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    Clinical Trial Results:
    Phase 2 Study of Talimogene Laherparepvec in Combination With Pembrolizumab in Subjects With Unresectable/Metastatic Stage IIIB-IVM1d Melanoma Who Have Progressed on Prior Anti-PD-1 Based Therapy

    Summary
    EudraCT number
    		 2019-001906-61
    Trial protocol
    		 NL   GR   PL   ES   FR   GB   DE   IT  
    Global end of trial date
    26 Feb 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Dec 2024
    First version publication date
    28 Dec 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    20180115
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04068181
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, United States, CA
    Public contact
    Study Director, Amgen Inc., +1 8665726436, medinfo@amgen.com
    Scientific contact
    Study Director, Amgen Inc., +1 8665726436, medinfo@amgen.com
    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
    26 Feb 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Feb 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the efficacy of talimogene laherparepvec in combination with pembrolizumab as assessed by objective response rate (ORR) in participants with unresectable/metastatic stage IIIB-IVM1d melanoma who have progressed on prior anti-programmed cell death-1 (anti-PD-1) therapy.
    Protection of trial subjects
    I agree to comply with the International Council for Harmonisation Tripartite Guideline on Good Clinical Practice, Declaration of Helsinki, and applicable national or regional regulations/guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Jan 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 36 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Greece: 12
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    United States: 14
    Country: Number of subjects enrolled
    Australia: 13
    Worldwide total number of subjects
    72
    EEA total number of subjects
    44
    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)
    34
    From 65 to 84 years
    35
    85 years and over
    3

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 72 participants were enrolled at 28 centers in Australia, Canada, France, Germany, Greece, Italy, the Netherlands, Poland, Spain and the United States from 22 January 2020 to 26 February 2024.

    Pre-assignment
    Screening details
    		 Participants must have received prior anti-programmed cell death protein (anti-PD-1) therapy for at least 2 to 3 consecutive cycles within an 8-week period and have disease progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

    Pre-assignment period milestones
    Number of subjects started
    		 72
    Number of subjects completed
    		 71

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Withdrawal of consent from study: 1
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance
    Arm description
    		 Included participants who received anti-PD-1 therapy in the locally recurrent/metastatic setting and experienced a best overall response of disease progression or stable disease prior to confirmed disease progression. Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 plaque-forming units (PFU)/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an intravenous (IV) infusion every 3 weeks for up to 35 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    MK-3475
    Other name
    Keytruda
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV infusion.

    Investigational medicinal product name
    Talimogene laherparepvec
    Investigational medicinal product code
    AMG 678
    Other name
    IMLYGIC
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    Intralesional injection into injectable cutaneous, subcutaneous and nodal legions.

    Arm title
    		 Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance
    Arm description
    		 Included participants who received anti-PD-1 therapy in the locally recurrent/metastatic setting and experienced confirmed disease progression following a complete or partial response on anti-PD-1 therapy. Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 PFU/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an IV infusion every 3 weeks for up to 35 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    MK-3475
    Other name
    Keytruda
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV infusion.

    Investigational medicinal product name
    Talimogene laherparepvec
    Investigational medicinal product code
    AMG 678
    Other name
    IMLYGIC
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    Intralesional injection into injectable cutaneous, subcutaneous and nodal legions.

    Arm title
    		 Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months
    Arm description
    		 Included participants who received anti-PD-1 therapy in the adjuvant setting and experienced confirmed disease progression following a disease-free interval of < 6 months after starting the adjuvant anti-PD-1 therapy. Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 PFU/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an IV infusion every 3 weeks for up to 35 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    MK-3475
    Other name
    Keytruda
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV infusion.

    Investigational medicinal product name
    Talimogene laherparepvec
    Investigational medicinal product code
    AMG 678
    Other name
    IMLYGIC
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    Intralesional injection into injectable cutaneous, subcutaneous and nodal legions.

    Arm title
    		 Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Arm description
    		 Included participants who received anti PD-1 therapy in the adjuvant setting and experienced confirmed disease progression following a disease-free interval of ≥ 6 months after starting the adjuvant PD-1 inhibitor. Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 PFU/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an IV infusion every 3 weeks for up to 35 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    MK-3475
    Other name
    Keytruda
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV infusion.

    Investigational medicinal product name
    Talimogene laherparepvec
    Investigational medicinal product code
    AMG 678
    Other name
    IMLYGIC
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    Intralesional injection into injectable cutaneous, subcutaneous and nodal legions.

    Number of subjects in period 1 [1]
    		Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Started
    26
    15
    15
    15
    Completed
    6
    3
    11
    8
    Not completed
    20
    12
    4
    7
         Adverse event, non-fatal
    17
    12
    4
    7
         Withdrawal of consent from study
    2
    -
    -
    -
         Lost to follow-up
    1
    -
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Inclusive of participants that received talimogene laherparepvec and pembrolizumab only.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance
    Reporting group description
    		 Included participants who received anti-PD-1 therapy in the locally recurrent/metastatic setting and experienced a best overall response of disease progression or stable disease prior to confirmed disease progression. Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 plaque-forming units (PFU)/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an intravenous (IV) infusion every 3 weeks for up to 35 cycles.

