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    Clinical Trial Results:
    A Phase 1b/3, Multicenter, Trial of Talimogene Laherparepvec in Combination With Pembrolizumab (MK-3475) for Treatment of Unresectable Stage IIIB to IVM1c Melanoma (MASTERKEY-265)

    Summary
    EudraCT number
    2014-000185-22
    Trial protocol
    SE   ES   BE   DE   AT   GR   IT   FI   CZ   PT   HU  
    Global end of trial date
    11 Mar 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Mar 2022
    First version publication date
    24 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20110265
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02263508
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@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 Mar 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Mar 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Phase 1b: To evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), of talimogene laherparepvec (T-VEC) in combination with pembrolizumab in subjects with previously untreated, unresectable, stage IIIB to IVM1c melanoma. Phase 3: To evaluate the efficacy of talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab, as assessed by progression-free survival (PFS) (response evaluation by blinded independent central review [BICR] using modified Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) and overall survival (OS).
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. The study protocol and all amendments, the informed consent form, and any accompanying materials provided to the subjects were reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics Committee (IEC) at each study center. The investigator or his/her designee informed the subject of all aspects pertaining to the subject’s participation in the study before any screening procedures were performed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Dec 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    60 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 76
    Country: Number of subjects enrolled
    Austria: 18
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Czechia: 43
    Country: Number of subjects enrolled
    Finland: 4
    Country: Number of subjects enrolled
    France: 24
    Country: Number of subjects enrolled
    Germany: 74
    Country: Number of subjects enrolled
    Greece: 43
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Korea, Republic of: 11
    Country: Number of subjects enrolled
    Netherlands: 13
    Country: Number of subjects enrolled
    Poland: 53
    Country: Number of subjects enrolled
    Portugal: 11
    Country: Number of subjects enrolled
    Russian Federation: 39
    Country: Number of subjects enrolled
    South Africa: 35
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    Switzerland: 21
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    United States: 166
    Worldwide total number of subjects
    713
    EEA total number of subjects
    335
    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)
    368
    From 65 to 84 years
    313
    85 years and over
    32

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted at 134 centers in Australia, Canada, Europe, South Africa, South Korea, and the United States. Phase 1b was an open-label, single-arm study and Phase 3 was a randomized, double-blind, placebo-controlled study.

    Pre-assignment
    Screening details
    In Phase 3 participants were randomized equally to 1 of 2 arms. Randomization was stratified by stage of disease: less advanced stages (IIIB, IIIC, and IVM1a) versus more advanced stages (IVM1b and IVM1c) and by prior BRAF inhibitor therapy (no prior BRAF inhibitor vs BRAF inhibitor with or without MEK inhibitor).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Phase 1b: Talimogene Laherparepvec + Pembrolizumab
    Arm description
    Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.
    Arm type
    Experimental

    Investigational medicinal product name
    Talimogene Laherparepvec
    Investigational medicinal product code
    AMG 678
    Other name
    IMLYGIC®, OncoVEX^GM-CSF, T-VEC
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    Talimogene laherparepvec administered by intratumoral injection at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL followed by up to 4 mL of 10⁸ PFU/mL 3 weeks later and every 2 weeks thereafter.

    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
    Administered at a dose of 200 mg as an intravenous infusion over approximately 30 minutes.

    Arm title
    Phase 3: Placebo + Pembrolizumab
    Arm description
    Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.
    Arm type
    Active comparator

    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
    Administered at a dose of 200 mg as an intravenous infusion over approximately 30 minutes.

    Investigational medicinal product name
    Placebo for Talimogene Laherparepvec
    Investigational medicinal product code
    AMG 678
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    Administered by intratumoral injection at an initial dose of up to 4 mL followed by up to 4 mL 3 weeks later and every 2 weeks thereafter.

    Arm title
    Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Arm description
    Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.
    Arm type
    Experimental

    Investigational medicinal product name
    Talimogene Laherparepvec
    Investigational medicinal product code
    AMG 678
    Other name
    IMLYGIC®, OncoVEX^GM-CSF, T-VEC
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    Talimogene laherparepvec administered by intratumoral injection at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL followed by up to 4 mL of 10⁸ PFU/mL 3 weeks later and every 2 weeks thereafter.

    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
    Administered at a dose of 200 mg as an intravenous infusion over approximately 30 minutes.

    Number of subjects in period 1
    Phase 1b: Talimogene Laherparepvec + Pembrolizumab Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Started
    21
    346
    346
    Received T-VEC/Placebo
    21
    345
    343
    Received Pembrolizumab
    21
    345
    343
    Completed
    0
    0
    0
    Not completed
    21
    346
    346
         Adverse event, serious fatal
    6
    151
    140
         Consent withdrawn by subject
    1
    23
    17
         Sponsor Decision
    12
    165
    182
         Lost to follow-up
    2
    7
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 1b: Talimogene Laherparepvec + Pembrolizumab
    Reporting group description
    Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.

    Reporting group title
    Phase 3: Placebo + Pembrolizumab
    Reporting group description
    Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.

    Reporting group title
    Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Reporting group description
    Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.

    Reporting group values
    Phase 1b: Talimogene Laherparepvec + Pembrolizumab Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab Total
    Number of subjects
    21 346 346 713
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    14 177 177 368
        From 65-84 years
    6 157 150 313
        85 years and over
    1 12 19 32
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    60.2 ± 13.4 62.3 ± 14.5 63.1 ± 13.7 -
    Sex: Female, Male
    Units: participants
        Female
    13 127 147 287
        Male
    8 219 199 426
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    0 9 13 22
        Not Hispanic or Latino
    21 337 331 689
        Unknown or Not Reported
    0 0 2 2
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0
        Asian
    0 4 7 11
        Black (or African American)
    0 1 2 3
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        White
    21 335 327 683
        Other
    0 6 10 16
    Disease Stage per the American Joint Committee on Cancer (AJCC) 7th Edition
    Stage IIIB: Ulcerated lesion and 1 lymph node or 2-3 nodes with micrometastasis, or any-depth lesion with no ulceration, and 1 lymph node or 2-3 nodes with macrometastasis; Stage IIIC: Ulcerated lesion and 1 lymph node with macrometastasis; 2-3 nodes with macrometastasis or ≥4 metastatic lymph nodes, matted lymph nodes, or in-transit met(s)/satellite(s); Stage IV: M1a: Spread to skin, subcutaneous tissue, or lymph nodes; normal lactate dehydrogenase (LDH) level; M1b: Spread to lungs, normal LDH; M1c: Spread to all other visceral organs, normal LDH or any distant disease with elevated LDH.
    Units: Subjects
        Stage IIIB - IVM1a
    9 169 169 347
        Stage IVM1b/c
    12 177 177 366
    Prior Serine/Threonine Protein Kinase B-Raf (BRAF) Inhibitor Therapy
    Units: Subjects
        Yes
    0 29 29 58
        No
    0 317 317 634
        Not collected
    21 0 0 21
    Programmed Cell Death-1 Ligand 1 (PD-L1) Status
    PD-L1 expression in tumor cells was assessed at a central laboratory using a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 to 5; a score ≥ 2 (membranous staining in ≥ 1% of cells within tumor nests, including neoplastic cells and intercalated and contiguous immune cells) was considered positive.
    Units: Subjects
        Positive
    17 218 231 466
        Not Positive
    4 128 115 247
    BRAF V600 Mutation Status
    Mutation status of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene was based on a gene mutation that results in an amino acid substitution from valine (V) to glutamic acid (E) at codon 600 (V600E) and/or a substitution from valine to lysine (K) (V600K).
    Units: Subjects
        Mutation
    4 116 124 244
        Mutation not present
    17 215 211 443
        Missing/unknown
    0 15 11 26

    End points

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    End points reporting groups
    Reporting group title
    Phase 1b: Talimogene Laherparepvec + Pembrolizumab
    Reporting group description
    Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.

