Editor's note: Although anti-tumor therapy has entered the era of targeted therapy and immunotherapy, chemotherapy is still the cornerstone of anti-tumor therapy, and many new drugs are still based on combination chemotherapy. The development of new chemotherapy drugs with more efficiency and low toxicity will meet more unmet clinical needs. At the 2024 ASCO conference held recently, the phase III EMERALD study reported positive results in the first-line treatment of HER2+ advanced breast cancer with eribulin combined with trippa, which once again expanded the chemotherapy application scenarios of breast cancer. In addition, eribulin has also demonstrated positive anti-tumor activity in a number of solid tumor fields such as lung cancer, urothelial carcinoma, and soft tissue sarcoma. Professor Biyun Wang was invited to share the latest ASCO research progress as follows.
EMERALD研究：HER2+ MBC一线化疗再“立”新选择
The EMERALD study is a Japanese-initiated, multicenter, randomized, non-inferiority, phase III clinical study[1]. A total of 446 patients with locally advanced or metastatic HER2+ breast cancer who had not been treated with chemotherapy prior were enrolled, with a median age of 56.0 years, 25.3% of the patients were not postmenopausal, 57.6% were ER+, 59.0% were stage IV., and 31% had received taxane therapy in the perioperative period. Trastuzumab and pertuzumab (HP dual-target) combined with eribulin regimens, as well as standard HP dual-target combined with taxanes for first-line treatment in 1:1 groups, respectively, were treated with a median treatment time (DOT) of 28.1 weeks in the eribulin + HP group, which lasted about 10 weeks longer than that in the taxane group (docetaxel 18.1 weeks, paclitaxel 20 weeks) + HP group.
△EMERALD study design
The results showed that the median progression-free survival (mPFS) of the aribulin+HP group and the taxane+HP group reached the non-inferiority endpoint of 14.0 vs. 12.9 months (HR=0.95, 95%CI 0.76-1.19, P=0.6817), and the performance was consistent among all subgroups. The objective response rate (ORR) was 76.8% vs. 75.2%; The clinical benefit rate (CBR) was 88.8% vs. 86.9%; In terms of overall survival (OS), the eribulin + HP group was not reached, and the taxane + HP group was 65.3 months, and the performance was consistent among all subgroups.
△ EFFICACY DATA OF THE EMERALD STUDY
In terms of safety, eribulin+HP group had lower perceived adverse events such as skin toxicity and edema. These suggest that eribulin + HP can be used as a potential first-line treatment for HER2+ advanced breast cancer.
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Professor Wang Biyun commented on how eribulin affects the clinical practice of breast cancer
Tumor Outlook: ASCO once again ushered in the new progress of eribulin, please talk about the status of eribulin in the field of breast cancer?
Prof. Biyun Wang: Effective treatment drugs for breast cancer include chemotherapy, targeted therapy, and immunotherapy. In recent years, there have not been many new drugs and related studies for chemotherapy, and the new chemotherapy drug recommended by the National Comprehensive Cancer Network (NCCN) guidelines in the United States is eribulin [2]. In 2010, the EMBRACE study established the efficacy and safety of eribulin in the treatment of breast cancer, and was recommended by guidelines as one of the standard chemotherapy drugs for breast cancer. However, it took ten years for eribulin to move from the international to the domestic market, and thanks to the publication of the results of the 304 study [3], eribulin finally benefited Chinese patients. At present, eribulin has become a commonly used chemotherapy drug in the treatment of breast cancer, and is generally used as the preferred regimen after taxane resistance, and the drug line sequence is earlier than that of "three bins" (capecitabine, gemcitabine, vinorelbine).
△NCCN guidelines 2024 v2 recommend eribulin as one of the preferred chemotherapy regimens
Tumor Outlook: At the ASCO Annual Meeting, the EMERALD study explored the first-line treatment of eribulin in combination with anti-HER2. Could you tell us more about the design and main results of the study?
Prof. Biyun Wang: The EMERALD study is a multicenter, randomized, non-inferiority, phase III clinical study initiated in Japan to explore the efficacy and safety of trastuzumab and pertuzumab (HP dual target) in combination with eribulin compared with standard HP dual target in combination with taxanes in the first-line treatment of HER2+ breast cancer. A total of 446 patients with HER2+ breast cancer were enrolled in the study, of which 59% were stage IV patients, much higher than the <10% in daily work, and about 30% of patients had received paclitaxel treatment in the perioperative period. Patients were given the above regimen in a 1:1 group, and the results showed that the median progression-free survival (mPFS) was 14.0 months in the HP dual-target plus eribulin group and 12.9 months in the control group, meeting the non-inferiority endpoint. In terms of overall survival (OS), the HP dual-target combined with eribulin group was not reached, and the control group was 65.3 months, which initially showed a trend of superiority, and the results were expected.
Oncology Watch: How would you rate the results of the study? What impact will it have on the clinical treatment of HER2-positive breast cancer in the future?