    Reporting group title
    Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance
    Reporting group description
    		 Included participants who received anti-PD-1 therapy in the locally recurrent/metastatic setting and experienced confirmed disease progression following a complete or partial response on anti-PD-1 therapy. Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 PFU/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an IV infusion every 3 weeks for up to 35 cycles.

    Reporting group title
    Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months
    Reporting group description
    		 Included participants who received anti-PD-1 therapy in the adjuvant setting and experienced confirmed disease progression following a disease-free interval of < 6 months after starting the adjuvant anti-PD-1 therapy. Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 PFU/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an IV infusion every 3 weeks for up to 35 cycles.

    Reporting group title
    Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Reporting group description
    		 Included participants who received anti PD-1 therapy in the adjuvant setting and experienced confirmed disease progression following a disease-free interval of ≥ 6 months after starting the adjuvant PD-1 inhibitor. Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 PFU/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an IV infusion every 3 weeks for up to 35 cycles.

    Reporting group values
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months Total
    Number of subjects
    		 26 15 15 15 71
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.2 ( 14.6 ) 65.5 ( 13.2 ) 59.4 ( 13.0 ) 63.5 ( 10.3 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 8 8 5 2 23
        Male
    		 18 7 10 13 48
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0 0
        Not Hispanic or Latino
    		 25 14 14 15 68
        Unknown or Not Reported
    		 1 1 1 0 3
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0
        Asian
    		 0 0 0 0 0
        Black (or African American)
    		 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        White
    		 25 14 14 15 68
        Other
    		 1 1 1 0 3

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance
    Reporting group description
    		 Included participants who received anti-PD-1 therapy in the locally recurrent/metastatic setting and experienced a best overall response of disease progression or stable disease prior to confirmed disease progression. Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 plaque-forming units (PFU)/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an intravenous (IV) infusion every 3 weeks for up to 35 cycles.

    Reporting group title
    Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance
    Reporting group description
    		 Included participants who received anti-PD-1 therapy in the locally recurrent/metastatic setting and experienced confirmed disease progression following a complete or partial response on anti-PD-1 therapy. Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 PFU/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an IV infusion every 3 weeks for up to 35 cycles.

    Reporting group title
    Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months
    Reporting group description
    		 Included participants who received anti-PD-1 therapy in the adjuvant setting and experienced confirmed disease progression following a disease-free interval of < 6 months after starting the adjuvant anti-PD-1 therapy. Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 PFU/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an IV infusion every 3 weeks for up to 35 cycles.

    Reporting group title
    Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Reporting group description
    		 Included participants who received anti PD-1 therapy in the adjuvant setting and experienced confirmed disease progression following a disease-free interval of ≥ 6 months after starting the adjuvant PD-1 inhibitor. Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 PFU/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an IV infusion every 3 weeks for up to 35 cycles.

    Primary: ORR per modified RECIST v1.1

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    End point title
    		 ORR per modified RECIST v1.1 [1]
    End point description
    ORR was defined as the incidence of a best overall response (BOR) of complete response (CR) or partial response (PR) per modified RECIST v1.1: - CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to < 10 mm. All lymph nodes must have been non-pathological in size (< 10mm short axis). - PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. - Non-CR/Non-progressive disease (PD): Persistence of 1 or more non-target lesion(s). Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
    End point type
    Primary
    End point timeframe
    Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
    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: No additional statistical analysis were pre-specified for this endpoint.
    End point values
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Number of subjects analysed
    26
    15
    15
    15
    Units: Percentage of Participants
        number (confidence interval 95%)
    3.8 (0.10 to 19.64)
    6.7 (0.17 to 31.95)
    40.0 (16.34 to 67.71)
    46.7 (21.27 to 73.41)
    No statistical analyses for this end point

    Secondary: Complete Response Rate (CRR) per Modified RECIST v1.1

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    End point title
    		 Complete Response Rate (CRR) per Modified RECIST v1.1
    End point description
    CRR was defined as the incidence of a BOR of CR per modified RECIST v1.1: - CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to < 10 mm. All lymph nodes must have been non-pathological in size (< 10mm short axis). Confirmation of CR was not required per modified RECIST v1.1. Values of "-99999" and "99999" represent an N/A value. Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
    End point values
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Number of subjects analysed
    26
    15
    15
    15
    Units: Percentage of Participants
        number (confidence interval 95%)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    20.0 (4.33 to 48.09)
    20.0 (4.33 to 48.09)
    No statistical analyses for this end point

    Secondary: Complete Response Rate (iCRR) per Modified Immune-related Response Criteria (irRC) RECIST v1.1

