ASCO 2024丨Professor Yang Jin: Eribulin has successfully expanded first-line therapy, and clinical trials and real-world studies have been well received
Editor's note: Eribulin is a novel tubulin inhibitor, which has been confirmed by many previous studies to have good efficacy and safety against a variety of solid tumors such as advanced breast cancer and soft tissue sarcoma, and has synergistic effects with targeted and immunotherapy. The new chemotherapy regimen has been approved for marketing in China, accumulating a wealth of evidence-based medical evidence for the posterior treatment of advanced breast cancer. At the 2024 ASCO Congress held recently, the Phase III EMBRACE study successfully expanded eribulin to first-line chemotherapy for HER2+ advanced breast cancer; Numerous real-world studies have also verified the high efficiency and low toxicity of eribulin in different molecular subtypes of breast cancer, showing the advantages of frontline expansion and combination therapy. Professor Yang Jin from the First Affiliated Hospital of Xi'an Jiaotong University was invited to share the latest ASCO research progress and look forward to a new transformation in the chemotherapy landscape of breast cancer.
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Tumor Outlook: The clinical application of eribulin has accumulated a very rich evidence-based evidence, and the phase III EMERALD study was reported at the ASCO conference to achieve positive results; Your research team also brought a single-center, real-world study using eribulin. Can you share with us about these latest developments?
Prof. Jin Yang: We know that based on important evidence-based medical evidence such as the 305 study (EMBRACE) and the 304 study [1-2], eribulin has been approved for the relevant indications of advanced breast cancer at home and abroad, mainly for patients who have failed ≥ second line of chemotherapy. The results of the phase III EMERALD study [3] reported at the ASCO Congress for the first time in the first-line treatment of advanced HER2-positive breast cancer (combined with tripaz dual-target therapy) showed that the median progression-free survival of patients in the eribulin group (PFS: HR 0.95, 95%CI 0.76~1.19, P=0.6817) was not inferior to that of the taxy group, and was numerically extended by 1.1 months (14.0 vs. 12.9 months) compared with the taxy group. The median duration of treatment (DOT) in the aribulin group was 28.1 weeks, which was about 10 weeks longer than that in the taxane group (docetaxel 18.1 weeks, paclitaxel 20 weeks), and the objective response rate (ORR: 76.8% vs. 75.2%) and clinical benefit rate (CBR: 88.8% vs. 86.9%) were also higher than those in the taxane group. OS results are not yet mature; In terms of safety, eribulin has a lower incidence of adverse events such as skin toxicity and edema. The results of this study have important clinical implications. At present, paclitaxel is still the main first-line chemotherapy for breast cancer, and the choice is relatively simple. Other drugs such as anthracyclines are also unsatisfactory in terms of toxicity, side effects and efficacy. Based on the positive results of the EMERALD study, eribulin is expected to be elevated to the first-line treatment camp for advanced breast cancer.
△EMBRACE研究主要终点PFS K-M曲线
△EMBRACE studied the duration of treatment in both groups
△Efficacy data from the EMBRACE study
Last year, eribulin was included in China's medical insurance list, benefiting more patients with advanced breast cancer. Therefore, our center published a retrospective, real-world study of the use of eribulin in advanced breast cancer at ASCO [4], aiming to observe the efficacy of eribulin in the real world. The study primarily included patients with advanced breast cancer treated with anthracyclines and taxanes, and defined paclitaxel-sensitive patients as those who had been on paclitaxel for more than 6 months on the last line of eribulin. A total of 89 patients with advanced breast cancer were included in the study, with a median age of 54 years, 40.4% of the patients had a median line of third-line therapy, 67.4% of patients had Ki-67>30%, 88.7% had visceral metastases, 25.8% were HER2+ breast cancer patients, and 46% were HR+/HER2- advanced breast cancer patients, some of whom had progressed after CDK4/6i treatment. The proportion of eribulin monotherapy was 30.3%, 25.8% were combined with trastuzumab, pyrotinib and other anti-HER2 treatments, and the rest were combined with bevacizumab and capecitabine.
