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A phase III clinical study to compare the combination therapy of eribulin mesylate + trastuzumab + pertuzumab with paclitaxel or Docetaxel + trastuzumab + pertuzumab (JBCRG-M06(EMERALD))

JBCRG-M06(EMERALD) (JBCRG-M06(EMERALD))

446

From October 2017 to July 2021,a total of 446 patients were enrolled from 109 institutions.In the intention-to-treat(ITT)population,the median age at the time of informed consent was 57.0 years(range:32-70)in the control group(n=222)and 56.0 years(range:29-70) in the experimental group(n=224). With respect to the stratification factor "use of taxane before or after curative surgery,"22 patients(9.9%)in the control group and 23 patients(10.3%)in the experimental group did not receive taxane, whereas 67 patients(30.2%)and 71 patients(31.7%),respectively,received taxane. Patients initially diagnosed with advanced or metastatic disease(Stage IV)accounted for 133(59.9%)in the control group and 130 (58.0%)in the experimental group. With respect to the use of antibody-drug conjugates as treatment for recurrence,216 patients(97.3%)in the control group and 220 patients(98.2%)in the experimental group did not receive ADCs,whereas 6 patients(2.7%)and 4 patients(1.8%), respectively, received ADCs. With respect to the presence of visceral metastases,76 patients(34.2%)in the control group and 78 patients(34.8%)in the experimental group had no visceral metastases, whereas 146 patients(65.8%)and 146 patients(65.2%),respectively,had visceral metastases. With respect to preoperative or postoperative therapy,taxane use was reported in 67 patients(30.2%)in the control group and 71 patients (31.7%)in the experimental group, whereas 6 patients(2.7%)and 8 patients(3.6%),respectively,did not receive taxane.With respect to anti-HER2 therapy,67 patients(30.2%)in the control group and 67 patients(29.9%)in the experimental group received anti-HER2 therapy,whereas 155 patients(69.8%)and 157 patients(70.1%), respectively,did not receive anti-HER2 therapy.

A total of 446 patients were enrolled in this study and were randomly assigned to either the control group(n= 222)or the experimental group(n=224). In the control group,treatment was initiated in 218 patients,excluding 4 untreated patients(2 patients who withdrew consent before treatment and 2 patients who discontinued before treatment).Among the 218 patients who started treatment,4 patients were found to be ineligible after treatment initiation. As of the data cutoff date of June 30,2023, 37 patients in the control group and 34 patients in the experimental group were continuing treatment. Treatment was discontinued in 185 patients in the control group and 190 patients in the experimental group. The median(range)of the observation period was 35.7(0.3-66.5)months. The reasons for treatment discontinuation were as follows:disease progression in 134 patients(72.4%)in the control group and 145 patients(76.3%)in the experimental group;adverse events in 16 patients(8.6%)and 14 patients(7.4%),respectively;patient request in 15 patients(8.1%)and 17 patients(8.9%),respectively;withdrawal of consent in 5 patients(2.7%)and 1 patient(0.5%), respectively;death in 2 patients(1.1%)and 0 patients (0%), respectively;and other reasons in 13 patients(7.0%)and 13 patients(6.8%), respectively. In the full analysis set(FAS),which represents the largest analysis population,216 of the 222 patients enrolled in the control group were included,while 6 patients were excluded from the FAS(2 patients withdrew consent before treatment and 4 patients were found to be ineligible after treatment initiation). In the experimental group, 221 of the 224 enrolled patients were included in the FAS,with 3 patients excluded(all found to be ineligible after treatment initiation). For the Safety Population(SP),218 out of 222 patients in the control group were included.2 patients were excluded due to withdrawal of consent before treatment,and 2 patients were excluded due to not receiving any treatment. In the experimental group,all 224 enrolled patients were included in the SP. Among the cases that did not comply with either the research protocol or the Clinical Research Act,seven serious non-compliances occurred and were reported. The reported serious non-compliances are listed in the table of the Summary Report(P6).