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    End point title
    		 Complete Response Rate (iCRR) per Modified Immune-related Response Criteria (irRC) RECIST v1.1
    End point description
    iCRR was defined as the incidence of a best overall response (iBOR) of a complete response (iCR) per modified irRC-RECIST: - iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have had a reduction in short axis to < 10 mm. Confirmation of iCR was required per modified irRC-RECIST. Values of "-99999" and "99999" represent an N/A value. Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
    End point values
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Number of subjects analysed
    26
    15
    15
    15
    Units: Percentage of Participants
        number (confidence interval 95%)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    26.7 (7.79 to 55.10)
    20.0 (4.33 to 48.09)
    No statistical analyses for this end point

    Secondary: BOR per Modified RECIST v1.1

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    End point title
    		 BOR per Modified RECIST v1.1
    End point description
    BOR was the best overall visit response up to & including the first overall visit response of PD: -CR: Disappearance of all target & non-target lesions. Any pathological lymph nodes must have had a reduction in short axis to <10 mm. All lymph nodes must have been non-pathological in size. -PR: ≥30% decrease in the sum of diameters of target lesions. -Stable disease (SD): Neither sufficient shrinkage to qualify for PR/CR nor sufficient increase to qualify for PD. -PD: ≥20% increase in the sum of diameters of target lesions and an increase of ≥5mm. Progression of existing non-target lesions. -Unable to evaluate (UE): Any lesion present at baseline which was not assessed or unable to be evaluated leading to an inability to determine the status of that particular tumor. -Non-CR/Non-PD: Persistence of 1+ non-target lesion(s). Non-CR/non-PD was relevant to participants who did not have measurable disease at baseline. Confirmation of CR, PR & PD were not required per modified RECIST 1.1.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
    End point values
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Number of subjects analysed
    26 [2]
    15 [3]
    15 [4]
    15 [5]
    Units: Participants
        CR
    0
    0
    3
    3
        PR
    1
    1
    3
    4
        SD
    7
    4
    0
    6
        PD
    11
    5
    9
    1
        UE
    0
    1
    0
    0
        Non-CR/Non-PD
    1
    0
    0
    0
        Not Done
    6
    4
    0
    1
    Notes
    [2] - Full Analysis Set.
    [3] - Full Analysis Set.
    [4] - Full Analysis Set.
    [5] - Full Analysis Set.
    No statistical analyses for this end point

    Secondary: Best Overall Response (iBOR) per Modified irRC-RECIST

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    End point title
    		 Best Overall Response (iBOR) per Modified irRC-RECIST
    End point description
    iBOR was defined as the best overall visit response up to and including the first overall visit response of progressive disease (iPD) per modified irRC-RECIST: - iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have a reduction in short axis to < 10 mm. - Partial response (iPR): Decrease in tumor burden ≥ 30% relative to baseline. - Stable disease (iSD): Neither sufficient shrinkage to qualify for iPR or iCR nor sufficient increase to qualify for iPD. - iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase. - Unable to evaluate (iUE): Any lesion present at baseline or a new measurable lesion which was not assessed or was unable to be evaluated leading to an inability to determine the status of that particular tumor for that time point. Confirmation of iCR, iPR and iPD was required per modified irRC-RECIST.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
    End point values
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Number of subjects analysed
    26 [6]
    15 [7]
    15 [8]
    15 [9]
    Units: Participants
        iCR
    0
    0
    4
    3
        iPR
    3
    1
    7
    4
        iSD
    10
    5
    0
    6
        iPD
    5
    4
    1
    0
        iUE
    2
    1
    2
    1
        Not Done
    6
    4
    1
    1
    Notes
    [6] - Full Analysis Set.
    [7] - Full Analysis Set.
    [8] - Full Analysis Set.
    [9] - Full Analysis Set.
    No statistical analyses for this end point

    Secondary: Durable Response Rate (DRR) per Modified RECIST v1.1

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    End point title
    		 Durable Response Rate (DRR) per Modified RECIST v1.1
    End point description
    DRR was defined as the percentage of participants with a CR or PR per modified RECIST v1.1 with a duration of response (DOR) ≥ 6 months. One month was calculated based on 365.25 days per year. - CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to < 10 mm. All lymph nodes must have been non-pathological in size (< 10mm short axis). - PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Confirmation of CR and PR were not required per modified RECIST v1.1. Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
    End point values
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Number of subjects analysed
    26
    15
    15
    15
    Units: Percentage of Participants
        number (confidence interval 95%)
    3.8 (0.10 to 19.64)
    6.7 (0.17 to 31.95)
    40.0 (16.34 to 67.71)
    26.7 (7.79 to 55.10)
    No statistical analyses for this end point

