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NCT01704287 · OUTCOME

Final Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status - Initial Treatment Period

Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Participants With Advanced Melanoma (MK-3475-002/P08719/KEYNOTE-002) · Source last updated 2020-05-18

Results reported by the registry submitting party. Population, time horizon, units and missing values must be read together.

Measure
MEDIAN
Unit
Months
Interval / dispersion
95% Confidence Interval
Time frame
Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)

What was measured

OS was defined as the time from randomization to death due to any cause. Participants with an Allred Proportion Score (APS) ≥2 (membranous staining in ≥1% of cells for PD-L1) were considered to be PD-L1 Positive and participants with an APS of 0 or 1 were considered to be PD-L1 Negative. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS duration based on the product-limit (Kaplan-Meier) method for censored data by PD-L1 tumor expression status is presented.

Analysis population: The analysis population consisted of all randomized participants who had a PD-L1 tumor expression status assessment. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.

Groups in this outcome

Pembrolizumab 2 mg/kg

Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to \~66 months)

Pembrolizumab 10 mg/kg

Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to \~66 months)

Investigator-Choice Chemotherapy (ICC)

Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to \~66 months)

Group identifiers and denominators belong to this outcome only. They may differ in another outcome or in safety reporting.

Analysis denominator · Participants

GroupSource count
Pembrolizumab 2 mg/kg180
Pembrolizumab 10 mg/kg181
Investigator-Choice Chemotherapy (ICC)179

Reported measurements

PD-L1 Positive

Analysis denominator · Participants

GroupSource count
Pembrolizumab 2 mg/kg99
Pembrolizumab 10 mg/kg97
Investigator-Choice Chemotherapy (ICC)98
Values in Months · Interval/dispersion: 95% Confidence Interval
GroupValueSpreadLowerUpperComment
Pembrolizumab 2 mg/kg15.0Not reported10.920.9Not reported
Pembrolizumab 10 mg/kg17.5Not reported13.728.9Not reported
Investigator-Choice Chemotherapy (ICC)12.1Not reported7.718.2Not reported
PD-L1 Negative

Analysis denominator · Participants

GroupSource count
Pembrolizumab 2 mg/kg48
Pembrolizumab 10 mg/kg46
Investigator-Choice Chemotherapy (ICC)40
Values in Months · Interval/dispersion: 95% Confidence Interval
GroupValueSpreadLowerUpperComment
Pembrolizumab 2 mg/kg10.5Not reported6.413.5Not reported
Pembrolizumab 10 mg/kg13.4Not reported4.623.3Not reported
Investigator-Choice Chemotherapy (ICC)9.3Not reported5.114.2Not reported

Source statistical analyses

Group order, estimate direction, methods and comments are retained. No treatment ranking is inferred.

