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A Randomized, Open-label Phase III Trial to Evaluate the Efficacy and Safety of Pertuzumab Retreatment in Previously Pertuzumab, Trastuzuamb and Chemotherapy Treated Her2-Positive Metastatic Locally Advanced and Metastatic Breast Cancer(Study of Perjeta re-treatment for clinical outcomes) (JBCRG-M05(PRECIOUS))

JBCRG-M05(PRECIOUS) (JBCRG-M05(PRECIOUS))

219

The median age (range) of total patients was 59.0 (27 to 83) years, and the median duration (range) of breast cancer was 39.4 (6.3 to 219.8) months. Of the total patients, 16.1% have family medical history. Patient background at baseline (ITT population) was generally well balanced between PTC and TC groups. The median of total observation period (range) was 26.5 (0-67.8) months in PTC group and 25.3 (1.5-64.2) months in TC group. Dose of trastuzumab and drug category in chemotherapy were generally well balanced between the two groups.

A total of 219 patients met the inclusion/exclusion criteria and were randomly assigned to either PTC group or TC group in a 1:1 ratio. Evaluation of the efficacy was performed for intent-to-treatment (ITT) population, including 108 patients in PTC group and 109 patients in TC group. Evaluation of the safety was performed for the safety population who received at least 1 dose of the study treatment among the patients who met the criteria. The safety population consisted of 105 patients in PTC group and 108 patients in TC group.

There was no significant difference in incidence rate of AEs and ADRs between PTC and TC groups. As for serious AEs, blood and lymphatic system disorders were most frequently observed in 8 (7.6%) of PTC group and 11 (10.2%) in TC group, followed by infections and infestations in 6 (5.7%) of PTC group and in 2 (1.9%) of TC group, and respiratory, thoracic and mediastinal disorders in 0 (0%) of PTC group and in 5 (4.6%) of TC group. For grade 3 or higher adverse events, blood and lymphatic system disorders were most frequently observed in 26 (24.8%) of PTC group and in 25 (23.1%) of TC group. The frequency of serious AEs and grade 3 or higher AEs were generally comparable in the both groups. As for serious ADRs, blood and lymphatic system disorders were most frequently observed in 5 (4.8%) of PTC group and in 5 (4.6%) of TC group, followed by infections and infestations in 3 (2.9%) of PTC group and in 0 (0%) of TC group, and respiratory, thoracic and mediastinal disorders in 0 (0%) of PTC group and in 3 (2.8%) of TC group. For grade 3 or higher ADRs, blood and lymphatic system disorders were most frequently observed in 16 (15.2%) of PTC group and in 15 (13.9%) of TC group. The frequency of serious ADRs and grade 3 or higher ADRs were generally comparable in the both groups.

Outcome measures: Primary Endpoint: Progression free survival (PFS) judged by principal/sub-investigator The median (95% confidence interval [CI]) of PFS judged by principal/sub-investigator in ITT population was 5.5 months (4.1-6.5) in PTC group and 4.2 months (3.2-4.8) in TC group, indicating that PFS judged by principal/sub-investigator was significantly prolonged in PTC group compared with that in TC group (stratified log-rank test: p=0.0376). The hazard ratio (HR) to TC group was 0.805 (95% upper CI: 1.024) .In stratified log-rank test, 4 stratified factors [1: presence of visceral metastasis, 2: ER expression (positive/negative), 3: number of prior regimens (2 regimens/ >=3 regimens), 4: duration of pertuzumab (ineffective : <180 days of first line treatment and <120 days of second line treatment; effective: >=180 days of first line treatment and >=120 days of second line treatment)] were used. Secondary Endpoint: Progression free survival (PFS) by central review The median PFS by central review was 4.4 months in PTC group and in TC group (95% CI in PTC group: 3.2-5.8; 95% CI in TC group: 3.7-5.6), indicating that there were no difference in PFS by central review between PTC and TC groups (p=0.5605). The HR to TC group was 1.026 (95% upper CI: 1.360. Secondary Endpoint: PFS in patients receiving trastuzumab emtansine (T-DM1) just before the start of study treatment. The median (95% CI) of PFS in patients receiving T-DM1 just before the start of study treatment was 5.7 months (4.1-7.6) in PTC group and 4.4 months (3.4-5.5) in TC group, indicating that PFS in patients receiving T-DM1 just before the start of study treatment was significantly prolonged in PTC group compared with that in TC group (p=0.0494). The HR to TC group was of 0.716 (95% upper CI: 1.002). Secondary Endpoint: Response rate Of 90 patients in PTC group and 92 patients in TC group who have a measurable lesion in ITT population, the best overall response of CR and PR (response rate %) was 17 patients (19.5%) in PTC group and 18 patients (20.7%) in TC group. Response rate was comparable in the both groups. Secondary Endpoint: Duration of response (DoR) The median (95% CI) of DoR was 6.9 months (5.7-11.6) in PTC group and 3.8 months (2.8-6.2) in TC group, indicating that DoR was numerically prolonged in PTC group compared with that in TC group, but there were no significant difference (p=0.1661). The HR to TC group was 0.597 (95% upper CI: 1.258). Secondary Endpoint: Overall survival (OS) The median (95% CI) of OS was 36.2 months (24.4-43.0) in PTC group and 26.5 months (20.0-35.0) in TC group, indicating that OS was significantly prolonged in PTC group compared with that in TC group (p=0.0323). The HR to TC group was 0.729 (95% upper CI: 0.967). Secondary Endpoint: QOL assessment using Patient-reported outcome (PRO) QOL assessment was performed as a measure of B-TOI score based on patient-reported outcome (PRO) questionnaire, where patients assess the impact of breast cancer on QOL. Time until B-TOI score decrease by 5 points or more from the score at the time of enrolment was defined as time to symptomatic progression (TTSP). The median (95% CI) of TTSP was 2.8 months (1.6-4.3) in PTC group and 4.3 months (2.9-6.0) in TC group, but the difference was not significant (p=0.2289). The HR to TC group was 1.274 (95% CI: 0.855-1.899).

