrences all number
    8
    Hypomagnesaemia
         subjects affected / exposed
    18 / 72 (25.00%)
         occurrences all number
    42

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jan 2013
    Through this amendment the following changes were implemented: 1- Incorporation of a new exploratory objective (identification of mutation through high-sensitivity methodology in biologic fluids, i.e. blood); 2- Protocol changes in order to enhance text comprehension; 3- Update of the principal investigators and study sites.
    21 Jun 2013
    The approval of this protocol amendment was on 25th July 2013. Through this amendment the following changes were implemented: 1- Modification of a selection criteria, extension of the mutation panel for KRAS and NRAS genes (initially patients may have had no mutation in KRAS exons 2 and 3, and after protocol amendment may have had no mutation in KRAS exons 2, 3 and 4 and NRAS exons 2, 3 and 4) and review of the sample size justification; 2- Protocol changes in order to enhance text comprehension; 3- Update of the principal investigators and study sites.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The impossibility to assess the role of PIK3CA status due to the low number of mutations. In addition, initially enrolled patients may have had mutation in KRAS 3/4 exons and NRAS 2/3/4 exons.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30840064
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