    Secondary: Durable Response Rate (iDRR) per Modified irRC-RECIST

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    End point title
    		 Durable Response Rate (iDRR) per Modified irRC-RECIST
    End point description
    iDRR was defined as the percentage of participants with an iCR or iPR per modified irRC-RECIST with a duration of response (iDOR) ≥ 6 months. One month was calculated based on 365.25 days per year. - iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have a reduction in short axis to < 10 mm. - iPR: Decrease in tumor burden ≥ 30% relative to baseline. Confirmation of iCR and iPR were required per modified irRC-RECIST. Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
    End point values
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Number of subjects analysed
    26
    15
    15
    15
    Units: Percentage of Participants
        number (confidence interval 95%)
    11.5 (2.45 to 30.15)
    6.7 (0.17 to 31.95)
    73.3 (44.90 to 92.21)
    40.0 (16.34 to 67.71)
    No statistical analyses for this end point

    Secondary: DOR per Modified RECIST v1.1

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    End point title
    		 DOR per Modified RECIST v1.1
    End point description
    DOR was defined as the time from the date of an initial response of CR or PR to the earlier of PD/death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date. -CR:Disappearance of all target & non-target lesions. All lymph nodes must have a reduction in short axis to <10 mm. Any pathological lymph nodes must have had a reduction in short axis to <10 mm. All lymph nodes must have been non-pathological in size (<10mm short axis). -PR:At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. -PD:At least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5mm. Unequivocal progression of existing non-target lesions. Confirmation of CR, PR and PD were not required per modified RECIST v1.1. Values of "-99999" and "99999" represent an N/A value.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
    End point values
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Number of subjects analysed
    1 [10]
    1 [11]
    6 [12]
    7 [13]
    Units: Months
        median (confidence interval 95%)
    22.768 (-99999 to 99999)
    7.655 (-99999 to 99999)
    99999 (19.351 to 99999)
    13.700 (5.520 to 99999)
    Notes
    [10] - Full Analysis Set. Only participants who had an initial response of CR or PR were included.
    [11] - Full Analysis Set. Only participants who had an initial response of CR or PR were included.
    [12] - Full Analysis Set. Only participants who had an initial response of CR or PR were included.
    [13] - Full Analysis Set. Only participants who had an initial response of CR or PR were included.
    No statistical analyses for this end point

    Secondary: iDOR per Modified irRC-RECIST

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    End point title
    		 iDOR per Modified irRC-RECIST
    End point description
    iDOR was defined as the time from the date of an initial response that is subsequently confirmed to the earlier of iPD per modified irRC-RECIST. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date. - iCR: Disappearance of all target and non-target lesions. All lymph nodes must have a reduction in short axis to < 10 mm. - iPR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. - iPD: At least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. Unequivocal progression of existing non-target lesions. Values of "-99999" and "99999" represent an N/A value.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
    End point values
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Number of subjects analysed
    3 [14]
    1 [15]
    11 [16]
    7 [17]
    Units: Months
        median (confidence interval 95%)
    99999 (22.768 to 99999)
    7.655 (-99999 to 99999)
    99999 (-99999 to 99999)
    99999 (11.302 to 99999)
    Notes
    [14] - Full Analysis Set. Only participants who had an initial response of iCR or iPR were included.
    [15] - Full Analysis Set. Only participants who had an initial response of iCR or iPR were included.
    [16] - Full Analysis Set. Only participants who had an initial response of iCR or iPR were included.
    [17] - Full Analysis Set. Only participants who had an initial response of iCR or iPR were included.
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) per Modified RECIST v1.1

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    End point title
    		 Disease Control Rate (DCR) per Modified RECIST v1.1
    End point description
    DCR per modified RECIST v1.1 was defined as the incidence of a BOR of CR, PR or SD. - CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to < 10 mm. All lymph nodes must have been non-pathological in size (< 10mm short axis - PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. - SD: Neither sufficient shrinkage to qualify for PR or CR nor sufficient increase to qualify for PD. Confirmation of CR and PR were not required per modified RECIST v1.1. Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
    End point values
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Number of subjects analysed
    26
    15
    15
    15
    Units: Percentage of Participants
        number (confidence interval 95%)
    30.8 (14.33 to 51.79)
    33.3 (11.82 to 61.62)
    40.0 (16.34 to 67.71)
    86.7 (59.54 to 98.34)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (iORR) per Modified irRC-RECIST

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    End point title
    		 Objective Response Rate (iORR) per Modified irRC-RECIST
    End point description
    iORR was defined as the incidence of an iBOR of iCR or iPR per modified irRC-RECIST - iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (whether target or nontarget) must have a reduction in short axis to < 10 mm. - iPR: Decrease in tumor burden ≥ 30% relative to baseline. Confirmation of iCR and iPR were required per modified irRC-RECIST. Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
    End point values
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Number of subjects analysed
    26
    15
    15
    15
    Units: Percentage of Participants
        number (confidence interval 95%)
    11.5 (2.45 to 30.15)
    6.7 (0.17 to 31.95)
    73.3 (44.90 to 92.21)
    46.7 (21.27 to 73.41)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (iDCR) per Modified irRC-RECIST