    Reporting group title
    Phase 3: Placebo + Pembrolizumab
    Reporting group description
    Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.

    Reporting group title
    Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Reporting group description
    Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.

    Primary: Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs)

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    End point title
    Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs) [1] [2]
    End point description
    A DLT was defined as any toxicity related to study drug which met any of the following criteria based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0: -Grade 4 non-hematologic toxicity. -Grade 3 or higher pneumonitis. -Grade 3 non-hematologic toxicity lasting > 3 days despite optimal supportive care, excluding grade 3 fatigue. -Any grade 3 or higher non-hematologic laboratory value if medical intervention was required, or the abnormality lead to hospitalization, or the abnormality persisted for > 1 week. -Febrile neutropenia grade 3 or 4. -Thrombocytopenia < 25 x 10^9/L if associated with a bleeding event which does not result in hemodynamic instability but required an elective platelet infusion, or a life-threatening bleeding event which resulted in urgent intervention and admission to intensive care unit. -Grade 5 toxicity (ie, death). -Any other intolerable toxicity leading to permanent discontinuation of talimogene laherparepvec or pembrolizumab.
    End point type
    Primary
    End point timeframe
    The DLT evaluation period was 6 weeks from the initial administration of pembrolizumab (week 6 to 12).
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses were not conducted in Phase 1b
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 1b participants only.
    End point values
    Phase 1b: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    21
    Units: participants
    0
    No statistical analyses for this end point

    Primary: Phase 3: Progression Free Survival (PFS) by Blinded Independent Central Review Assessed Using Modified RECIST 1.1

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    End point title
    Phase 3: Progression Free Survival (PFS) by Blinded Independent Central Review Assessed Using Modified RECIST 1.1 [3]
    End point description
    PFS per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 is defined as the interval from randomization to the earlier event of progressive disease (PD) per modified RECIST 1.1 or death from any cause. PD: Increase in size of target lesions from nadir by ≥ 20% and ≥ 5 mm absolute increase above nadir, or the appearance of a new lesion. Median PFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date. The primary analysis of PFS was specified to be conducted when 407 PFS events had occurred (data cut-off date 02 March 2020).
    End point type
    Primary
    End point timeframe
    From randomization until the data-cut-off date of 02 March 2020; median (range) time on follow-up was 25.5 (0.6, 44.7) months in the Placebo + Pembrolizumab arm and 25.6 (0.3, 45.8) months in the Talimogene Laherparepvec + Pembrolizumab arm.
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 3 participants only.
    End point values
    Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    346
    346
    Units: months
        median (confidence interval 95%)
    8.5 (5.72 to 13.54)
    14.3 (10.25 to 22.11)
    Statistical analysis title
    Analysis of PFS
    Comparison groups
    Phase 3: Placebo + Pembrolizumab v Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects included in analysis
    692
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.13 [4]
    Method
    Stratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    1.04
    Notes
    [4] - Log-rank test stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status.

    Primary: Phase 3: Overall Survival

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    End point title
    Phase 3: Overall Survival [5]
    End point description
    Overall survival (OS) is defined as the interval from randomization to death from any cause. Median overall survival was calculated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date. "99999" indicates values that could not be estimated due to the low number of events.
    End point type
    Primary
    End point timeframe
    From randomization until the end of study; median (range) time on follow-up was 34.8 (0.6, 58.3) months in the Placebo + Pembrolizumab arm and 36.8 (0.3, 58.4) months in the Talimogene Laherparepvec + Pembrolizumab arm.
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 3 participants only.
    End point values
    Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    346
    346
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Analysis of OS
    Comparison groups
    Phase 3: Placebo + Pembrolizumab v Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects included in analysis
    692
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.77 [6]
    Method
    Stratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.77
         upper limit
    1.21
    Notes
    [6] - Log-rank test stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status.

    Secondary: Phase 1b: Objective Response Rate (ORR)

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    End point title
    Phase 1b: Objective Response Rate (ORR) [7]
    End point description
    ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) using the modified Immune-related Response Criteria (irRC), by Investigator assessment. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart. Radiographic imaging for assessment of lesions was performed using computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI), or ultrasound. Clinical measurement of cutaneous, subcutaneous, and palpable nodal tumor lesions was conducted with calipers.
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 1b participants only.
    End point values
    Phase 1b: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    21
    Units: percentage of participants
        number (confidence interval 95%)
    61.9 (38.4 to 81.9)
    No statistical analyses for this end point

    Secondary: Phase 1b: Best Overall Response (BOR)

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    End point title
    Phase 1b: Best Overall Response (BOR) [8]
    End point description
    Best overall response is defined as the best overall visit response in the following order: CR, PR, stable disease (SD), progressive disease (PD), or unevaluable (UE), based on investigator assessment using the modified irRC up to the start of any subsequent anti-cancer therapy. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 77 days elapsed after enrollment. Responses and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 1b participants only.
    End point values
    Phase 1b: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    21
    Units: participants
        Complete Response (CR)
    9
        Partial Response (PR)
    4
        Stable Disease (SD)
    1
        Progressive Disease (PD)
    6
        Unable to Evaluate (UE)
    1
    No statistical analyses for this end point

    Secondary: Phase 1b: Durable Response Rate (DRR)

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    End point title
    Phase 1b: Durable Response Rate (DRR) [9]
    End point description
    DRR is defined as the percentage of participants with a best overall response of CR or PR using the modified irRC per Investigator assessment with a duration of response of at least 6 months. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 1b participants only.
    End point values
    Phase 1b: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    21
    Units: percentage of participants
        number (confidence interval 95%)
    57.1 (34.0 to 78.2)
    No statistical analyses for this end point

    Secondary: Phase 1b: Duration of Response (DOR)

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    End point title
    Phase 1b: Duration of Response (DOR) [10]
    End point description
    Duration of response (DOR) is defined as the time from the date of an initial response (CR or PR) that is subsequently confirmed to the earlier of confirmed PD or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment before start of the first subsequent anticancer therapy. "99999" indicates values that could not be estimated due to the low number of events. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir. Response and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 1b participants only.
    End point values
    Phase 1b: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    13 [11]
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    Notes
    [11] - Participants enrolled in Phase 1b who received ≥ 1 dose of study drug with a CR or PR.
    No statistical analyses for this end point