In the safety analysis population, the incidence of adverse events was 96.3% in the control group and 93.8% in the experimental group. The number of cases (incidence rates) of key adverse events in the control and experimental groups were as follows: peripheral sensory neuropathy in 115 patients (52.8%) and 138 patients (61.6%), skin-related events including nail disorders in 137 patients (62.8%) and 101 patients (45.1%), diarrhea in 120 patients (55.0%) and 86 patients (38.4%), neutropenia in 67 patients (30.7%) and 138 patients (61.6%), infusion reactions in 54 patients (24.8%) and 30 patients (13.4%), edema in 97 patients (44.5%) and 23 patients (10.3%), cardiac events in 15 patients (6.9%) and 17 patients (7.6%), and peripheral motor neuropathy in 8 patients (3.7%) and 13 patients (5.8%), respectively. The incidence of serious adverse events was 20.2% in the control group and 13.4% in the experimental group. Among serious adverse events observed in 4 or more patients overall, the number of cases (incidence) in the control and experimental groups were as follows for each group: infusion reactions in 4 patients (1.8%) and 2 patients (0.9%), diarrhea in 3 patients (1.4%) and 1 patient (0.4%), febrile neutropenia of grade 3 or higher in 5 patients (2.3%) and 6 patients (2.7%), and pneumonitis in 3 patients (1.4%) and 2 patients (0.9%), respectively. Serious adverse events in this study were defined as: (1) fatal events, (2) life-threatening events, (3) events requiring hospitalization or prolongation of hospitalization (excluding hospitalization due to disease progression or pre-planned hospitalization), (4) events resulting in permanent or significant disability or dysfunction, and (5) events causing congenital anomalies in offspring. The incidence of adverse drug reactions was 96.3% in the control group and 93.3% in the experimental group. The number of cases (incidence rates) of key adverse drug reactions in the control and experimental groups were: peripheral sensory neuropathy in 115 patients (52.8%) and 137 patients (61.2%), skin-related events including nail disorders in 136 patients (62.4%) and 91 patients (40.6%), diarrhea in 118 patients (54.1%) and 82 patients (36.6%), neutropenia in 67 patients (30.7%) and 138 patients (61.6%), edema in 92 patients (42.2%) and 19 patients (8.5%), infusion reactions in 54 patients (24.8%) and 30 patients (13.4%), cardiac events in 13 patients (6.0%) and 16 patients (7.1%), and peripheral motor neuropathy in 8 patients (3.7%) and 12 patients (5.4%), respectively. The incidence of serious adverse drug reactions was 15.6% in the control group and 8.9% in the experimental group. Among serious adverse drug reactions observed in 4 or more patients overall, the number of cases (incidence) in the control and experimental groups were as follows for each group: infusion reactions in 4 patients (1.8%) and 2 patients (0.9%), febrile neutropenia of grade 3 or higher in 5 patients (2.3%) and 6 patients (2.7%), and pneumonitis in 3 patients (1.4%) and 2 patients (0.9%), respectively.

1. Primary Endpoint In the intention-to-treat (ITT) population, the number of progression-free survival (PFS) events was 153 in the control group and 159 in the experimental group. The occurrence of events in the control and experimental groups was as follows: radiographic progression in 80.4% and 87.4%, clinical progression in 30.1% and 30.8%, other progression in 1.3% and 0.6%, and death in 3.3% and 0%, respectively. The median progression-free survival (PFS) in the control and experimental groups was 12.9 months (95% confidence interval [CI]: 10.8-15.6) and 14.0 months (95% CI: 11.7-16.2), respectively.The hazard ratio (experimental/control) and its 95% confidence interval were 0.95 (95% CI: 0.76-1.19). Since the upper limit of the confidence interval was below the non-inferiority margin of 1.33, non-inferiority of the experimental treatment was demonstrated. Furthermore, as the upper limit was also below the stricter non-inferiority margin of 1.25, a superiority test was conducted using the chi-square statistic, which yielded a X2 value of 0.2 and a p-value of 0.65, indicating that superiority was not demonstrated. 2. Secondary Endpoints In the ITT population, the objective response rate (ORR) was 75.2% in the control group and 76.8% in the experimental group. The between-group difference (95% CI) was 1.6% (-6.4, 9.5). The median duration of response was 13.1 months (95% CI: 10.3-16.2) in the control group and 13.1 months (95% CI: 9.8-16.9) in the experimental group. The hazard ratio (95% CI) was 0.94 (0.72-1.22). Similarly, the median overall survival (OS) was not reached in the control group and was 78.5 months (95% CI: 64.3-not estimable) in the experimental group. The hazard ratio (95% CI) was 1.25 (0.92-1.71). OS was calculated based on the survival survey conducted as of December 2024, after the end of the observation period, with the data cutoff date set at January 31, 2025. Similarly, the median new metastases-free survival (nMFS) was 26.8 months (95% CI: 20.3-31.8) in the control group and 31.5 months (95% CI: 23.0-39.5) in the experimental group. The hazard ratio and its 95% confidence interval were 0.92 (0.70-1.21). Among the Full Analysis Set (FAS), the duration of subsequent therapy was analyzed in cases eligible for subsequent treatment analysis. In these cases, the median duration of subsequent therapy (95% CI: lower limit, upper limit) was 9.4 months (7.8, 14.3) in the control group (n=115) and 5.4 months (4.4, 6.5) in the study group (n=134). The hazard ratio and its 95% CI were 1.63 (1.23, 2.17). In the full analysis set FAS, the mean +- standard deviation of the Global Health Status score from the EORTC QLQ-C30 at baseline was 58.41 +- 25.27 in the control group and 59.52 +- 22.66 in the experimental group. The median duration of quality of life (QOL) maintenance and its 95% confidence interval in the control and experimental groups were 139 days (95% CI: 127-187) and 218 days (95% CI: 191-253), respectively. The hazard ratio (experimental/control) and its 95% confidence interval were 0.80 (95% CI: 0.66-0.90). Since the lower limit of the confidence interval exceeded the non-inferiority margin of -0.1, non-inferiority of the experimental treatment was demonstrated. A superiority test using the log-rank test was subsequently conducted, yielding a p-value of 0.0807, indicating that superiority was not demonstrated. Safety results are summarized in the section "Summary of Adverse Events." Special Note: The analyses of the translational research (TR), which were planned in the research implementation protocol, are not included in this final report. These analyses will be conducted separately for academic dissemination, such as conference presentations and journal publications.