PFS judged by the primary investigator/sub-investigator was significantly prolonged for 1.3months by adding pertuzumab to treatment with trastuzumab and chemotherapy(stratified log-rank test: p=0.0376). OS was significantly prolonged for 9.7months by combination with pertuzumab(p=0.0323). With regarding ADR, non-severe gastrointestinal disorder and skin/subcutaneous tissue disorder were observed more frequently in patients treated with pertuzumab. However, there was no difference in numbers of serious ADRs.

Jan. 24, 2025

Jan. 24, 2025

https://doi.org/10.1200/JCO-24-01673

Yes

A clinical research protocol for a translational research study of tumor tissue will be prepared separately and will be implemented at a limited institution.

https://jrct.mhlw.go.jp/latest-detail/jRCTs041180153

Yamamoto Yutaka

Kumamoto University Hospital

1-1-1 Chuo-ku, Honjo, Kumamoto City, Kumamoto,860-8556 JAPAN

ys-yama@triton.ocn.ne.jp

Yamamoto Yutaka

Kumamoto University Hospital

1-1-1 Chuo-ku, Honjo, Kumamoto City, Kumamoto,860-8556 JAPAN

+81-96-373-5521

ys-yama@triton.ocn.ne.jp

Complete

Aug. 01, 2015

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

1.Histologically or cytologically confirmed invasive breast cancer
2.A confirmed HER2-positive status assessed by means of immunohistochemical analysis (with 3+ indicating positive status) and/or in situhybridization (with an amplification ratio>=2.0 indicating positive) by each institute
3.History of pertuzumab and trastuzumab-containing chemotherapy for locally advanced and metastatic breast cancer(2 or 3 regimen as previous chemotherapy regimen for locally advanced or metastatic breast cancer). The latest regimen before enrollment dose not include pertuzumab.
4.Patients have meas urable and/or non-measurable disease according to RECIST ver1.1.
5.Female patients and aged >= 20 years.
6.Lef t Ventricular Ejection Fraction (LVEF) >= 50% at baseline (within 28 days before enrollment) as determined by either ECHO or MUGA
7. Eastern Cooperative Oncology Group performance status of 0,1 or 2.
8.Life expectancy of patients is exp ected at least 3 months.
9.Signed and written i nformed consent (approved by the Institutional Review Board or Independent Ethics Committee) is obtained before any study procedure.

1.History of chemotherapy>4 regimen for locally advance or metastatic disease except for cancer chemotherapeuticagent-free treatment regimen
2.Persistent Grade>=3 non-he matologic toxicity according to CTCAE v4.0 resulting from previous therapy at the time of enrollment
3.Symptomatic or uncontrolled central nervous system metastases
4.Multiple malignancies witho ut history of breast cancer
5.History of exposu re to the following cumulative doses of anthracyclines: doxorubicin or liposomal doxorubicin >360mg/m2 epirubicin>720mg/m2 mitoxantrone>100mg/m2
If more than 1 anthracyclin e has been used, then the cumulative dose must not exceed the equivalent of 360mg/m2 of doxorubicin
6.Current uncontro lled hypertension or unstable angina
7.History of CHF o f any NYHA criteria, or serious cardiac arrhythmia requiring treatment
8.History of m yocardial infarction within 6 months of enrollment
9.Dyspnea at rest due to c omplications of advanced malignancy
10.Inadequate organ funct ion, as determined by the following laboratory results, within 28 days before enrollment:
Ab solute neutrophil count<1,500/mm3
Platelet count<100,000/mm3
Hemoglobin<8.0g/dL
Total bilirubin>2.0mg/ dL, unless the patient has documented Gilbert's syndrome AST o r ALT >100IU/L
Serum creatinine value >2.0mg/dL or 177umol/L
11.Current s evere uncontrolled systemic disease
12. Uncontro lled malignancy-associated hypercalcemia syndrome under bisphosphonates or denosumab treatment
13.Radiation related grade>=2 adverse event within 14 days before enrollment
14.M ajor surgical procedure or significant traumatic injury within 28 days before enrollment or anticipation of need for major surgery during the course of study treatment
15.Pregnant wom an or positive pregnancy test
16.Nursing
17.History o f receiving any investigational treatment within 28 days before enrollment
18.Current known and active infection with HIV
19.Receip t of intravenous antibiotics for infection within 14 days before enrollment
20. Current chronic daily treatment (continuous for > 3 months) with corticosteroids (dose equivalent to or greater than 10 mg/day methylprednisolone), excluding inhaled steroids.
21.Known hypersensitivity to pertuzumab or trastuzumab without infusion reaction related to these drugs
22.Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol.

Female

HER2-positive locally advanced or metastatic breast cancer

chemotherapy

HER2-positive locally advanced or metastatic breast cancer

Progression-free survival (assessed by investigators)

PFS (assessed by independent review), PFS in patients treated with trastuzumab emtansine (T-DM1) as the latest regimen, Response rate, Duration of response, Overall survival (OS), Patient-reported-outcome (QOL), Safety, biomarkers

+81-52-762-6111

Nov. 08, 2018

none