A Study of Pertuzumab in Combination With Trastuzumab Plus an Aromatase Inhibitor in Participants With Metastatic Human Epidermal Growth Factor Receptor 2 (HER2)-Positive and Hormone Receptor-Positive Advanced Breast Cancer

Hoffmann-La Roche258 enrolled

Overview

This randomized, open-label, two-arm, multi-center, Phase II study will evaluate the efficacy and safety of pertuzumab in combination with trastuzumab plus an aromatase inhibitor (AI) in first-line participants with HER2-positive and hormone receptor-positive advanced breast cancer. Participants will be randomized to one of two treatment arms; Arm A (pertuzumab in combination with trastuzumab plus an AI) or Arm B (trastuzumab plus an AI). Participants may also receive induction chemotherapy (a taxane, either docetaxel or paclitaxel) at the investigator's discretion in combination with the assigned treatment arm. The anticipated time on study treatment is until disease progression, unacceptable toxicity, withdrawal of consent, or death whichever occurs first.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

258

Conditions

Breast Cancer

Interventions

Induction ChemotherapyDRUG

Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period will receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective pertuzumab and/or trastuzumab infusions at the investigator's discretion.

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Participants with HER2-positive and hormone receptor-positive advanced metastatic or locally advanced breast cancer * Post-menopausal status over 1 year * HER2-positive as assessed by local laboratory on primary or metastatic tumor * Hormone-receptor positive defined as estrogen receptor-positive and/or progesterone receptor-positive * At least one measurable lesion and/or non-measurable disease evaluable according to Response Evaluation Criteria In Solid Tumors Version 1.1 Exclusion Criteria: * Previous systemic non-hormonal anticancer therapy in the metastatic or locally advanced breast cancer setting * Previous treatment with anti-HER2 agents for breast cancer, except trastuzumab and/or lapatinib in the neoadjuvant or adjuvant setting * Disease progression while receiving adjuvant trastuzumab and/or lapatinib treatment * History of persistent Grade 2 or higher hematological toxicity according to National Cancer Institute-Common Toxicity Criteria Version 4.0 * Disease-free interval from completion of adjuvant/neo-adjuvant systemic non-hormonal treatment to recurrence of within 6 months * Other malignancies within the last 5 years, except for carcinoma in situ of the cervix or basal cell carcinoma * Clinical or radiographic evidence of central nervous system metastases or significant cardiovascular disease

Locations (82)

University of Alabama at Birmingham

Birmingham, Alabama, United States

Ironwood Cancer TX & Rsch Ctrs

Chandler, Arizona, United States

Genesis Cancer Center

Hot Springs, Arkansas, United States

Comprehensive Blood & CA Ctr; Research

Bakersfield, California, United States

Rocky Mountain Cancer Center - Denver

Denver, Colorado, United States

Outcomes

Primary Outcomes

Progression-Free Survival (PFS)

Progression-free survival (PFS) was defined as the time from randomization until the first radiographically documented progression of disease or death from any cause, whichever occurred first (either during study treatment or during follow-up). Progression of disease was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 and is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum of target lesion diameters must also demonstrate an absolute increase of at least 5 mm (Note: the appearance of one or more new lesions is also considered progression). Participants with no PFS events were censored at the time of the last evaluable tumor assessment. The primary analysis of PFS was planned to be performed when a total of 165 PFS events had occurred, and the final analysis after at least 60 months follow-up.

Time frame: Median [full range] of follow-up time on study for: Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B; Final Analysis: 73.20 [0.03-88.34] months vs. 71.06 [0.03-88.97] months in Arm A vs. Arm B

Secondary Outcomes

Overall Survival (OS)

Overall survival (OS) was defined as the time from the date of randomization to the date of death, regardless of the cause of death. Participants who were alive at the time of the analysis were censored at the date of the last follow-up assessment. Participants without follow-up assessment were censored at the day of last study medication (pertuzumab, trastuzumab, AI or induction chemotherapy), and participants with no post-baseline information were censored at the date of randomization. The primary analysis of OS was planned to be performed at the same time as for PFS (when a total of 165 PFS events had occurred), and the final analysis was planned after at least 60 months follow-up for all participants.