    Secondary: Phase 1b: Disease Control Rate (DCR)

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    End point title
    Phase 1b: Disease Control Rate (DCR) [12]
    End point description
    DCR is defined as the percentage of participants with a best overall response of CR, PR, or SD using the modified irRC per Investigator assessment. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 84 days elapsed after enrollment.
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 1b participants only.
    End point values
    Phase 1b: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    21
    Units: percentage of participants
        number (confidence interval 95%)
    66.7 (43.0 to 85.4)
    No statistical analyses for this end point

    Secondary: Phase 1b: Overall Survival (OS)

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    End point title
    Phase 1b: Overall Survival (OS) [13]
    End point description
    Overall survival is defined as the interval from first dose to death from any cause. OS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date. "99999" indicates values that could not be estimated due to the low number of events.
    End point type
    Secondary
    End point timeframe
    From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months.
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 1b participants only.
    End point values
    Phase 1b: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    21
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Phase 1b: Progression-free Survival (PFS)

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    End point title
    Phase 1b: Progression-free Survival (PFS) [14]
    End point description
    Progression-free survival is defined as the time from first dose to the earlier event of confirmed PD per modified irRC or death from any cause. PFS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment. "99999" indicates values that could not be estimated due to the low number of events.
    End point type
    Secondary
    End point timeframe
    From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months.
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 1b participants only.
    End point values
    Phase 1b: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    21
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Phase 3: Complete Response Rate Assessed Using Modified irRC-RECIST (iCRR)

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    End point title
    Phase 3: Complete Response Rate Assessed Using Modified irRC-RECIST (iCRR) [15]
    End point description
    Complete response rate per modified Immune-related Response Criteria (irRC) simulating RECIST 1.1 (irRC-RECIST) is defined as the percentage of participants with a best overall response of complete response assessed using the modified irRC-RECIST (iCR) evaluated by blinded independent central review. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks after the criteria were first met. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must have been measurable by CT or MRI only.
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 3 participants only.
    End point values
    Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    346
    346
    Units: percentage of participants
        number (confidence interval 95%)
    8.1 (5.22 to 10.97)
    14.5 (10.75 to 18.16)
    Statistical analysis title
    Analysis of iCRR
    Comparison groups
    Phase 3: Placebo + Pembrolizumab v Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects included in analysis
    692
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.012 [16]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.15
         upper limit
    3.07
    Notes
    [16] - Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status.

    Secondary: Phase 3: Progression Free Survival Assessed Using Modified irRC-RECIST (iPFS)

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    End point title
    Phase 3: Progression Free Survival Assessed Using Modified irRC-RECIST (iPFS) [17]
    End point description
    PFS per modified irRC-RECIST is defined as the interval from randomization to the earlier event of progressive disease assessed by modified irRC-RECIST (iPD) evaluated by blinded independent central review, or death from any cause. iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase relative to nadir (minimum recorded tumor burden) confirmed by a repeat, consecutive assessment at least 4 weeks after the initial detection. Median iPFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date. "99999" indicates values that could not be estimated due to the low number of events. The primary analysis of iPFS was specified to be conducted when 256 iPFS events had occurred (data cut-off date 29 September 2020).
    End point type
    Secondary
    End point timeframe
    From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 3 participants only.
    End point values
    Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    346
    346
    Units: months
        median (confidence interval 95%)
    25.3 (17.68 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Analysis of iPFS
    Comparison groups
    Phase 3: Talimogene Laherparepvec + Pembrolizumab v Phase 3: Placebo + Pembrolizumab
    Number of subjects included in analysis
    692
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.14 [18]
    Method
    Stratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.82
         upper limit
    1.34
    Notes
    [18] - Log-rank test stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status.

    Secondary: Phase 3: Overall Survival Excluding Stage IVM1c Participants

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    End point title
    Phase 3: Overall Survival Excluding Stage IVM1c Participants [19]
    End point description
    Overall survival is defined as the interval from randomization to death from any cause. Median OS was calculated using the Kaplan-Meier method. Participants without an event were censored at the last known alive date. "99999" indicates values that could not be estimated due to the low number of events.
    End point type
    Secondary
    End point timeframe
    From randomization until the end of study; median (range) time on follow-up was 34.8 (0.6, 58.3) months in the Placebo + Pembrolizumab arm and 36.8 (0.3, 58.4) months in the Talimogene Laherparepvec + Pembrolizumab arm.
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 3 participants only.
    End point values
    Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    203 [20]
    201 [21]
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [20] - Participants randomized in Phase 3 with stage IIIB to IVM1a/b.
    [21] - Participants randomized in Phase 3 with stage IIIB to IVM1a/b.
    Statistical analysis title
    Analysis of OS Excluding Stage IVM1c Participants
    Comparison groups
    Phase 3: Placebo + Pembrolizumab v Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.47 [22]
    Method
    Stratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.63
         upper limit
    1.24
    Notes
    [22] - Log-rank test stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status.

    Secondary: Phase 3: Objective Response Rate Assessed Using Modified RECIST 1.1

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    End point title
    Phase 3: Objective Response Rate Assessed Using Modified RECIST 1.1 [23]
    End point description
    ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) assessed using modified RECIST version 1.1, evaluated by blinded independent central review. CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. Modifications to conventional RECIST 1.1 included the following: target lesions were measurable on CT or MRI; otherwise, they were considered as nontarget lesions. A maximum of 10 target lesions was allowed with up to 5 per organ.
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 3 participants only.
    End point values
    Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    346
    346
    Units: percentage of participants
        number (confidence interval 95%)
    41.3 (36.14 to 46.52)
    48.6 (43.29 to 53.82)
    Statistical analysis title
    Analysis of ORR
    Comparison groups
    Phase 3: Placebo + Pembrolizumab v Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects included in analysis
    692
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.081 [24]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.97
         upper limit
    1.79
    Notes
    [24] - Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status.