This study demonstrated that the combination of trastuzumab, pertuzumab, and eribulin as first-line therapy for HER2-positive advanced or recurrent breast cancer was non-inferior in progression-free survival (PFS) compared with trastuzumab, pertuzumab, and a taxane. Global health status assessed by EORTC QLQ-C30 showed a favorable trend. These findings suggest that this regimen could be considered a potential first-line treatment option for patients with HER2-positive advanced or recurrent breast cancer.

Dec. 31, 2025

April. 10, 2025

https://pubmed.ncbi.nlm.nih.gov/39787453/

Yes

Deidentified patient data will be made available upon reasonable request. Requests for data access must be submitted in writing, and approval will be considered based on scientific merit, feasibility, and the timing of the request. The data will be made available starting from the publication of the primary analysis results.

https://jrct.mhlw.go.jp/latest-detail/jRCTs021180027

Yamashita Toshinari

Kanagawa Cancer Center

2-3-2 Nakao Asahi-ku Yokohama-shi Kanagawa, 241-8515 Japan

yamashita.0610h@kanagawa-pho.jp

Yamashita Toshinari

Kanagawa Cancer Center

2-3-2 Nakao Asahi-ku Yokohama-shi Kanagawa, 241-8515 Japan

+81-45-520-2222

yamashita.0610h@kanagawa-pho.jp

Complete

Aug. 01, 2017

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

1)Patients with breast cancer that is confirmed histologically or cytologically
2)Patients who are confirmed to be HER2 positive for the primary or a metastatic lesion at a participating medical institution
3)Patients with no medical history of treatment for advanced/recurrent cancer using a regimen of drugs including chemotherapeutics
4) >=6 months have passed since perioperative treatment with anticancer agents
5)The patient must have an evaluable lesion. (Measurable lesions are not necessary, but lesions that can confirm progress are essential)
6)Female aged 20-70 years old at the time of consent acquisition
7)Baseline left ventricular ejection fraction (LVEF) measured by ECHO or MUGA of >=50%
8)Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-1
9)Patients who have maintained major organ functions, meeting all of the following criteria on a test within 28 days before enrollment. If there are multiple test results during this period, that obtained immediately before enrollment should be adopted.
(1)Neutrophil count: >=1,500/mm3
(2)Platelet count: >=100,000/mm3
(3)Hemoglobin: >=9.0 g/dL
(4)Total bilirubin: <=1.5 mg/dL
(5)AST (GOT), ALT (GPT): <=2.5 times the ULN (<=5 times in those with liver metastasis)
(6)Serum creatinine: <=1.5 mg/dL
10)Patients with a life expectancy of at least 6 months
11)Patient who submits written consent herself after receiving sufficient explanation about this study
12)Patients who can undergo QOL investigation

1)Patients planning to undergo radical surgery if they respond to a treatment
2)Patients who have non-hematological adverse events assessed as Grade >=3 in the Common Terminology Criteria for Adverse Events ver. 4.0 in the Japanese JCOG version (CTCAE v4.0-JCOG) at the time of enrollment
3)Patients who have symptomatic metastases to the central nervous system or whose symptoms are hard to control
4)Patients who have active double cancer
5)Patients who have poorly controlled hypertension, or unstable angina
6)Patients who have a past history of congestive heart failure assessed as Class ll or higher in the New York Heart Association (NYHA) classification, or clinically significant arrhythmia requiring treatment
7)Patients with a past history of myocardial infarction within 6 months before enrollment
8)Patients who are expected to undergo major surgical treatment or who had severe injury within 28 days before enrollment, or who require major surgical treatment during the study treatment period
9)Patients with interstitial pneumonia which is symptomatic or requires treatment
10)Pregnant women, those with a positive pregnancy test, and lactating women
11)Patients with active systemic infection (including HCV and HBV), or who are found to be HIV-positive
12)Patients with hypersensitivity against pertuzumab and trastuzumab
13)Patients whom the investigator consider unable or unwilling to follow the protocol requirements

Female

HER2-positive progressive-recurrent breast cancer

Trastuzumab + pertuzumab + Taxane
Taxane is chosen from the following;Docetaxel or Paclitaxel
Trastuzumab+ Pertuzumab + Eribulin

HER2-positive progressive-recurrent breast cancer

Progression-free survival: PFS
If noninferiority has been proved, a superiority test is performed as a subsequent analysis.

1.Response rate
2.Duration of response
3.Overall survival
4.Patient-reported outcomes
5.Safety. Biomaker
6.new Metastases free survival
7.Treatment duration of next treatment
The TR results will not be included in the summary report. The results will be published in place of academic publications (conferences and papers).

+81-24-547-1825

Jan. 28, 2019

none