  1. ci Lower Limit
    0.66
    ci Num Sides
    TWO_SIDED
    ci Pct Value
    95
    ci Upper Limit
    1.28
    estimate Comment
    Numerator=Pembrolizumab 2 mg/kg Denominator=ICC
    group Description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)
    group Ids
    1. OG000
    2. OG002
    non Inferiority Comment
    PD-L1-Positive Participants
    non Inferiority Type
    SUPERIORITY_OR_OTHER_LEGACY
    p Value
    0.3113
    p Value Comment
    One-sided p-value based on stratified log rank test
    param Type
    Hazard Ratio (HR)
    param Value
    0.92
    statistical Method
    Log Rank
  2. ci Lower Limit
    0.50
    ci Num Sides
    TWO_SIDED
    ci Pct Value
    95
    ci Upper Limit
    0.99
    estimate Comment
    Numerator=Pembrolizumab 10 mg/kg Denominator=ICC
    group Description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)
    group Ids
    1. OG001
    2. OG002
    non Inferiority Comment
    PD-L1 Positive Participants
    non Inferiority Type
    SUPERIORITY_OR_OTHER_LEGACY
    p Value
    0.0208
    p Value Comment
    One-sided p-value based on stratified log rank test
    param Type
    Hazard Ratio (HR)
    param Value
    0.70
    statistical Method
    Log Rank
  3. ci Lower Limit
    0.50
    ci Num Sides
    TWO_SIDED
    ci Pct Value
    95
    ci Upper Limit
    1.00
    estimate Comment
    Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg
    group Description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)
    group Ids
    1. OG000
    2. OG001
    non Inferiority Comment
    PD-L1 Positive Participants
    non Inferiority Type
    SUPERIORITY_OR_OTHER_LEGACY
    p Value
    0.0496
    p Value Comment
    Two-sided p-value based on stratified log rank test
    param Type
    Hazard Ratio (HR)
    param Value
    0.71
    statistical Method
    Log Rank
  4. ci Lower Limit
    0.65
    ci Num Sides
    TWO_SIDED
    ci Pct Value
    95
    ci Upper Limit
    1.76
    estimate Comment
    Numerator=Pembrolizumab 2 mg/kg Denominator=ICC
    group Description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)
    group Ids
    1. OG000
    2. OG002
    non Inferiority Comment
    PD-L1 Negative Participants
    non Inferiority Type
    SUPERIORITY_OR_OTHER_LEGACY
    p Value
    0.6043
    p Value Comment
    One-sided p-value based on stratified log rank test
    param Type
    Hazard Ratio (HR)
    param Value
    1.07
    statistical Method
    Log Rank
  5. ci Lower Limit
    0.37
    ci Num Sides
    TWO_SIDED
    ci Pct Value
    95
    ci Upper Limit
    1.04
    estimate Comment
    Numerator=Pembrolizumab 10 mg/kg Denominator=ICC
    group Description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)
    group Ids
    1. OG001
    2. OG002
    non Inferiority Comment
    PD-L1 Negative Participants
    non Inferiority Type
    SUPERIORITY_OR_OTHER_LEGACY
    p Value
    0.0335
    p Value Comment
    One-sided p-value based on stratified log rank test
    param Type
    Hazard Ratio (HR)
    param Value
    0.62
    statistical Method
    Log Rank
  6. ci Lower Limit
    0.44
    ci Num Sides
    TWO_SIDED
    ci Pct Value
    95
    ci Upper Limit
    1.13
    estimate Comment
    Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg
    group Description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)
    group Ids
    1. OG000
    2. OG001
    non Inferiority Comment
    PD-L1 Negative Participants
    non Inferiority Type
    SUPERIORITY_OR_OTHER_LEGACY
    p Value
    0.1504
    p Value Comment
    Two-sided p-value based on stratified log rank test
    param Type
    Hazard Ratio (HR)
    param Value
    0.71
    statistical Method
    Log Rank
Complete source fields
analyses
  1. ci Lower Limit
    0.66
    ci Num Sides
    TWO_SIDED
    ci Pct Value
    95
    ci Upper Limit
    1.28
    estimate Comment
    Numerator=Pembrolizumab 2 mg/kg Denominator=ICC
    group Description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)
    group Ids
    1. OG000
    2. OG002
    non Inferiority Comment
    PD-L1-Positive Participants
    non Inferiority Type
    SUPERIORITY_OR_OTHER_LEGACY
    p Value
    0.3113
    p Value Comment
    One-sided p-value based on stratified log rank test
    param Type
    Hazard Ratio (HR)
    param Value
    0.92
    statistical Method
    Log Rank
  2. ci Lower Limit
    0.50
    ci Num Sides
    TWO_SIDED
    ci Pct Value
    95
    ci Upper Limit
    0.99
    estimate Comment
    Numerator=Pembrolizumab 10 mg/kg Denominator=ICC
    group Description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)
    group Ids
    1. OG001
    2. OG002
    non Inferiority Comment
    PD-L1 Positive Participants
    non Inferiority Type
    SUPERIORITY_OR_OTHER_LEGACY
    p Value
    0.0208
    p Value Comment
    One-sided p-value based on stratified log rank test
    param Type
    Hazard Ratio (HR)
    param Value
    0.70
    statistical Method
    Log Rank
  3. ci Lower Limit
    0.50
    ci Num Sides
    TWO_SIDED
    ci Pct Value
    95
    ci Upper Limit
    1.00
    estimate Comment
    Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg
    group Description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)