Prof. Biyun Wang: Eribulin is one of the chemotherapy drugs commonly used in our clinical practice, which is generally used after taxane and before "Sanbin". However, an increasing number of patients have been treated with taxanes in the neoadjuvant and adjuvant stages of early-stage breast cancer, so we confirm the patient's taxo resistance after disease metastasis. If taxy resistance develops, we consider eribulin; If yew is sensitive, yew may be challenged again, but yew drugs often have adverse reactions such as edema and peripheral neurotoxicity, and clinical treatment is relatively difficult. The results of the non-inferior eribulin to paclitaxel in the EMERALD study suggest that eribulin may be considered in these patients to overcome the cumulative toxicity of paclitaxel with long-term use. Especially for patients with HER2+ breast cancer, the HP dual-target combination with eribulin has better efficacy, controllable toxicity, less perceptible adverse reactions, and better treatment experience and quality of life. Therefore, I believe that this study is of great significance, and it has strongly promoted the advancement of eribulin medication line, making it a new first-line standard treatment for HER2+ breast cancer alongside yew and thus has greater clinical application value.
Eribulin: The advantages of drug mechanism make it have a wider range of application scenarios
Eribulin is a new anti-microtubule chemotherapeutic agent, but unlike traditional taxane and vinblastine tubulin inhibitors, eribulin is a derivative of soft spongiferin B extracted from marine organisms. Eribulin binds to the elongated high-affinity site of microtubules, but not to the tubulin side chain[4]. This combination allows eribulin to remain effective in taxane-resistant patients, providing new treatment opportunities for patients who are resistant to traditional chemotherapy drugs.
Numerous in vitro or preclinical studies have shown that eribulin has a good synergistic effect with targeted or immunotherapy. In a variety of xenograft models, eribulin has better vascular remodeling and antitumor activity than vinorelbine. Moreover, eribulin can counteract the action of TGF-β on vascular endothelial cells and the induced epithelial-mesenchymal transition (EMT), thereby inhibiting tumor vascular endothelial cell proliferation and destroying tumor cytoskeleton [5-6]. In addition, retrospective analysis of breast cancer samples showed that eribulin could promote anti-tumor immune responses, manifested by decreased expression of PD-1, PD-L1, and FOXP3 and increased expression of CD8 [7]. These studies suggest that eribulin can be used as a basis for chemotherapy for targeted or immunocombination therapy, exerting a more powerful anti-tumor effect.
The above-mentioned drug advantages of eribulin are not only reflected in the field of advanced breast cancer, but also in many other solid tumor fields. At the ASCO Congress, a number of clinical trials were reported showing the positive anti-tumor activity of eribulin combination therapy. In a multicenter phase II study in the United States [8], 29 patients with solid tumors who had received at least ≥ 3 lines of chemotherapy, including stage IV breast cancer, lung cancer, and sarcoma, were treated with eribulin in combination with a small molecule tyrosine kinase inhibitor (TKI) lenvatinib, resulting in a 25% ORR and a median PFS of 7.4 months, and the safety profile of the combination therapy was manageable, with a grade ≥3 adverse event rate of 34.5%, with neutropenia (17.2%) and hypertension (13.8%) being common. The rate of AE-related discontinuation was only 6.8%.
△疗效瀑布图和FPS K-M曲线
GC regimen (gemcitabine + cisplatin) is the standard regimen for systemic chemotherapy for urothelial carcinoma, but cisplatin cannot be tolerated by many patients in clinical practice. In 2019, JCO reported a phase II study from the California Cancer League [9], in which 24 patients with metastatic urothelial carcinoma (mUC) who were not eligible for cisplatin therapy were given first-line chemotherapy with gemcitabine + eribulin, and the results showed good anti-tumor activity with an ORR of 50%. Based on this, a multicenter phase III SWOG S1937 study in the United States was reported at the ASCO Congress [10], in which eribulin plus gemcitabine was given versus standard of care in patients with mUC who were refractory to or intolerant to PD-1/L1. The study is underway, and its results are promising, with mUC expected to add new standards of chemotherapy.
summary
As a novel tubulin inhibitor, eribulin has a novel mechanism of action compared with traditional taxane and vinblastine tubulin inhibitors, making it a promising new and preferred treatment for malignant tumors. At present, eribulin has made many breakthroughs in the field of breast cancer, and the EMERALD study reported at the ASCO Congress showed that eribulin combined with trospag dual-target first-line therapy is not inferior to the traditional paclitaxel regimen, adding a new first-line treatment option for such patients. In addition, eribulin has a good synergistic effect with targeted or immunotherapy combination therapy, and some phase 2 studies reported at the ASCO conference show that it has shown positive anti-tumor activity in the combination of small molecule TKI therapy with multiple tumor types, and the phase III study in the field of mUC is expected to provide a new standard of chemotherapy that is different from the GC regimen.
Prof. Biyun Wang
Department of Medical Oncology, Fudan University Cancer Hospital
Director of Breast and Urological Oncology, Chief Physician, Master's Supervisor
Director of CSCO of Chinese Society of Clinical Oncology
Chairman of the CSCO Youth Committee of the Chinese Society of Clinical Oncology
He is a standing member and secretary general of the CSCO Patient Education Expert Committee of the Chinese Society of Clinical Oncology
Member of the CSCO Breast Cancer Expert Committee of the Chinese Society of Clinical Oncology
Vice Chairman and Secretary-General of CRPC of the Cancer Rehabilitation and Palliative Care Committee of Shanghai Anti-Cancer Association, and chairman-elect
He is a member of the Standing Committee of the Breast Cancer Committee of the Shanghai Anti-Cancer Association
Executive Director of the Youth Council of Shanghai Anti-Cancer Association