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NCT01120184 · OUTCOME

Progression-Free Survival (PFS) According to IRF Assessment

A Study of Trastuzumab Emtansine (T-DM1) Plus Pertuzumab/Pertuzumab Placebo Versus Trastuzumab [Herceptin] Plus a Taxane in Participants With Metastatic Breast Cancer (MARIANNE) · Source last updated 2024-03-04

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 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)

What was measured

Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis, and corresponding confidence intervals (CIs) were computed using the Brookmeyer-Crowley method.

Analysis population: ITT Population.

Groups in this outcome

Trastuzumab + Taxane

Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m\^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m\^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.

Trastuzumab Emtansine + Placebo

Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.

Trastuzumab Emtansine + Pertuzumab

Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.

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

Analysis denominator · Participants

GroupSource count
Trastuzumab + Taxane365
Trastuzumab Emtansine + Placebo367
Trastuzumab Emtansine + Pertuzumab363

Reported measurements

Source class 1
Values in months · Interval/dispersion: 95% Confidence Interval
GroupValueSpreadLowerUpperComment
Trastuzumab + Taxane13.7Not reported12.414.9Not reported
Trastuzumab Emtansine + Placebo14.1Not reported10.916.8Not reported
Trastuzumab Emtansine + Pertuzumab15.2Not reported12.518.8Not reported