    group Ids
    1. OG000
    2. OG001
    non Inferiority Comment
    PD-L1 Positive Participants
    non Inferiority Type
    SUPERIORITY_OR_OTHER_LEGACY
    p Value
    0.0496
    p Value Comment
    Two-sided p-value based on stratified log rank test
    param Type
    Hazard Ratio (HR)
    param Value
    0.71
    statistical Method
    Log Rank
  4. ci Lower Limit
    0.65
    ci Num Sides
    TWO_SIDED
    ci Pct Value
    95
    ci Upper Limit
    1.76
    estimate Comment
    Numerator=Pembrolizumab 2 mg/kg Denominator=ICC
    group Description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)
    group Ids
    1. OG000
    2. OG002
    non Inferiority Comment
    PD-L1 Negative Participants
    non Inferiority Type
    SUPERIORITY_OR_OTHER_LEGACY
    p Value
    0.6043
    p Value Comment
    One-sided p-value based on stratified log rank test
    param Type
    Hazard Ratio (HR)
    param Value
    1.07
    statistical Method
    Log Rank
  5. ci Lower Limit
    0.37
    ci Num Sides
    TWO_SIDED
    ci Pct Value
    95
    ci Upper Limit
    1.04
    estimate Comment
    Numerator=Pembrolizumab 10 mg/kg Denominator=ICC
    group Description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)
    group Ids
    1. OG001
    2. OG002
    non Inferiority Comment
    PD-L1 Negative Participants
    non Inferiority Type
    SUPERIORITY_OR_OTHER_LEGACY
    p Value
    0.0335
    p Value Comment
    One-sided p-value based on stratified log rank test
    param Type
    Hazard Ratio (HR)
    param Value
    0.62
    statistical Method
    Log Rank
  6. ci Lower Limit
    0.44
    ci Num Sides
    TWO_SIDED
    ci Pct Value
    95
    ci Upper Limit
    1.13
    estimate Comment
    Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg
    group Description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)
    group Ids
    1. OG000
    2. OG001
    non Inferiority Comment
    PD-L1 Negative Participants
    non Inferiority Type
    SUPERIORITY_OR_OTHER_LEGACY
    p Value
    0.1504
    p Value Comment
    Two-sided p-value based on stratified log rank test
    param Type
    Hazard Ratio (HR)
    param Value
    0.71
    statistical Method
    Log Rank
classes
  1. categories
    1. measurements
      1. group Id
        OG000
        lower Limit
        10.9
        upper Limit
        20.9
        value
        15.0
      2. group Id
        OG001
        lower Limit
        13.7
        upper Limit
        28.9
        value
        17.5
      3. group Id
        OG002
        lower Limit
        7.7
        upper Limit
        18.2
        value
        12.1
    denoms
    1. counts
      1. group Id
        OG000
        value
        99
      2. group Id
        OG001
        value
        97
      3. group Id
        OG002
        value
        98
      units
      Participants
    title
    PD-L1 Positive
  2. categories
    1. measurements
      1. group Id
        OG000
        lower Limit
        6.4
        upper Limit
        13.5
        value
        10.5
      2. group Id
        OG001
        lower Limit
        4.6
        upper Limit
        23.3
        value
        13.4
      3. group Id
        OG002
        lower Limit
        5.1
        upper Limit
        14.2
        value
        9.3
    denoms
    1. counts
      1. group Id
        OG000
        value
        48
      2. group Id
        OG001
        value
        46
      3. group Id
        OG002
        value
        40
      units
      Participants
    title
    PD-L1 Negative
denoms
  1. counts
    1. group Id
      OG000
      value
      180
    2. group Id
      OG001
      value
      181
    3. group Id
      OG002
      value
      179
    units
    Participants
description
OS was defined as the time from randomization to death due to any cause. Participants with an Allred Proportion Score (APS) ≥2 (membranous staining in ≥1% of cells for PD-L1) were considered to be PD-L1 Positive and participants with an APS of 0 or 1 were considered to be PD-L1 Negative. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS duration based on the product-limit (Kaplan-Meier) method for censored data by PD-L1 tumor expression status is presented.
dispersion Type
95% Confidence Interval
groups
  1. description
    Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to \~66 months)
    id
    OG000
    title
    Pembrolizumab 2 mg/kg
  2. description
    Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to \~66 months)
    id
    OG001
    title
    Pembrolizumab 10 mg/kg
  3. description
    Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to \~66 months)
    id
    OG002
    title
    Investigator-Choice Chemotherapy (ICC)
param Type
MEDIAN
population Description
The analysis population consisted of all randomized participants who had a PD-L1 tumor expression status assessment. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.
reporting Status
POSTED
time Frame
Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
title
Final Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status - Initial Treatment Period
type
SECONDARY
unit Of Measure
Months

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Preserved source evidence · Not medical advice