Trastuzumab and pertuzumab in combination with eribulin mesylate or a taxane as first-line chemotherapeutic treatment for HER2-positive, locally advanced or metastatic breast cancer: Results of a multicenter, randomized, non-inferiority phase 3 trial in Japan (JBCRG-M06/EMERALD).

person Toshinari Yamashita Kanagawa Cancer Center, Kanagawa, Japan info_outline Toshinari Yamashita, Shigehira Saji, Toshimi Takano, Yoichi Naito, Michiko Tsuneizumi, Akiyo Yoshimura, Masato Takahashi, Junji Tsurutani, Tsuguo Iwatani, Masahiro Kitada, Hiroshi Tada, Natsuko Mori, Toru Higuchi, Tsutomu Iwasa, Kazuhiro Araki, Kazuko Sakai, Hiroki Hasegawa, Yohei Uchida, Satoshi Morita, Norikazu Masuda

Authors person Toshinari Yamashita Kanagawa Cancer Center, Kanagawa, Japan info_outline Toshinari Yamashita, Shigehira Saji, Toshimi Takano, Yoichi Naito, Michiko Tsuneizumi, Akiyo Yoshimura, Masato Takahashi, Junji Tsurutani, Tsuguo Iwatani, Masahiro Kitada, Hiroshi Tada, Natsuko Mori, Toru Higuchi, Tsutomu Iwasa, Kazuhiro Araki, Kazuko Sakai, Hiroki Hasegawa, Yohei Uchida, Satoshi Morita, Norikazu Masuda Organizations Kanagawa Cancer Center, Kanagawa, Japan, Fukushima Medical University, Fukushima, Japan, Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan, National Cancer Center Hospital East, Japan, Kashiwa-Shi, Japan, Department of Breast Surgery, Shizuoka General Hospital, Shizuoka, Japan, Aichi Cancer Center, Nagoyashi Chikusaku, Japan, Department of Breast Surgery, Hokkaido University Hospital, Sapporo, Japan, Showa University, Tokyo, Japan, Department of Breast and Endocrine Surgery, Okayama University Hospital, Okayama, Japan, Asahikawa Medical University Hospital, Asahikawa, Japan, Department of Breast and Endocrine Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan, Seirei Hamamatsu General Hospital, Hamamatsu, Japan, Saitama Red Cross Hospital, Saitama-Shi Chuo-Ku, Japan, Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan, Gunma Prefectural Cancer Center, Ohta City, Gunma, Japan, Kindai University Faculty of Medicine, Osaka, Japan, Eisai Co., Ltd, Shinjuku-Ku, Japan, Eisai, Tokyo, Japan, Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan, Nagoya University Graduate School of Medicine, Aichi, Japan Abstract Disclosures Research Funding Eisai Co., Ltd Background: Trastuzumab (H) + pertuzumab (P) + taxane is a current standard first-line therapy for recurrent or metastatic human epidermal growth factor 2–positive (HER2+) breast cancer (BC). However, taxane-induced toxicities, which reduce patient quality of life (QoL), necessitate development of less toxic but at least equally effective taxane alternatives. We investigated the non-inferiority of eribulin to taxane when used in combination with dual HER2 blockade (HP). Methods: The multicenter randomized open-label parallel-group phase 3 EMERALD trial (UMIN000027938, NCT03264547) was carried out to test the non-inferiority of eribulin + HP (study regimen) against docetaxel/paclitaxel + HP (control regimen) as first-line chemotherapeutic treatment in patients with locally advanced or metastatic HER2+ BC. The study design has been published (doi: 10.1186/s13063-020-04341-y). Patients were randomized (1:1) to receive, by intravenous infusion in a 21-day cycle, either (i) eribulin 1.4 mg/m2 on days 1 and 8, or (ii) a taxane (docetaxel 75 mg/m2 on day 1 or paclitaxel 80 mg/m2 on days 1, 8 and 15), each being administered in combination with HP on day 1. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, overall survival (OS), QoL and safety. Non-inferiority was tested using the Cox proportional hazards model to estimate hazard ratios (HRs) for PFS events. The upper limit of acceptance of non-inferiority HR margins (1.33 and 1.25) was tested in a stepwise manner. Results: Between August 2017 and June 2021, 446 patients (224 and 222 in the study and control groups, respectively) were enrolled: median age was 56.0 (29–70) years, 244 (54.7%) had ER-positive BC, 285 (63.9%) had visceral metastasis. While 247 patients (55.4%) had de novostage 4 disease, 199 (44.6%) underwent radical surgery and 138 (30.9%) received taxanes perioperatively. Both groups’ baseline characteristics were well balanced. Median PFS was 14.0 mos in the study group and 12.9 mos in the control group (HR, 0.96; 95% CI, 0.77–1.20), confirming non-inferiority of the study regimen. Median OS was 65.3 mos in the control group but has not been reached in the study group. Incidences of adverse drug reactions including grade ≥3 febrile neutropenia, edema and diarrhea were numerically lower in the study group than in the control group (4.9% vs 8.7%, 8.5% vs 42.2% and 36.6% vs 54.1%, respectively). Conclusions: This is the first study to show non-inferiority of eribulin to taxane when used in combination with dual HER2 blockade. As a less toxic but equally effective alternative to the taxane-containing regimen, eribulin combined with HP could be first-line treatment of locally advanced or metastatic HER2+ BC. Clinical trial information: UMIN000027938, jRCTs021180027.

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