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    End point title
    		 Disease Control Rate (iDCR) per Modified irRC-RECIST
    End point description
    iDCR per modified irRC-RECIST was defined as the incidence of an iBOR of iCR, iPR or iSD. - iCR: Disappearance of all target and non-target lesions. All lymph nodes must have a reduction in short axis to < 10 mm. - iPR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. - iSD: Neither sufficient shrinkage to qualify for iPR or iCR nor sufficient increase to qualify for iPD. Confirmation of iCR and iPR were required per modified irRC-RECIST. Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
    End point values
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Number of subjects analysed
    26
    15
    15
    15
    Units: Percentage of Participants
        number (confidence interval 95%)
    50.0 (29.93 to 70.07)
    40.0 (16.34 to 67.71)
    73.3 (44.90 to 92.21)
    86.7 (59.54 to 98.34)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (iPFS) per Modified irRC-RECIST

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    End point title
    		 Progression Free Survival (iPFS) per Modified irRC-RECIST
    End point description
    iPFS per modified irRC-RECIST was defined as the interval from first dose to the earlier event of iPD or death from any cause. Participants without an event were censored at their last evaluable post-baseline tumor assessment if available, otherwise were censored on study Day 1. One month was calculated based on 365.25 days per year. - iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase. Values of "99999" represent an N/A value. Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
    End point values
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Number of subjects analysed
    26
    15
    15
    15
    Units: Months
        median (confidence interval 95%)
    6.899 (2.793 to 25.232)
    8.214 (2.694 to 15.014)
    99999 (2.694 to 99999)
    25.955 (16.756 to 99999)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) per Modified RECIST v1.1

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    End point title
    		 Progression Free Survival (PFS) per Modified RECIST v1.1
    End point description
    PFS per modified RECIST 1.1 was defined as the interval from first dose to the earlier event of PD or death from any cause. Participants without an event were censored at their last evaluable post-baseline tumor assessment if available, otherwise were censored on study Day 1. One month was calculated based on 365.25 days per year. - PD: At least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. Unequivocal progression of existing non-target lesions. Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
    End point values
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Number of subjects analysed
    26
    15
    15
    15
    Units: Months
        median (confidence interval 95%)
    3.614 (2.793 to 5.520)
    4.830 (2.431 to 13.207)
    2.793 (2.661 to 27.433)
    13.897 (5.552 to 19.318)
    No statistical analyses for this end point

    Secondary: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)

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    End point title
    		 Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)
    End point description
    Evaluation of TEAEs included the number of participants with at least 1: - TEAE - Treatment-related TEAE - Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 TEAE - Treatment-related CTCAE grade ≥ 3 TEAE - Serious TEAE - Serious treatment-related TEAE - Fatal TEAE - Fatal treatment-related TEAE - TEAE of interest Serious TEAEs were collected up to 90 days post-last dose of treatment. Non-serious TEAEs were collected up to 30 days post-last dose of treatment. A CTCAE grade ≥ 3 was determined using the CTCAE grading systems based on CTCAE version 5.0 per the below definitions: - Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. - Grade 4: Life-threatening consequences; urgent intervention indicated. - Grade 5: Death related to TEAE. Abnormal laboratory tests were also recorded as TEAEs.
    End point type
    Secondary
    End point timeframe
    Serious TEAEs were collected up to 90 days post-last dose of treatment. Non-serious TEAEs were collected up to 30 days post-last dose of treatment. The maximum duration of treatment exposure was 105.9 weeks.
    End point values
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Number of subjects analysed
    26 [18]
    15 [19]
    15 [20]
    15 [21]
    Units: Participants
        TEAEs
    24
    15
    15
    14
        Treatment-related TEAEs
    17
    10
    14
    13
        CTCAE Grade ≥ 3 TEAEs
    11
    8
    4
    8
        CTCAE Grade ≥ 3 Treatment-related TEAEs
    2
    3
    0
    6
        Serious TEAEs
    12
    7
    4
    7
        Serious Treatment-related TEAEs
    1
    2
    0
    3
        Fatal TEAEs
    5
    3
    1
    3
        Fatal Treatment-related TEAEs
    0
    0
    0
    1
        TEAEs of Interest
    21
    14
    15
    14
    Notes
    [18] - Safety Analysis Set: All enrolled participants who received at least 1 dose of study treatment.
    [19] - Safety Analysis Set: All enrolled participants who received at least 1 dose of study treatment.
    [20] - Safety Analysis Set: All enrolled participants who received at least 1 dose of study treatment.
    [21] - Safety Analysis Set: All enrolled participants who received at least 1 dose of study treatment.
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the interval from first dose to death from any cause. Participants without an event were censored at the last date known to be alive. One month was calculated based on 365.25 days per year. Values of "99999" represent an N/A value. Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
    End point values
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Number of subjects analysed
    26
    15
    15
    15
    Units: Months
        median (confidence interval 95%)
    24.608 (6.538 to 42.086)
    15.014 (2.760 to 38.374)
    99999 (8.575 to 99999)
    99999 (20.370 to 99999)
    No statistical analyses for this end point