    Secondary: Phase 3: Best Overall Response Assessed Using Modified RECIST 1.1

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    End point title
    Phase 3: Best Overall Response Assessed Using Modified RECIST 1.1 [25]
    End point description
    Best overall response is defined as the best overall visit response up to and including the first overall visit response of PD in the following order: CR, PR, SD, non-CR/Non-PD (NN), PD or UE assessed using modified RECIST version 1.1, evaluated by blinded independent central review. CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. NN was defined as persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. SD was defined as neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD with ≥ 84 days elapsed after randomization. PD was defined as an increase from nadir by ≥ 20% or ≥ 5 mm absolute increase above nadir of target lesions or appearance of any new lesion.
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 3 participants only.
    End point values
    Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    346
    346
    Units: participants
        Complete response (CR)
    40
    62
        Partial response (PR)
    103
    106
        Stable disease (SD)
    30
    28
        Non-CR/Non-PD (NN)
    16
    11
        Progressive disease (PD)
    120
    106
        Unevaluable (UE)
    11
    3
        Not done
    26
    30
    No statistical analyses for this end point

    Secondary: Phase 3: Durable Response Rate (DRR) Assessed Using Modified RECIST 1.1

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    End point title
    Phase 3: Durable Response Rate (DRR) Assessed Using Modified RECIST 1.1 [26]
    End point description
    DRR is defined as the percentage of participants with a CR or PR per modified RECIST 1.1 and evaluated by blinded independent central review with a duration of response for ≥ 6 months.
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 3 participants only.
    End point values
    Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    346
    346
    Units: percentage of participants
        number (confidence interval 95%)
    34.1 (29.11 to 39.10)
    42.2 (36.99 to 47.40)
    Statistical analysis title
    Analysis of DRR
    Comparison groups
    Phase 3: Placebo + Pembrolizumab v Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects included in analysis
    692
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.039 [27]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.02
         upper limit
    1.9
    Notes
    [27] - Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status.

    Secondary: Phase 3: Duration of Response (DOR) Assessed Using Modified RECIST 1.1

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    End point title
    Phase 3: Duration of Response (DOR) Assessed Using Modified RECIST 1.1 [28]
    End point description
    Duration of response (DOR) is defined as the time from the date of an initial response of CR or PR to the earlier of PD per modified RECIST 1.1, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before start of the first subsequent anticancer therapy. "99999" indicates values that could not be estimated due to the low number of events.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 3 participants only.
    End point values
    Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    143
    168
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    43.7 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Phase 3: Disease Control Rate (DCR) Assessed Using RECIST 1.1

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    End point title
    Phase 3: Disease Control Rate (DCR) Assessed Using RECIST 1.1 [29]
    End point description
    Disease control rate (DCR) per modified RECIST 1.1 is defined as the percentage of participants with a best overall response of CR, PR or SD evaluated by blinded independent central review. CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. SD was defined as neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD with ≥ 84 days elapsed after randomization.
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 3 participants only.
    End point values
    Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    346
    346
    Units: percentage of participants
        number (confidence interval 95%)
    50.0 (44.73 to 55.27)
    56.6 (51.43 to 61.87)
    Statistical analysis title
    Analysis of DCR
    Comparison groups
    Phase 3: Placebo + Pembrolizumab v Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects included in analysis
    692
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.11 [30]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.94
         upper limit
    1.75
    Notes
    [30] - Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status.

    Secondary: Phase 3: Objective Response Rate Assessed Using Modified irRC-RECIST (iORR)

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    End point title
    Phase 3: Objective Response Rate Assessed Using Modified irRC-RECIST (iORR) [31]
    End point description
    Objective response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or partial response assessed using modified irRC-RECIST (iPR) evaluated by blinded independent central review. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation. Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must be measurable by CT or MRI only.
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
    Notes
    [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 3 participants only.
    End point values
    Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    346
    346
    Units: percentage of participants
        number (confidence interval 95%)
    39.9 (34.72 to 45.04)
    49.1 (43.87 to 54.40)
    Statistical analysis title
    Analysis of iORR
    Comparison groups
    Phase 3: Placebo + Pembrolizumab v Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects included in analysis
    692
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.02 [32]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.06
         upper limit
    1.96
    Notes
    [32] - Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status.

    Secondary: Phase 3: Best Overall Response Assessed Using Modified irRC-RECIST

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    End point title
    Phase 3: Best Overall Response Assessed Using Modified irRC-RECIST [33]
    End point description
    Best overall response is defined as the best overall visit response in the following order: iCR, iPR, stable disease per modified irRC-RECIST (iSD), iPD, or UE per modified irRC-RECIST (iUE), evaluated by blinded independent central review. iCR: Disappearance of all lesions and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes must have reduction in short axis to <10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation. iPD: Increase in tumor burden ≥ 20 % and at least 5 mm absolute increase relative to nadir confirmed by a repeat, consecutive assessment at least 4 weeks from the initial detection. iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD with ≥ 84 days elapsed after randomization.
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
    Notes
    [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 3 participants only.
    End point values
    Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    346
    346
    Units: participants
        Complete response (iCR)
    28
    50
        Partial response (iPR)
    110
    120
        Stable disease (iSD)
    57
    51
        Progressive disease (iPD)
    56
    65
        Unevaluable (iUE)
    69
    30
        Not done
    26
    30
    No statistical analyses for this end point

    Secondary: Phase 3: Durable Response Rate Assessed Using Modified irRC-RECIST (iDRR)

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    End point title
    Phase 3: Durable Response Rate Assessed Using Modified irRC-RECIST (iDRR) [34]
    End point description
    Durable response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or iPR per modified irRC-RECIST evaluated by blinded independent central review with a duration of response ≥ 6 months. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
    Notes
    [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 3 participants only.
    End point values
    Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    346
    346
    Units: percentage of participants
        number (confidence interval 95%)
    34.4 (29.39 to 39.40)
    45.7 (40.42 to 50.91)
    Statistical analysis title
    Analysis of iDRR
    Comparison groups
    Phase 3: Placebo + Pembrolizumab v Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects included in analysis
    692
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.004 [35]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.16
         upper limit
    2.17
    Notes
    [35] - Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status.

    Secondary: Phase 3: Duration of Response Assessed Using Modified irRC-RECIST (iDOR)

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    End point title
    Phase 3: Duration of Response Assessed Using Modified irRC-RECIST (iDOR) [36]
    End point description
    Duration of response per modified irRC-RECIST is defined as the time from the date of an initial response of iCR or iPR that was subsequently confirmed to the earlier of iPD per modified irRC-RECIST evaluated by blinded independent central review, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before the start of the first subsequent anticancer therapy. "99999" indicates values that could not be estimated due to the low number of events.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.
    Notes
    [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 3 participants only.
    End point values
    Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    138
    170
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    43.7 (34.53 to 43.73)
    No statistical analyses for this end point

    Secondary: Phase 3: Disease Control Rate Assessed Using Modified irRC-RECIST (iDCR)

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    End point title
    Phase 3: Disease Control Rate Assessed Using Modified irRC-RECIST (iDCR) [37]
    End point description
    Disease control rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR, iCR, or iSD assessed using modified irRC-RECIST evaluated by blinded independent central review. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation. iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD with ≥ 84 days elapsed after randomization.
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
    Notes
    [37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 3 participants only.
    End point values
    Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    346
    346
    Units: percentage of participants
        number (confidence interval 95%)
    56.4 (51.13 to 61.58)
    63.9 (58.81 to 68.93)
    Statistical analysis title
    Analysis of iDCR
    Comparison groups
    Phase 3: Placebo + Pembrolizumab v Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects included in analysis
    692
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.058 [38]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.99
         upper limit
    1.85
    Notes
    [38] - Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status.