Source statistical analyses

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

  1. ci Lower Limit
    0.73
    ci Num Sides
    TWO_SIDED
    ci Pct Value
    97.5
    ci Upper Limit
    1.13
    estimate Comment
    Direction of comparison: Trastuzumab Emtansine + Placebo vs. Trastuzumab + Taxane
    group Description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes \[trastuzumab and/or lapatinib\], yes \[no trastuzumab and/or lapatinib\]), and visceral disease (present, absent).
    group Ids
    1. OG000
    2. OG001
    non Inferiority Comment
    The study was powered for superiority with target hazard ratio (HR) equal to 0.75, as well as for non-inferiority with HR equal to 1.1765 for comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm. Non-inferiority was established if the upper bound of the 97.5% CI was less than (\<) 1.1765. Superiority was achieved if the upper bound of the 97.5% CI was \<1.00.
    non Inferiority Type
    NON_INFERIORITY_OR_EQUIVALENCE_LEGACY
    p Value
    0.3125
    p Value Comment
    Test and p-value apply for superiority test. Two-sided significance level of 2.5% was used to adjust for independent comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm.
    param Type
    Hazard Ratio (HR)
    param Value
    0.91
    statistical Method
    Log Rank
  2. ci Lower Limit
    0.69
    ci Num Sides
    TWO_SIDED
    ci Pct Value
    97.5
    ci Upper Limit
    1.08
    estimate Comment
    Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs. Trastuzumab + Taxane
    group Description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes \[trastuzumab and/or lapatinib\], yes \[no trastuzumab and/or lapatinib\]), and visceral disease (present, absent).
    group Ids
    1. OG000
    2. OG002
    non Inferiority Comment
    The study was powered for superiority with target HR equal to 0.75, as well as for non-inferiority with HR equal to 1.1765 for comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm. Non-inferiority was established if the upper bound of the 97.5% CI was \<1.1765. Superiority was achieved if the upper bound of the 97.5% CI was \<1.00.
    non Inferiority Type
    NON_INFERIORITY_OR_EQUIVALENCE_LEGACY
    p Value
    0.1407
    p Value Comment
    Test and p-value apply for superiority test. Two-sided significance level of 2.5% was used to adjust for independent comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm.
    param Type
    Hazard Ratio (HR)
    param Value
    0.87
    statistical Method
    Log Rank
  3. ci Lower Limit
    0.73
    ci Num Sides
    TWO_SIDED
    ci Pct Value
    97.5
    ci Upper Limit
    1.13
    estimate Comment
    Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs. Trastuzumab Emtansine + Placebo
    group Description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes \[trastuzumab and/or lapatinib\], yes \[no trastuzumab and/or lapatinib\]), and visceral disease (present, absent).
    group Ids
    1. OG001
    2. OG002
    non Inferiority Comment
    The study was powered for superiority with target HR equal to 0.75, as well as for non-inferiority with HR equal to 1.1765 for comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm.
    non Inferiority Type
    NON_INFERIORITY_OR_EQUIVALENCE_LEGACY
    p Value
    0.3075
    p Value Comment
    Test and p-value apply for superiority test. Primary endpoint did not meet superiority of PFS for trastuzumab emtansine + pertuzumab versus trastuzumab + taxane (two-sided significance level 2.5%); thus, tests and p-value are considered descriptive.
    param Type
    Hazard Ratio (HR)
    param Value
    0.91
    statistical Method
    Log Rank
Complete source fields
analyses
  1. ci Lower Limit
    0.73
    ci Num Sides
    TWO_SIDED
    ci Pct Value
    97.5
    ci Upper Limit
    1.13
    estimate Comment
    Direction of comparison: Trastuzumab Emtansine + Placebo vs. Trastuzumab + Taxane
    group Description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes \[trastuzumab and/or lapatinib\], yes \[no trastuzumab and/or lapatinib\]), and visceral disease (present, absent).
    group Ids
    1. OG000
    2. OG001
    non Inferiority Comment
    The study was powered for superiority with target hazard ratio (HR) equal to 0.75, as well as for non-inferiority with HR equal to 1.1765 for comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm. Non-inferiority was established if the upper bound of the 97.5% CI was less than (\<) 1.1765. Superiority was achieved if the upper bound of the 97.5% CI was \<1.00.
    non Inferiority Type
    NON_INFERIORITY_OR_EQUIVALENCE_LEGACY
    p Value
    0.3125
    p Value Comment
    Test and p-value apply for superiority test. Two-sided significance level of 2.5% was used to adjust for independent comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm.
    param Type
    Hazard Ratio (HR)
    param Value
    0.91
    statistical Method
    Log Rank
  2. ci Lower Limit
    0.69
    ci Num Sides
    TWO_SIDED
    ci Pct Value
    97.5
    ci Upper Limit
    1.08
    estimate Comment
    Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs. Trastuzumab + Taxane
    group Description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes \[trastuzumab and/or lapatinib\], yes \[no trastuzumab and/or lapatinib\]), and visceral disease (present, absent).
    group Ids
    1. OG000
    2. OG002
    non Inferiority Comment
    The study was powered for superiority with target HR equal to 0.75, as well as for non-inferiority with HR equal to 1.1765 for comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm. Non-inferiority was established if the upper bound of the 97.5% CI was \<1.1765. Superiority was achieved if the upper bound of the 97.5% CI was \<1.00.
    non Inferiority Type
    NON_INFERIORITY_OR_EQUIVALENCE_LEGACY
    p Value
    0.1407
    p Value Comment
    Test and p-value apply for superiority test. Two-sided significance level of 2.5% was used to adjust for independent comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm.
    param Type
    Hazard Ratio (HR)
    param Value
    0.87
    statistical Method
    Log Rank
  3. ci Lower Limit
    0.73
    ci Num Sides
    TWO_SIDED
    ci Pct Value
    97.5
    ci Upper Limit
    1.13
    estimate Comment
    Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs. Trastuzumab Emtansine + Placebo
    group Description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes \[trastuzumab and/or lapatinib\], yes \[no trastuzumab and/or lapatinib\]), and visceral disease (present, absent).
    group Ids
    1. OG001
    2. OG002
    non Inferiority Comment
    The study was powered for superiority with target HR equal to 0.75, as well as for non-inferiority with HR equal to 1.1765 for comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm.
    non Inferiority Type
    NON_INFERIORITY_OR_EQUIVALENCE_LEGACY
    p Value
    0.3075
    p Value Comment
    Test and p-value apply for superiority test. Primary endpoint did not meet superiority of PFS for trastuzumab emtansine + pertuzumab versus trastuzumab + taxane (two-sided significance level 2.5%); thus, tests and p-value are considered descriptive.
    param Type
    Hazard Ratio (HR)
    param Value
    0.91
    statistical Method
    Log Rank
classes
  1. categories
    1. measurements
      1. group Id
        OG000
        lower Limit
        12.4
        upper Limit
        14.9
        value
        13.7
      2. group Id
        OG001
        lower Limit
        10.9
        upper Limit
        16.8
        value
        14.1
      3. group Id
        OG002
        lower Limit
        12.5
        upper Limit
        18.8
        value
        15.2
denoms
  1. counts
    1. group Id
      OG000
      value
      365
    2. group Id
      OG001
      value
      367
    3. group Id
      OG002
      value
      363
    units
    Participants
description
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis, and corresponding confidence intervals (CIs) were computed using the Brookmeyer-Crowley method.
dispersion Type
95% Confidence Interval
groups
  1. description
    Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m\^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m\^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
    id
    OG000
    title
    Trastuzumab + Taxane
  2. description
    Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
    id
    OG001
    title
    Trastuzumab Emtansine + Placebo
  3. description
    Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
    id
    OG002
    title
    Trastuzumab Emtansine + Pertuzumab
param Type
MEDIAN
population Description
ITT Population.
reporting Status
POSTED
time Frame
Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
title
Progression-Free Survival (PFS) According to IRF Assessment
type
PRIMARY
unit Of Measure
months

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Preserved source evidence · Not medical advice