The results showed that the ORR of 89 patients was 22.5%, the disease control rate (DCR) was high at 84.3%, and the total population mPFS reached 6 months. Univariate analysis showed that PFS was longer in HER2+ patients, 30% of patients with Ki-67<, paclitaxel-sensitive patients, patients with advanced breast cancer treated with 1-2 lines, and patients with partial response. It is worth emphasizing that HER2+ patients had a longer mPFS than HR+/HER2- and TNBC, which was 13.5 vs. 4.5 vs. 3.7 months, P=0.011, among which HER2+ patients mostly failed first-line anti-HER2 therapy, and HR+/HER2- mostly progressed after CDK4/6i treatment. In terms of safety, the main adverse reactions of eribulin and its combination regimen were hematologic toxicity, including leukopenia and neutropenia, while peripheral neurotoxicity occurred less.
△Results and subgroup analysis of a single-center real-world study of eribulin in the treatment of advanced breast cancer in China
Overall, for patients with advanced breast cancer treated with anthracyclines and yew, eribulin and its combination therapy regimens have brought overall survival improvement to patients. The phase III EMERALD study confirmed that eribulin is not inferior to paclitaxel in first-line treatment, and is expected to add a new first-line standard of care for patients with advanced breast cancer.
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Tumor Outlook: In terms of theoretical mechanism and clinical application, what guidance does this real-world study provide for clinical optimization of the practical application of eribulin?
Prof. Jin Yang: From a mechanistic perspective, eribulin, as a novel anti-microtubule chemotherapy drug, can inhibit the growth of microtubules and effectively counteract the TGF-β-induced change of cell shape to elongated spindle-shaped morphology. It better counteracts TGF-β-induced epithelial-mesenchymal transition (EMT) effects than other antimicrotubule agents [5-6]. As a result, eribulin can continue to be effective in paclitaxel-resistant patients. At the same time, eribulin can also promote the decrease of the expression of PD-1, PD-L1, and FOXP3 in tumors, increase the expression of CD8, and increase the infiltration of NK cells, thereby further strengthening the anti-tumor immune effect[7]. On this basis, eribulin can exert synergistic effects with anti-HER2 targeted therapy drugs and common immunotherapy drugs, so as to have therapeutic effects on different molecular subtypes of breast cancer.
From the perspective of clinical research, in TNBC, in a study of eribulin combined with PD-1 monoclonal antibody and VEGF small molecule targeted drugs for the ≥second-line treatment of advanced TNBC, the mPFS reached 8.7 months, doubling that of previous studies [8]. In HR+ breast cancer, previous real-world studies have also shown that eribulin has been shown to have an effect on mPFS for 10 months in CDK4/6i-experienced patients [9]. In HER2+ breast cancer, the EMERALD study published by ASCO this year also showed the effectiveness of eribulin in combination with tripazal dual-targeted first-line therapy. The real-world study we announced this time is another confirmation of the results of the above trials, and eribulin has shown reliable efficacy and safety in the real world for patients with advanced breast cancer with different molecular types, different baseline levels, and different treatment line sequences. For example, the use of eribulin combined with capecitabine for TNBC patients, trastuzumab and pyrotinib dual-target combined with eribulin for HER2+ patients who have progressed on ADC therapy, and eribulin for CDK4/6i-experienced patients have all shown good effects of rapid response. It is suggested that we will continue to explore more possible combinations of eribulin in different molecular subtypes in the future.
In terms of selection of dominant populations, one-way regression analysis of our real-world studies showed that eribulin was superior in Ki-67≤30 percent and paclitaxel-sensitive patients [4]. It is well known that treatment interruption is often due to peripheral neurotoxicity during the use of paclitaxel or nab-paclitaxel in patients with advanced breast cancer. Our study showed that eribulin was treated with mPFS at 8 months and 4 months in paclitaxel-sensitive patients compared with drug-resistant patients, and the neurotoxicity was low, suggesting that patients who are sensitive but intolerant to paclitaxel should be used as soon as possible to achieve more benefit for patients.