    Secondary: Phase 3: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Core Module (EORTC QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) Score

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    End point title
    Phase 3: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Core Module (EORTC QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) Score [39]
    End point description
    The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status/quality of life scale, 5 functional scales, and 9 symptom scales/items. The global health/QoL scale consists of 2 questions that ask participants to rate their overall health and overall quality of life during the past week on a scale from 1 (very poor) to 7 (excellent). The GHS/QoL subscale score was derived as the mean of each score then transformed to a scale from 0 to 100 where higher scores represent a better health status and a positive change from baseline indicates improvement. The overall change from baseline (calculated from all on-treatment visits) was calculated using a restricted maximum likelihood-based mixed model for repeated measures (MMRM) (see model details in statistical analysis section).
    End point type
    Secondary
    End point timeframe
    Baseline and day 1 of weeks 3, 6, 9, 12, then every 6 weeks until end of study treatment; median (range) duration of treatment was 39.0 (0.1, 107.3) weeks in Placebo + Pembrolizumab and 54.1 (0.1, 109.6) weeks in Talimogene Laherparepvec + Pembrolizumab.
    Notes
    [39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was pre-specified for Phase 3 participants only.
    End point values
    Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    329 [40]
    328 [41]
    Units: score on a scale
        least squares mean (standard error)
    -0.20 ± 1.02
    -0.02 ± 1.02
    Notes
    [40] - Participants who received at least 1 dose of study drug with baseline and ≥ 1 on-treatment value.
    [41] - Participants who received at least 1 dose of study drug with baseline and ≥ 1 on-treatment value.
    Statistical analysis title
    Analysis of EORTC QLQ-C30 GHS/QOL
    Statistical analysis description
    Mixed Model for Repeated Measures include the fixed and categorical effects of treatment, visit and treatment-by-visit interaction, the fixed and continuous covariates of baseline HRQL score, randomization stratification factors (stage of disease and prior BRAF inhibitor therapy per IVRS) and baseline PD-L1 status (positive and not positive). Random subject effect was modeled using within subject-error correlation structure.
    Comparison groups
    Phase 3: Placebo + Pembrolizumab v Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects included in analysis
    657
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.84
    Method
    Mixed Model for Repeated Measures
    Parameter type
    Difference
    Point estimate
    0.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.67
         upper limit
    2.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.95

    Secondary: Number of Participants with Treatment-emergent Adverse Events (TEAEs)

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    End point title
    Number of Participants with Treatment-emergent Adverse Events (TEAEs)
    End point description
    An adverse event (AE) is any untoward medical occurrence in a clinical trial subject, including worsening of a pre-existing medical condition. The event does not necessarily have a causal relationship with study treatment. TEAEs include AEs from the first dose of study drug to 30 days after the last dose. A serious adverse event (SAE) is an AE that met at least 1 of the following criteria: -fatal; -life threatening; -required in-patient hospitalization or prolongation of existing hospitalization; -resulted in persistent or significant disability/incapacity; -congenital anomaly/birth defect; -other medically important serious event. Treatment-emergent SAEs are any SAE occurring from first dose of study drug through 90 days after the last dose or 30 days after the last dose if new anticancer therapy was started, whichever was earlier. AEs were graded for severity using CTCAE V4.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5.
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days after last dose (90 days for SAEs); median (range) duration was 48 (5.1, 110.1) weeks in Phase 1b, 39 (0.1, 107.3) weeks in Placebo + Pembrolizumab and 56 (0.1, 109.6) weeks in Phase 3 Talimogene Laherparepvec + Pembrolizumab.
    End point values
    Phase 1b: Talimogene Laherparepvec + Pembrolizumab Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Number of subjects analysed
    21
    344
    344
    Units: participants
        Any treatment-emergent adverse events
    21
    331
    338
        Grade ≥ 2
    20
    279
    306
        Grade ≥ 3
    13
    151
    161
        Grade ≥ 4
    2
    29
    33
        Serious adverse events
    8
    141
    154
        Leading to discontinuation of T-VEC/Placebo
    0
    24
    26
        Leading to discontinuation of pembrolizumab
    2
    41
    43
        Fatal adverse events
    1
    42
    45
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug to 30 days after last dose (90 days for SAEs); median (range) duration was 48 (5.1, 110) weeks in Phase 1b, 39 (0.1, 107) weeks in Placebo arm and 56 (0.1, 110) weeks in T-VEC arm. Deaths are reported up to the end of study.
    Adverse event reporting additional description
    Adverse events are reported for all subjects who received at least 1 dose of T-VEC or pembrolizumab. One subject who was randomized in Phase 3 to receive placebo received T-VEC; thus the Safety Analysis Set consisted of 344 subjects in the talimogene laherparepvec + pembrolizumab group and 344 subjects in the placebo + pembrolizumab arm.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Phase 1b: Talimogene Laherparepvec + Pembrolizumab
    Reporting group description
    Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.

    Reporting group title
    Phase 3: Placebo + Pembrolizumab
    Reporting group description
    Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.

    Reporting group title
    Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Reporting group description
    Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.