    Secondary: Time to First Subsequent Anti-cancer Therapy

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    End point title
    		 Time to First Subsequent Anti-cancer Therapy
    End point description
    Time to first subsequent anti-cancer therapy was defined as the time from enrollment to the start of subsequent anticancer therapy. Participants who did not start subsequent anticancer therapy were censored as the last known to be alive date. One month was calculated based on 365.25 days per year. Values of "99999" represent an N/A value. Full Analysis Set: Includes all enrolled participants who have received at least 1 dose of talimogene laherparepvec and 1 dose of pembrolizumab in combination.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks. Maximum overall time on-study (treatment + follow up) was 46.23 months
    End point values
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Number of subjects analysed
    26
    15
    15
    15
    Units: Months
        median (confidence interval 95%)
    11.466 (6.209 to 38.111)
    7.852 (2.793 to 99999)
    99999 (25.758 to 99999)
    23.097 (11.532 to 99999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious TEAEs were collected up to 90 days post-last dose of treatment. Non-serious TEAEs were collected up to 30 days post-last dose of treatment. The maximum duration of treatment exposure was 105.9 weeks .
    Adverse event reporting additional description
    All-cause mortality was collected for all enrolled participants. Serious TEAEs and non-serious TEAEs were collected for the safety analysis set which included all enrolled participants who received at least 1 dose of talimogene laherparepvec or pembrolizumab.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance
    Reporting group description
    		 Included participants who received anti-PD-1 therapy in the locally recurrent/metastatic setting and experienced a best overall response of disease progression or stable disease prior to confirmed disease progression. Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 PFU/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an IV infusion every 3 weeks for up to 35 cycles.

    Reporting group title
    Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months
    Reporting group description
    		 Included participants who received anti PD-1 therapy in the adjuvant setting and experienced confirmed disease progression following a disease-free interval of ≥ 6 months after starting the adjuvant PD-1 inhibitor. Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 PFU/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an IV infusion every 3 weeks for up to 35 cycles.

    Reporting group title
    Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months
    Reporting group description
    		 Included participants who received anti-PD-1 therapy in the adjuvant setting and experienced confirmed disease progression following a disease-free interval of < 6 months after starting the adjuvant anti-PD-1 therapy. Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 PFU/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an IV infusion every 3 weeks for up to 35 cycles.

    Reporting group title
    Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance
    Reporting group description
    		 Included participants who received anti-PD-1 therapy in the locally recurrent/metastatic setting and experienced confirmed disease progression following a complete or partial response on anti-PD-1 therapy. Participants received talimogene laherparepvec at an initial dose of up to 4.0 mL of 10^6 PFU/mL by intralesional injection into injectable cutaneous, subcutaneous and nodal legions on Day 1. Subsequent doses of up to 4.0 mL of 10^8 PFU/mL were administered every 3 weeks for up to 35 cycles in total. Participants also received pembrolizumab at a dose of 200 mg as an IV infusion every 3 weeks for up to 35 cycles.