In terms of safety, eribulin, as an anti-microtubule agent, has low peripheral neurotoxicity in real-world applications, with the main adverse effect being hematologic toxicity[4]. For patients who are poorly tolerated in the later line of therapy, our experience is to use eribulin 1 mg on day 1 and 2 mg on day 8, followed by long-acting white needle prophylaxis, so as to ensure the safety of the patient's bone marrow and achieve the continuous implementation of the patient's treatment regimen. When the patient's tolerance improves, the dose is gradually increased. Therefore, in the clinical application of eribulin, it is necessary to pay attention to the assessment, prevention and hierarchical management of hematologic toxicity in patients to ensure the continuous development of treatment and maximize the therapeutic effect.
In fact, there are several real-world studies of eribulin in the treatment of breast cancer in China [10-12], all of which have shown very good efficacy and safety, including patients with different molecular subtypes such as HER2 low expression, HER2 negative, HR positive, or HR negative. Of particular note, a retrospective study of 159 TNBC patients at Fujian Provincial Cancer Hospital using propensity score matching (PSM) showed that eribulin had longer PFS compared with platinum (HR 0.441, P = 0.006), nab-paclitaxel (HR 0.36, P = 0.001), and other chemotherapy (HR 0.39, P<0.001) [12].
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Tumor Watch: In this real-world study, the HER2-positive breast cancer subtype performed relatively well. In your opinion, what changes will eribulin bring to the treatment of breast cancer in the future?
Prof. Jin Yang: The main randomized controlled clinical studies of eribulin in the past have mainly focused on HER2-negative advanced breast cancer. In this real-world study, we included a subset of patients with HER2+ breast cancer and saw the effects of eribulin in combination with anti-HER2 therapy, especially in the use of non-cross-resistant chemotherapy. While there is no sufficient evidence-based evidence or guidelines to recommend eribulin in combination with anti-HER2 therapy in the real world, our real-world study at the ASCO Annual Meeting echoes the EMERALD study to demonstrate the therapeutic potential of eribulin in HER2+ breast cancer. Nowadays, small molecule TKIs such as pyrotinib and ADCs such as T-DM1 are booming, but chemotherapy is still the cornerstone of HER2+ breast cancer treatment. With the emergence of more and more patients with HER2+ breast cancer with multiple lines of therapy, we need to consider a more diversified treatment combination and further explore the efficacy of eribulin in combination with different anti-HER2 therapeutic agents.
In addition to HER2+ breast cancer, I would like to highlight the efficacy of eribulin in the treatment of HER2– advanced breast cancer. For example, patients with HR+ or TNBC with high tumor burden such as CDK4/6i treatment, diffuse liver metastases, brain metastases, etc., eribulin can achieve rapid remission and bring benefits to patients. A domestic multicenter phase II study [13] reported at the ASCO congress showed positive efficacy and safety in the second-line treatment of HER2- advanced breast cancer with eribulin + gemcitabine (see table below), with an ORR of 48.6% and a DCR of 92.9%, respectively, indicating that the treatment sequence of eribulin in HER2- advanced breast cancer can also be pushed forward.
△Results of a single-center, single-arm study of eribulin + gemcitabine in patients with HER2- advanced breast cancer who have received at least first-line chemotherapy in China
On the whole, for breast cancer with different molecular types, the combination of eribulin combined with different types of therapeutic drugs is a research direction worth exploring in the future.
As a new anti-tubulin inhibitor, in addition to the breakthrough progress made in breast cancer, eribulin has also shown positive application value in many other solid tumor fields.
△ ASCO conference collection and EMERALD research report site
Oral 1007
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).
Trastuzumab and pertuzumab in combination with eribulin mesylate or paclitaxel as first-line treatment for HER2-positive locally advanced or metastatic breast cancer: results from a multicenter, randomized, non-inferiority phase 3 trial in Japan (JBCRG-M06/EMERALD).