    Serious adverse events
    Phase 1b: Talimogene Laherparepvec + Pembrolizumab Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 21 (38.10%)
    141 / 344 (40.99%)
    154 / 344 (44.77%)
         number of deaths (all causes)
    6
    155
    145
         number of deaths resulting from adverse events
    Vascular disorders
    Arteritis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Labile blood pressure
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 344 (0.58%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Axillary lymphadenectomy
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder adenocarcinoma stage unspecified
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 344 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 21 (0.00%)
    26 / 344 (7.56%)
    27 / 344 (7.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 26
    1 / 29
         deaths causally related to treatment / all
    0 / 0
    0 / 19
    0 / 20
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Melanoma recurrent
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    3 / 344 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Metastases to lung
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to nervous system
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    0 / 21 (0.00%)
    10 / 344 (2.91%)
    7 / 344 (2.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 11
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 8
    0 / 5
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytokine release syndrome
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 344 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 344 (0.58%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Condition aggravated
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Death
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Disease progression
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    3 / 344 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 344 (0.58%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 344 (0.58%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    Pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 21 (9.52%)
    4 / 344 (1.16%)
    7 / 344 (2.03%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 4
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Swelling
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Confusional state
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Mental status changes
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obsessive-compulsive disorder
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somatic symptom disorder
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gynaecomastia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Bone contusion
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    3 / 344 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomeningocele
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Synovial rupture
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Traumatic arthritis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 344 (0.58%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 344 (0.58%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 344 (0.58%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral valve prolapse
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 344 (0.87%)
    4 / 344 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Myocarditis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 344 (0.87%)
    5 / 344 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Immune-mediated pneumonitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 344 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 344 (0.58%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumonitis
         subjects affected / exposed
    1 / 21 (4.76%)
    4 / 344 (1.16%)
    5 / 344 (1.45%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary sarcoidosis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 344 (0.58%)
    3 / 344 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    8 / 344 (2.33%)
    9 / 344 (2.62%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 17
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia of malignant disease
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymph node pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Granulomatous lymphadenitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 344 (0.58%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal ganglia infarction
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Central nervous system necrosis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neurological symptom
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 344 (0.58%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Papilloedema
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal oedema
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 344 (0.58%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    5 / 344 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    4 / 344 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoperitoneum
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal motility disorder
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hepatitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dermatitis bullous
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin hypopigmentation
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin lesion
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint effusion
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 344 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 344 (0.87%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psoriatic arthropathy
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Addison's disease
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adrenocortical insufficiency acute
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorder
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 344 (0.58%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphocytic hypophysitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroid mass
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroiditis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    3 / 344 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 344 (0.58%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 344 (0.87%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Bronchitis
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 344 (0.58%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 344 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 21 (4.76%)
    4 / 344 (1.16%)
    4 / 344 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chorioretinitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dermo-hypodermitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 344 (0.58%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extradural abscess
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected cyst
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymph gland infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 344 (0.00%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 21 (0.00%)
    4 / 344 (1.16%)
    3 / 344 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Postoperative wound infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Scrotal abscess
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureteritis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 344 (0.87%)
    5 / 344 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 344 (0.00%)
    2 / 344 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Phase 1b: Talimogene Laherparepvec + Pembrolizumab Phase 3: Placebo + Pembrolizumab Phase 3: Talimogene Laherparepvec + Pembrolizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 21 (100.00%)
    305 / 344 (88.66%)
    317 / 344 (92.15%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 21 (4.76%)
    22 / 344 (6.40%)
    19 / 344 (5.52%)
         occurrences all number
    1
    36
    36
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    3 / 21 (14.29%)
    1 / 344 (0.29%)
    1 / 344 (0.29%)
         occurrences all number
    3
    2
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 21 (9.52%)
    29 / 344 (8.43%)
    27 / 344 (7.85%)
         occurrences all number
    2
    38
    33
    Chills
         subjects affected / exposed
    8 / 21 (38.10%)
    17 / 344 (4.94%)
    73 / 344 (21.22%)
         occurrences all number
    14
    19
    153
    Fatigue
         subjects affected / exposed
    15 / 21 (71.43%)
    94 / 344 (27.33%)
    137 / 344 (39.83%)
         occurrences all number
    25
    128
    214
    Face oedema
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 344 (0.00%)
    3 / 344 (0.87%)
         occurrences all number
    3
    0
    3
    Influenza like illness
         subjects affected / exposed
    5 / 21 (23.81%)
    26 / 344 (7.56%)
    64 / 344 (18.60%)
         occurrences all number
    10
    35
    143
    Injection site pain
         subjects affected / exposed
    2 / 21 (9.52%)
    14 / 344 (4.07%)
    15 / 344 (4.36%)
         occurrences all number
    2
    24
    20
    Injection site reaction
         subjects affected / exposed
    2 / 21 (9.52%)
    3 / 344 (0.87%)
    10 / 344 (2.91%)
         occurrences all number
    4
    3
    14
    Oedema peripheral
         subjects affected / exposed