    Serious adverse events
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 26 (46.15%)
    7 / 15 (46.67%)
    4 / 15 (26.67%)
    7 / 15 (46.67%)
         number of deaths (all causes)
    17
    7
    4
    12
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    3 / 26 (11.54%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 2
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intussusception
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Liver injury
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Purpura
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal disorder
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenocortical insufficiency acute
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1 – Locally Recurrent/Metastatic - Primary Resistance Cohort 4 – Adjuvant Setting – Disease Free Interval ≥ 6 months Cohort 3 – Adjuvant Setting – Disease Free Interval < 6 months Cohort 2 – Locally Recurrent/Metastatic - Acquired Resistance
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 26 (76.92%)
    14 / 15 (93.33%)
    15 / 15 (100.00%)
    15 / 15 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    2
    Seborrhoeic keratosis
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Tumour fistulisation
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Benign salivary gland neoplasm
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tumour pain
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 26 (3.85%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Surgical and medical procedures
    Skin neoplasm excision
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    1
    Chest discomfort
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Axillary pain
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Asthenia
         subjects affected / exposed
    3 / 26 (11.54%)
    2 / 15 (13.33%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
         occurrences all number
    4
    2
    6
    2
    Chills
         subjects affected / exposed
    6 / 26 (23.08%)
    2 / 15 (13.33%)
    2 / 15 (13.33%)
    2 / 15 (13.33%)
         occurrences all number
    12
    21
    2
    3
    Fatigue
         subjects affected / exposed
    4 / 26 (15.38%)
    5 / 15 (33.33%)
    6 / 15 (40.00%)
    5 / 15 (33.33%)
         occurrences all number
    5
    5
    6
    5
    Hyperthermia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    5
    1
    Influenza like illness
         subjects affected / exposed
    2 / 26 (7.69%)
    2 / 15 (13.33%)
    7 / 15 (46.67%)
    1 / 15 (6.67%)
         occurrences all number
    4
    21
    26
    1
    Injection site extravasation
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injection site haemorrhage
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Injection site inflammation
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    7 / 26 (26.92%)
    7 / 15 (46.67%)
    5 / 15 (33.33%)
    6 / 15 (40.00%)
         occurrences all number
    12
    10
    8
    12
    Peripheral swelling
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Pain
         subjects affected / exposed
    2 / 26 (7.69%)
    3 / 15 (20.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    3
    5
    0
    0
    Injection site reaction
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Injection site paraesthesia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Injection site pain
         subjects affected / exposed
    3 / 26 (11.54%)
    1 / 15 (6.67%)
    4 / 15 (26.67%)
    2 / 15 (13.33%)
         occurrences all number
    3
    1
    5
    2
    Injection site oedema
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Face oedema
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Xerosis
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sarcoidosis
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Seasonal allergy
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Penile dermatitis
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Cough
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 15 (13.33%)
    3 / 15 (20.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    4
    0
    Dyspnoea
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Laryngeal inflammation
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    1
    Pleural effusion
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    3
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Depressed mood
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Depression
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Sleep disorder
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Insomnia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Anxiety
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    2
    2
    1
    1
    Lipase increased
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    4
    Blood creatinine increased
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    2
    2
    0
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    1
    Body temperature increased
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 26 (3.85%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    5
    4
    1
    0
    Weight decreased
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    2
    2
    0
    3
    Transaminases increased
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Limb injury
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    1
    Ligament sprain
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Head injury
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Accident at home
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Wound dehiscence
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Skin wound
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Skin laceration
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Immunisation reaction
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    1
    2
    Migraine
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Headache
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    5 / 15 (33.33%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    9
    4
    Dizziness
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia vitamin B12 deficiency
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Eosinophilia
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    12
    0
    1
    Neutropenia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Anaemia
         subjects affected / exposed
    4 / 26 (15.38%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
         occurrences all number
    4
    5
    1
    3
    Thrombocytopenia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    1
    Leukopenia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Dry eye
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Retinal disorder
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Xerophthalmia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Conjunctival suffusion
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Abdominal pain
         subjects affected / exposed
    1 / 26 (3.85%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    2
    2
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    1
    Diarrhoea
         subjects affected / exposed
    3 / 26 (11.54%)
    7 / 15 (46.67%)
    2 / 15 (13.33%)
    2 / 15 (13.33%)
         occurrences all number
    3
    12
    5
    2
    Constipation
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Colitis
         subjects affected / exposed
    1 / 26 (3.85%)
    2 / 15 (13.33%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences all number
    2
    3
    2
    0
    Anal haemorrhage
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    3
    4
    Nausea
         subjects affected / exposed
    6 / 26 (23.08%)
    3 / 15 (20.00%)
    3 / 15 (20.00%)
    4 / 15 (26.67%)
         occurrences all number
    9
    3
    6
    9
    Vomiting
         subjects affected / exposed
    4 / 26 (15.38%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    4
    2
    0
    2
    Toothache
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Stomatitis
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Enteritis
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Change of bowel habit
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Hepatic cytolysis
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Umbilical discharge
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Skin hypopigmentation
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Skin hyperplasia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    4
    Scab
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    2
    Rash