Overall Response Rate (ORR)

The overall response rate (ORR) was defined as the percentage of participants with best (confirmed) overall response (BOR) of either complete response (CR) or partial response (PR) from start of study treatment until progressive disease (PD)/recurrence or death, as assessed by the investigator according to RECIST version 1.1. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference baseline sum diameters; stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Participants needed to have two consecutive assessments of PR or CR at least 4 weeks apart to be a responder. Analysis of this outcome measure was only planned to occur at the time of primary analysis.

Time frame: Median [full range] of follow-up time on study for Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B

Clinical Benefit Rate (CBR)

Clinical Benefit Rate (CBR) was defined as the percentage of participants with best (confirmed) partial response (PR) or complete response (CR) or stable disease (SD) for at least 6 months. According to RECIST version 1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Analysis of this outcome measure was only planned to occur at the time of primary analysis.

Time frame: Median [full range] of follow-up time on study for Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B

Duration of Response (DOR)

Duration of response (DOR) was defined as the period from the date of initial confirmed partial response (PR) or complete response (CR) until the date of progressive disease or death from any cause. According to RECIST version 1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants with no documented progression after CR or PR were censored at the last date at which they were known to have had the CR or PR, respectively. The primary analysis of DOR was planned to be performed at the same time as for PFS (when a total of 165 PFS events had occurred), and the final analysis was planned after at least 60 months follow-up for all participants.

Time to Response (TTR)

Time to Response (TTR) was defined as the time from the date of randomization to the date of first complete response (CR) or partial response (PR). According to RECIST version 1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For participants who did not have a confirmed response, a censored TTR was calculated at the date of the last adequate tumor assessment. If no tumor assessment is performed for the participant (or all post-baseline assessments are not evaluable or PD) the censoring day would be set to day 1 (date of randomization). Analysis of this outcome measure was only planned to occur at the time of primary analysis.

Time frame: Median [full range] of follow-up time on study for Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B

Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores

The EQ-5D VAS is a participant-rated questionnaire to assess health-related quality of life (QoL) in terms of a single index value. The VAS component rates current health state on a scale from 0 mm (worst imaginable health state) to 100 mm (best imaginable health state); higher scores indicate a better health state.

Time frame: Baseline and every 3 cycles until treatment discontinuation (up to Cycle 120; 1 cycle is 21 days)

Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03

All adverse events (AEs) occurring during the study and until the post-treatment safety follow-up visit approximately 28 days after last study medication were recorded; thereafter, only study drug-related serious adverse events (SAEs) continued to be collected. The investigator graded all AEs for severity per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. AEs suggestive of congestive heart failure (CHF) were identified by the SMQ (wide) "Cardiac Failure" with a status of "serious", which included the preferred terms cardiac failure, left ventricular dysfunction, and pulmonary oedema.

Time frame: From Baseline until the end of post-treatment follow-up (up to 89 months)

Number of Participants Who Died Over the Course of the Study by Reported Cause of Death and Time of Death Relative to First or Last Dose of Study Treatment

The causes of death over the course of the study, regardless of whether the death was related to study treatment, are listed by preferred term according to the Medical Dictionary for Regulatory Activities (MedDRA), version 22.1.

Time frame: From Baseline until the end of post-treatment follow-up (up to 89 months)

Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study

Left ventricular ejection fraction (LVEF) is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. A normal LVEF ranges from 55% to 70%, as measured by echocardiogram or multiple-gated acquisition (MUGA) scan. All participants must have had a baseline LVEF of at least (≥)50% to enroll in the study; patients with clinically significant cardiovascular disease or baseline LVEF below 50% were not eligible for this study.

Time frame: Baseline and every 3 cycles until treatment discontinuation (up to Cycle 120; 1 cycle is 21 days)