    5 / 21 (23.81%)
    22 / 344 (6.40%)
    27 / 344 (7.85%)
         occurrences all number
    8
    23
    35
    Pain
         subjects affected / exposed
    1 / 21 (4.76%)
    18 / 344 (5.23%)
    24 / 344 (6.98%)
         occurrences all number
    2
    23
    33
    Pyrexia
         subjects affected / exposed
    10 / 21 (47.62%)
    33 / 344 (9.59%)
    128 / 344 (37.21%)
         occurrences all number
    29
    46
    352
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 21 (9.52%)
    7 / 344 (2.03%)
    11 / 344 (3.20%)
         occurrences all number
    2
    7
    13
    Insomnia
         subjects affected / exposed
    3 / 21 (14.29%)
    27 / 344 (7.85%)
    23 / 344 (6.69%)
         occurrences all number
    5
    29
    27
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 344 (0.00%)
    4 / 344 (1.16%)
         occurrences all number
    2
    0
    7
    Contusion
         subjects affected / exposed
    2 / 21 (9.52%)
    3 / 344 (0.87%)
    4 / 344 (1.16%)
         occurrences all number
    2
    4
    4
    Procedural pain
         subjects affected / exposed
    2 / 21 (9.52%)
    5 / 344 (1.45%)
    9 / 344 (2.62%)
         occurrences all number
    2
    5
    9
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 21 (14.29%)
    16 / 344 (4.65%)
    20 / 344 (5.81%)
         occurrences all number
    3
    25
    29
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 21 (14.29%)
    23 / 344 (6.69%)
    26 / 344 (7.56%)
         occurrences all number
    6
    34
    35
    Blood iron decreased
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences all number
    2
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 21 (9.52%)
    7 / 344 (2.03%)
    15 / 344 (4.36%)
         occurrences all number
    3
    9
    19
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 21 (38.10%)
    44 / 344 (12.79%)
    58 / 344 (16.86%)
         occurrences all number
    8
    49
    72
    Dyspnoea
         subjects affected / exposed
    4 / 21 (19.05%)
    24 / 344 (6.98%)
    23 / 344 (6.69%)
         occurrences all number
    4
    26
    37
    Pneumonitis
         subjects affected / exposed
    2 / 21 (9.52%)
    7 / 344 (2.03%)
    18 / 344 (5.23%)
         occurrences all number
    2
    11
    28
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 21 (9.52%)
    26 / 344 (7.56%)
    33 / 344 (9.59%)
         occurrences all number
    6
    45
    46
    Leukopenia
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 344 (0.58%)
    0 / 344 (0.00%)
         occurrences all number
    2
    4
    0
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 344 (0.00%)
    4 / 344 (1.16%)
         occurrences all number
    2
    0
    5
    Headache
         subjects affected / exposed
    9 / 21 (42.86%)
    44 / 344 (12.79%)
    62 / 344 (18.02%)
         occurrences all number
    13
    59
    144
    Paraesthesia
         subjects affected / exposed
    2 / 21 (9.52%)
    6 / 344 (1.74%)
    13 / 344 (3.78%)
         occurrences all number
    3
    7
    13
    Eye disorders
    Visual impairment
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 344 (0.58%)
    6 / 344 (1.74%)
         occurrences all number
    2
    2
    7
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 21 (9.52%)
    24 / 344 (6.98%)
    23 / 344 (6.69%)
         occurrences all number
    2
    26
    29
    Abdominal pain upper
         subjects affected / exposed
    2 / 21 (9.52%)
    12 / 344 (3.49%)
    7 / 344 (2.03%)
         occurrences all number
    2
    14
    8
    Constipation
         subjects affected / exposed
    4 / 21 (19.05%)
    28 / 344 (8.14%)
    52 / 344 (15.12%)
         occurrences all number
    5
    36
    63
    Diarrhoea
         subjects affected / exposed
    13 / 21 (61.90%)
    73 / 344 (21.22%)
    70 / 344 (20.35%)
         occurrences all number
    17
    124
    118
    Dry mouth
         subjects affected / exposed
    1 / 21 (4.76%)
    19 / 344 (5.52%)
    14 / 344 (4.07%)
         occurrences all number
    1
    21
    16
    Nausea
         subjects affected / exposed
    7 / 21 (33.33%)
    61 / 344 (17.73%)
    92 / 344 (26.74%)
         occurrences all number
    10
    78
    123
    Frequent bowel movements
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 344 (0.29%)
    0 / 344 (0.00%)
         occurrences all number
    2
    1
    0
    Vomiting
         subjects affected / exposed
    7 / 21 (33.33%)
    29 / 344 (8.43%)
    56 / 344 (16.28%)
         occurrences all number
    8
    35
    86
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    2 / 21 (9.52%)
    4 / 344 (1.16%)
    6 / 344 (1.74%)
         occurrences all number
    4
    6
    6
    Alopecia
         subjects affected / exposed
    3 / 21 (14.29%)
    3 / 344 (0.87%)
    10 / 344 (2.91%)
         occurrences all number
    3
    3
    11
    Erythema
         subjects affected / exposed
    2 / 21 (9.52%)
    15 / 344 (4.36%)
    15 / 344 (4.36%)
         occurrences all number
    2
    15
    19
    Pruritus
         subjects affected / exposed
    7 / 21 (33.33%)
    55 / 344 (15.99%)
    61 / 344 (17.73%)
         occurrences all number
    9
    67
    74
    Rash
         subjects affected / exposed
    9 / 21 (42.86%)
    42 / 344 (12.21%)
    61 / 344 (17.73%)
         occurrences all number
    16
    56
    99
    Rash erythematous
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 344 (0.29%)
    4 / 344 (1.16%)
         occurrences all number
    12
    1
    4
    Rash macular
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 344 (0.29%)
    6 / 344 (1.74%)
         occurrences all number
    7
    1
    7
    Rash maculo-papular
         subjects affected / exposed
    3 / 21 (14.29%)
    17 / 344 (4.94%)
    20 / 344 (5.81%)
         occurrences all number
    3
    23
    29
    Skin lesion
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 344 (0.58%)
    11 / 344 (3.20%)
         occurrences all number
    2
    2
    13
    Skin mass
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 344 (0.58%)
    0 / 344 (0.00%)
         occurrences all number
    4
    2
    0
    Urticaria
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 344 (0.58%)
    3 / 344 (0.87%)
         occurrences all number
    2
    3
    3
    Vitiligo
         subjects affected / exposed
    5 / 21 (23.81%)
    32 / 344 (9.30%)
    44 / 344 (12.79%)
         occurrences all number
    5
    32
    47
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 21 (38.10%)
    66 / 344 (19.19%)
    82 / 344 (23.84%)
         occurrences all number
    16
    93
    140
    Back pain
         subjects affected / exposed
    3 / 21 (14.29%)
    30 / 344 (8.72%)
    35 / 344 (10.17%)
         occurrences all number
    6
    39
    40
    Muscle spasms
         subjects affected / exposed
    2 / 21 (9.52%)
    5 / 344 (1.45%)
    9 / 344 (2.62%)
         occurrences all number
    2
    6
    10
    Myalgia
         subjects affected / exposed
    2 / 21 (9.52%)
    16 / 344 (4.65%)
    33 / 344 (9.59%)
         occurrences all number
    2
    22
    46
    Pain in extremity
         subjects affected / exposed
    4 / 21 (19.05%)
    21 / 344 (6.10%)
    29 / 344 (8.43%)
         occurrences all number
    5
    26
    37
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    3 / 21 (14.29%)
    20 / 344 (5.81%)
    22 / 344 (6.40%)
         occurrences all number
    3
    20
    22
    Hypothyroidism
         subjects affected / exposed
    6 / 21 (28.57%)
    49 / 344 (14.24%)
    48 / 344 (13.95%)
         occurrences all number
    10
    61
    60
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    3 / 21 (14.29%)
    11 / 344 (3.20%)
    19 / 344 (5.52%)
         occurrences all number
    11
    16
    60
    Decreased appetite
         subjects affected / exposed
    0 / 21 (0.00%)
    26 / 344 (7.56%)
    43 / 344 (12.50%)
         occurrences all number
    0
    29
    53
    Hyperkalaemia
         subjects affected / exposed
    2 / 21 (9.52%)
    5 / 344 (1.45%)
    2 / 344 (0.58%)
         occurrences all number
    2
    6
    2
    Hypophosphataemia
         subjects affected / exposed
    2 / 21 (9.52%)
    3 / 344 (0.87%)
    14 / 344 (4.07%)
         occurrences all number
    3
    9
    18
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    2 / 21 (9.52%)
    9 / 344 (2.62%)
    14 / 344 (4.07%)
         occurrences all number
    2
    12
    19
    Influenza
         subjects affected / exposed
    2 / 21 (9.52%)
    7 / 344 (2.03%)
    9 / 344 (2.62%)
         occurrences all number
    2
    9
    9
    Nasopharyngitis
         subjects affected / exposed
    1 / 21 (4.76%)
    23 / 344 (6.69%)
    21 / 344 (6.10%)
         occurrences all number
    1
    27
    26
    Oral herpes
         subjects affected / exposed
    2 / 21 (9.52%)
    16 / 344 (4.65%)
    15 / 344 (4.36%)
         occurrences all number
    2
    16
    20
    Rhinitis
         subjects affected / exposed
    2 / 21 (9.52%)
    11 / 344 (3.20%)
    7 / 344 (2.03%)
         occurrences all number
    2
    12
    8
    Urinary tract infection
         subjects affected / exposed
    1 / 21 (4.76%)
    17 / 344 (4.94%)
    22 / 344 (6.40%)
         occurrences all number
    1
    22
    30
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 21 (9.52%)
    17 / 344 (4.94%)
    17 / 344 (4.94%)
         occurrences all number
    3
    20
    20