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 15 (6.67%)
    4 / 15 (26.67%)
    0 / 15 (0.00%)
         occurrences all number
    3
    1
    4
    0
    Pruritus
         subjects affected / exposed
    2 / 26 (7.69%)
    2 / 15 (13.33%)
    5 / 15 (33.33%)
    0 / 15 (0.00%)
         occurrences all number
    2
    2
    6
    0
    Hair colour changes
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Erythema
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Eczema
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Dry skin
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Alopecia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Vitiligo
         subjects affected / exposed
    2 / 26 (7.69%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
    3 / 15 (20.00%)
         occurrences all number
    2
    2
    1
    3
    Skin lesion
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash papular
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Rash macular
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    1
    Rash erythematous
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psoriasis
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lichen planus
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin burning sensation
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash pruritic
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Proteinuria
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urethral dilatation
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hypophysitis
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Hyperthyroidism
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    1
    Joint effusion
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Compartment syndrome
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Bone pain
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Back pain
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 15 (6.67%)
    4 / 15 (26.67%)
    2 / 15 (13.33%)
         occurrences all number
    2
    2
    4
    2
    Arthritis
         subjects affected / exposed
    0 / 26 (0.00%)
    3 / 15 (20.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Arthralgia
         subjects affected / exposed
    3 / 26 (11.54%)
    4 / 15 (26.67%)
    2 / 15 (13.33%)
    2 / 15 (13.33%)
         occurrences all number
    3
    5
    4
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    2
    1
    Myalgia
         subjects affected / exposed
    3 / 26 (11.54%)
    0 / 15 (0.00%)
    4 / 15 (26.67%)
    0 / 15 (0.00%)
         occurrences all number
    3
    0
    6
    0
    Neck pain
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    4 / 26 (15.38%)
    2 / 15 (13.33%)
    2 / 15 (13.33%)
    3 / 15 (20.00%)
         occurrences all number
    6
    2
    2
    3
    Rhabdomyolysis
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rheumatic disorder
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tendonitis
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Joint stiffness
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Skin infection
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tinea versicolour
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    3
    1
    Cellulitis
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cellulitis orbital
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Genital herpes simplex
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Herpes simplex
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Herpes simplex reactivation
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Wound infection
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    COVID-19
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    2
    1
    Cystitis
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Dermatophytosis
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vaginal infection
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Postoperative wound infection
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Fungal skin infection
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Mastoiditis
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Hypomagnesaemia
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    2 / 26 (7.69%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    3
    0
    0
    Gout
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Decreased appetite
         subjects affected / exposed
    3 / 26 (11.54%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jul 2019
    - Updated the protocol to “Subjects with stage IVM1d and up to 3 cerebral metastases may be enrolled, provided that all lesions have been adequately treated with stereotactic radiation therapy, craniotomy, or gamma knife therapy, with no evidence of progression and not requiring steroids for at least 2 months prior to enrollment.”. - Added “Subsequent anticancer therapies will be collected from the end of investigational product administration through safety and survival follow-up until the subject ends study” - Added “Subjects with grade 2 endocrinopathies (ie, requiring replacement therapy only) may be enrolled upon review and approval by the medical monitor.”. - Changed when concomitant medication was to be recorded from the safety follow-up during the follow-up period to the end of the study. - The investigator can no longer decide when discontinue treatment or a participant from the study. - Added disease stage (stage IVM1b or lower, stage IVM1c/d) at baseline to the covariate analysis. - Added 24-hour urine creatine clearance.
    10 Mar 2020
    - Added participants with prior treatment and disease progression on more than 1 line of anti-PD-1 therapy are excluded. - Added efficacy will also be performed Per Protocol Analysis Set (PPAS). The PPAS was defined as a subset of the full analysis set and includes participants who do not have important protocol deviations that are considered to have an impact on efficacy outcomes. - Added to lesion and efficacy assessment “Subjects who have reached a confirmed CR may increase their interval of radiographic assessments up to 6 months (26 weeks) after the first 2 years beyond confirmed CR and up to 12 months (52 weeks) after the first 5 years beyond confirmed CR as long as CR is maintained.”. - Added an optional pharmacogenetic assessment. - Added an exploratory assessment of measuring the target lesions (visceral, injected, and uninjected non visceral). - Added that sperm donation within the prescribed period of time is prohibited. - Added the investigator must document the changes to the schedule of activities.
    09 Jun 2021
    - Added the number of participants (72 participants were enrolled with 27 participants in cohort 1 and 15 participants in cohorts 2, 3, and 4). - Updated language throughout the protocol to allow treatment with pembrolizumab to continue if a complete response was observed. - Safety reporting language updated for adherence to current Amgen standard operating procedures. - Immune-related adverse events updated to include neurological toxicities and exfoliative dermatologic conditions to align with the pembrolizumab Investigator Brochure. - Serious adverse events (SAEs) after the protocol-required reporting period, specifically participants ending study due to death, have not been reported as SAEs for other studies on the program. As a result, additional clarification was added to Section 9.2.3.1.1.3 - “Serious Adverse Events After the Protocol-required Reporting Period” and throughout the protocol for consistency to mitigate this. Furthermore, these changes align with Amgen’s current protocol template and guidance. - Clarified that the visit windows are +/- 3 days during the treatment period, as operationally, it is more reasonable for sites to have the minus window. It was further noted that the week 0 visit was an exception, where the -3 days does not apply. All assessments for Week 0 should be completed following enrollment (via Interactive Response Technology), using the + 3-day window for the first dose. - Additionally, the visit window for radiographic assessments for participants who discontinued treatment for any reason other than confirmed iPD (by modified irRC-RECIST) was updated from 12 weeks (+ 1 week) to (+/- 1 week). - Minor clarifications added to align with the statistical analysis plan: - Clarified in Section 9.2.2.2-Modified RECIST v1.1, that "Following modified RECIST v1.1 tumor assessments will continue through to the first PD". - Physical Measurements removed from safety analysis.

    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.
    None reported
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