Trastuzumab, pertuzumab, and eribulin mesylate versus trastuzumab, pertuzumab, and a taxane as a first-line or second-line treatment for HER2-positive, locally advanced or metastatic breast cancer: study protocol for a randomized controlled, non-inferiority, phase III trial in Japan (JBCRG-M06/EMERALD)

Abstract

Background: Trastuzumab (Tmab), pertuzumab (Pmab), and taxane has been a standard first-line treatment for recurrent or metastatic human epidermal growth factor (HER2)-positive breast cancer (HER2+ mBC) but has some safety issues due to taxane-induced toxicities. This has led to ongoing efforts to seek less toxic alternatives to taxanes that are equally effective when used in combination with Tmab plus Pmab. This study aims to show the non-inferiority of eribulin, a non-taxane microtubule inhibitor, against taxane, as a partner for dual HER2 blockade.

Methods/design: This multicenter, randomized, open-label, parallel-group, phase III study will involve a total of 480 Japanese women with HER2+ mBC who meet the following requirements: (1) age 20-70 years; (2) no prior cytotoxic chemotherapy (excluding trastuzumab-emtansine) for mBC; (3) ≥ 6 months after prior neoadjuvant or adjuvant cytotoxic chemotherapy; (4) presence of any radiologically evaluable lesion; (5) left ventricular ejection fraction ≥ 50%; (6) Eastern Cooperative Oncology Group performance status score of 0 or 1; (7) adequate organ function; and (8) life expectancy of at least 6 months. They will be randomized 1:1 to receive eribulin (1.4 mg/m2 on days 1 and 8) or taxane (docetaxel 75 mg/m2 on day 1 or paclitaxel 80 mg/m2 on days 1, 8, and 15) in combination with Tmab (8 mg/kg then 6 mg/kg) plus Pmab (840 mg then 420 mg) on day 1 of each 21-day cycle. The treatment will be continued until disease progression or unmanageable toxicity. The primary endpoint is progression-free survival as per investigator according to RECIST v1.1 criteria. Key secondary endpoints include objective response rate, overall survival, quality of life and safety. Non-inferiority will be tested with two margins of 1.33 and 1.25 in a stepwise manner. If non-inferiority is shown with a margin of 1.25, superiority will then be tested.

Discussion: If this study shows the non-inferiority, or even superiority, of Tmab, Pmab, and eribulin against the existing taxane-containing regimen, this new regimen may become a standard first- or second-line treatment option for HER2+ mBC in Japan.

Trial registration: ClinicalTrials.gov, ID: NCT03264547. Registered on 28 June 2017.

Keywords: Combination therapy; Eribulin; HER2-positive; Metastatic breast cancer; Non-inferiority; Pertuzumab; Taxane; Trastuzumab.

Conflict of interest statement

The authors declare the following conflicts of interest: TY has received honoraria from Eisai Co., Ltd., outside the submitted work. NM has received honoraria and research funding from Chugai, AstraZeneca, Pfizer, Eli Lily, and Eisai Co., Ltd., honoraria from Takeda, and research funding from Kyowa Hakko Kirin, MSD, Novartis, and Daiichi Sankyo outside the submitted work, and has served as a board member of JBCRG. SS has received grants and honoraria from Eisai Co., Ltd., Chugai, and AstraZeneca, Takeda, Novartis, and Taiho, honoraria from Kyowa Hakko Kirin, Pfizer, Daiichi Sankyo, and Nihon Kayaku, and grants from Ono outside the submitted work, and has served as a board member of JBCRG. YI has received funding from Chugai and Eisai Co., Ltd., and grants from Daiichi Sankyo, Novartis, Parexel, EPS, MSD, AstraZeneca, Eli Lilly, Kyowa Hakko Kirin, Covance, Taiho, and A2 Healthcare outside the submitted work. TT has received honoraria and research funding from Daiichi Sankyo, Kyowa Hakko Kirin, and Eisai Co., Ltd., honoraria from Pfizer and Eli Lilly, and research funding from Ono, MSD, Merck Serono, Taiho, Novartis, and Chugai outside the submitted work. MT has received lecture fees from Eisai Co., Ltd., Chugai, AstraZeneca, Pfizer, Taiho, Kyowa Hakko Kirin, and Eli Lilly outside the submitted work. HH is an employee of Eisai Co., Ltd. SM has received honoraria from Chugai and Eisai Co., Ltd., AstraZeneca, Pfizer, and Taiho outside the submitted work. SO has received honoraria and research funding from Chugai, Eisai Co., Ltd., and Daiichi Sankyo, research funding from Taiho, and honoraria from AstraZeneca, Novartis, and Kyowa Hakko Kirin outside the submitted work, and has served as a board member of JBCRG. YK has received research funds and honoraria for lectures from Chugai, Kyowa Hakko Kirin, and Eisai Co., Ltd. outside the submitted work. YS has received honoraria for lectures and an article from Eisai Co., Ltd. outside the submitted work. KA, JT, T Iwatani, KK, MK, HT, T Iwasa, and TK have no conflicts of interest to declare.

Figures

Fig. 1

Study design flowchart

Fig. 2

Schedule of enrollment, interventions, and assessments