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 May 2015
    •Changed the Phase 2 part to Phase 3 •Included 2 Phase 3 primary endpoints, PFS and OS. The primary analysis of PFS will be based on tumor evaluation by a blinded independent central review (BICR) using RECIST 1.1 with modifications: 1) increased total target lesions to maximum of 10 (max 5 per organ), 2) new skin lesions will be considered in the overall non-target lesion assessment but will not automatically result in a response of PD. •Removed cross-over combination treatment. •Increased sample size of Phase 3 to 660 subjects for formal testing of PFS and OS. •Revised Phase 3 treatment schedule. •Updated Phase 3 prior therapy inclusion criteria. •Use irRC-RECIST for Phase 3 treatment decisions and secondary endpoints. •Added an event-driven analysis of the secondary PFS endpoint based on irRC-RECIST. •Updated Phase 3 measurable disease and tumor sample inclusion criteria. •Skin photographs and radiographs in Phase 3 will be submitted to BICR for evaluation of PFS and secondary response-related endpoints. •Removed option for retreatment. •Added Phase 1b re-analysis time points. •Added 2 interim safety, 1 interim ORR futility, 1 interim efficacy, and 1 interim analysis for OS in Phase 3. •Utilized an independent, external DMC in phase 3 to monitor safety and evaluate futility. •Updated the pembrolizumab-related pneumonitis toxicity management guidelines. •Updated tumor sample collection schedule in Phase 3. •Revised the schedule of safety laboratory assessments. •Secondary objectives of anti-pembrolizumab antibodies, pembrolizumab PK and changes in PD-L1 changed to exploratory objectives. •Ordinal categorical response score and deep response rate endpoints removed. •Moved evaluation of PRO in phase 3 from exploratory to secondary objective. •Clarified the responsibilities of the DLRT in Phase 1b. •Increased follow-up to 60 months after last subject enrolled. •Changed reporting period for pembrolizumab Events of Clinical Interest and the reporting period for SAEs.
    25 Sep 2015
    •Changed Phase 3 part to be double-blind and added placebo to the pembrolizumab arm. •Reordered sections to separate Phase 1b and Phase 3 throughout. •Updated background information for T-VEC and pembrolizumab to reflect recent data. •Added results of the completed dose level review team (DLRT) evaluation for Phase 1b. •Allowed for more flexibility in frequency of radiographic follow-up for subjects who have reached a confirmed clinical response (CR) in long term follow-up. •Updated contraception language for exclusion criterion and sections related to pembrolizumab. •Shortened period from ending prior adjuvant therapy to 28 days prior to enrollment. •Prior ipilimumab as adjuvant therapy is now allowed. •Added exclusion criteria for allogeneic hematopoietic stem cell transplantation and active tuberculosis. •Updated text related to pembrolizumab events of clinical interest, rescue medications, dose adjustment, overdose, and supportive care guidelines. Immune-related AEs are no longer considered pembrolizumab events of interest. •Combined the schedule of assessments tables for Phase 3 arms 1 and 2. •Injectable investigational product-related AEs during long-term follow-up will be collected. •Updated pregnancy and lactation reporting language. •Updated text for interim analysis and interim ORR futility analysis in Phase 3. If futility is declared on ORR, DCR will also need to have futility declared. This is to prevent the study treatment being declared futile when the ORR may not be adequately improved but the DCR is at the time of the interim analysis. •Updated text pertaining to the analysis for the secondary endpoint of PFS per irRC-RECIST (phase 3) and included text regarding multiplicity adjustment for clarification. •Removed RECIST 1.1 modification that new skin lesions will be considered in the overall non-target lesion assessment but will not automatically result in esponse of PD. •Updated language to clarify the modified response criteria in the appendices.
    12 Apr 2017
    •An event-driven overall survival interim analysis at 282 events (including futility analysis) added to the planned analyses in order to evaluate the efficacy/futility with approximately 70% power of the combination treatment at an earlier time point in order to facilitate regulatory submission if the combination demonstrates significant improvement in overall survival or stopping the study for futility in overall survival. •The interim futility analysis based on overall response rate and disease control rate for the data monitoring committee review was changed from the investigator assessment to a blinded independent central review. Using blinded independent central review assessed responses would provide a robust and consistent assessment of overall response rate and disease control rate as for the primary endpoint of progression free survival, which also utilizes blinded independent central review. The Bayesian priors for the combination arm were also revised to reflect new data available from the phase 1b part of the study. •The fallback procedure to test overall survival and progression free survival dual primaries with the Maurer-Bretz multiple testing procedure was revised. •The secondary objectives were updated to test additional hypotheses per modified irRC-RECIST by blinded independent central review, and overall survival excluding stage IVM1c. •The secondary and exploratory objectives related to patient reported outcomes were updated.
    24 Jan 2018
    •Replace the Dose Modification Guidelines for Pembrolizumab Related Adverse Events Table with the Pembrolizumab-related Adverse Event Management table to incorporate the new myocarditis risk and management and remove redundant and outdated information about management of pembrolizumab-related AEs. •Update the information and table regarding management of pembrolizumab-related infusion reactions. •Add thyroid testing up to 3 days before dosing and that study treatment can be administered before the results are reported if the subject is asymptomatic. •Clarify the response evaluation criteria used for Phase 1b and Phase 3 endpoints and update the matrix for determining overall response at each assessment. •Clarify the collection of archival biopsy. •Clarify when subjects should undergo safety follow-up procedures. •Allow survival status to be assessed at additional time points not specified in the Schedule of Assessments. •Clarify that for subjects with PD QLQ-C30 is not collected in long-term follow-up; however, EQ-5D-3L will be collected. •Clarify the timing of the beginning of the registry protocol; update the primary completion and end of trial dates. •Update T-VEC and pembrolizumab background information and the rationale for combination therapy. •Clarify timing of safety monitoring by the DMC. •Clarify that both clinical and photographic evaluations must be done for lesions which cannot be evaluated by radiographic imaging. •Clarify that prior tumor vaccines are allowable if administered in the adjuvant setting. •Clarify that subjects should return to the clinic within 3 days after notification of a suspected herpetic lesion. •Clarify that photographs of all visible lesions must be done at baseline to allow for follow-up of lesions during treatment. •Clarify that laboratory assessment up to 3 days prior to administration of study treatment is allowed. •Clarify the PRO analysis set. •Clarify the futility analysis of OS for a non-constant treatment effect.
    15 Jan 2020
    • Update statistical characteristics of the group sequential OS analyses and add a third interim OS analysis planned after 315 events. To optimize the opportunity to observe statistical significance prior to the OS primary analysis (PA) if there is a late survival effect that would not be achieved at OS interim analysis (IA)1 or OS IA2, an additional look at OS IA3 (n = 315) was added prior to the OS PA. The trigger for 315 was selected to achieve approximately half the information gain between n = 282 and n = 346, and is halfway between the expected timings of OS IA2 and OS PA. The protocol is amended to include this additional analysis prior to any formal evaluation of efficacy related to PFS or OS. Appropriate alpha was allocated for all of the efficacy analyses. • Update the background to include the updated OS results from the KEYNOTE-006 and CHECKMATE-067 trials. •Update exploratory objectives to evaluate PROs as assessed by the EORTC QLQ-C30 and EuroQoL-5D-3L (EQ-5D-3L) subscales and add language for PRO population assessment. • An exploratory endpoint assessing lesion level response was added. • Clarify covariates for efficacy in subgroup or multivariate analyses. • Clarify language for interim efficacy analyses including possible hypotheses tests at planned analyses and operating characteristics of the primary analysis of PFS and sequential tests of OS. • Add text to clarify that in the Phase 1b part when nodal disease regresses to below 10 mm, the nodal lesion measurement should be recorded as 0 x 0 mm instead of the actual measurement. • Clarify that no index lesions identified at baseline is associated with “Not applicable (NA)” instead of “Not done” in the matrix for determining overall response. Add “unevaluable (UE) or iUE (unevaluable by modified irRC-RECIST) to the matrix for determining overall response. • Clarify number of days after the date of enrollment for visit response of stable disease by modified irRC-RECIST (iSD) or better.

    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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