Poster 3158
Phase II study of the combination of lenvatinib(L)and eribulin(E)in advanced solid tumors
A Phase II study of lenvatinib in combination with eribulin in advanced solid tumors
Poster 11551
Results of a randomized phase II trial of 2nd-line treatment for advanced soft tissue sarcoma comparing trabectedin,eribulin and pazopanib:Japan Clinical Oncology Group study JCOG1802(2ND-STEP)
RESULTS OF A PHASE II RANDOMIZED STUDY COMPARING TRABECTEDIN, ERIBULIN, AND PAZOPANIB FOR THE SECOND-LINE TREATMENT OF ADVANCED SOFT TISSUE SARCOMA: JAPANESE CLINICAL ONCOLOGY GROUP STUDY JCOG1802 (2ND-STEP)
Poster 11561
Safety and efficacy of eribulin plus anlotinib in patients with advanced soft tissue sarcoma(ERAS):A multi-center phase II study
Safety and efficacy of eribulin in combination with anlotinib in advanced soft tissue sarcoma: a multicenter phase II study
Poster TPS4617
A phase III randomized trial of eribulin(E)with gemcitabine(G)vs standard of care(SOC)for patients(pts)with metastatic urothelial carcinoma(mUC)refractory to or ineligible for PD-1/PD-L1 antibody(Ab):SWOG S1937 updated design.
A Phase III Randomized Trial of Elibulin (E) in Combination With Gemcitabine (G) Versus Standard of Care (SOC) in Patients With Metastatic Urothelial Carcinoma (mUC) Refractory or Intolerant to PD-1/PD-L1 Antibody (Ab): SWOG S1937 Updated Design
Poster e23502
Eribulin and irinotecan for refractory or recurrent Ewing sarcoma:A retrospective study.
A retrospective study of eribulin and irinotecan in refractory or relapsed Ewing sarcoma
Poster e13123
Multicentric retrospective study on the treatment characteristics,efficacy and safety of eribulin in Slovenian patients with breast cancer
A multicenter retrospective study of the treatment characteristics, efficacy, and safety of eribulin in breast cancer patients in Slovenia
Poster e13002
Survival and safety analysis of eribulin in Indian patients with metastatic breast cancer:A real world clinical experience.
A survival and safety analysis of eribulin treatment in patients with metastatic breast cancer in India: a real-world clinical experience
Poster e13118
Treatment(Tx)patterns,efficacy and safety of eribulin for advancec and heayily pretreated breast cancer(ABc):Updated results from a single-center,real-world study.
Treatment modality, efficacy, and safety of eribulin in patients with advanced breast cancer who have undergone multiple treatments: updated results from a single-center, real-world study
Poster e13139
Efficacy and safety of eribulin plus gemcitabine in second-line or beyond for patients with HER2-neaative metastatic breast cancel(MBC):A multicenter,open-label,single-arm,phase ll study.
Efficacy and Safety of Irinotecan in Combination With Gemcitabine as Second-Line or Above Treatment in Patients With HER2-Negative Metastatic Breast Cancer (MBC): A Multicenter, Open-label, Single-arm, Phase II Study
Poster e13121
Efficacy and safety of eribulin-based chemotherapy in patients with advanced breast cancer:A single-centre retrospective study.
Efficacy and Safety of Elibulin-based Chemotherapy in Patients With Advanced Breast Cancer: A Single-center Retrospective Study
Poster e13010
Clinical outcomes of patients with HR-positive advanced breast cancer treated with eribulin:A retrospective multicenter study from China
Clinical outcomes of eribulin in patients with HR-positive advanced breast cancer: a retrospective multicenter study from China
Poster e13135
Feasibility and tolerability of eribulin-based chemotherapy versus other chemotherapy regimens for patients with metastatic triple negative breast cancer:A single-centre retrospective study.
Feasibility and tolerability of eribulin-based chemotherapy compared to other chemotherapy in patients with metastatic triple-negative breast cancer: a single-center retrospective study
Bibliography:
[1] Cortes J, O'Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study[J]. Lancet. 2011; 377(9769):914-23.
[2] Yuan P, Hu X, Sun T, et al. Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial. Eur J Cancer. 2019;112:57-65. doi:10.1016/j.ejca.2019.02.002
[3] Toshinari Yamashita, et al. 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). J Clin Oncol 42, 2024 (suppl 16; abstr 1007)
[4] Treatment (Tx) patterns, efficacy and safety of eribulin for advanced and heavily pretreated breast cancer (ABC): Updated results from a single-center, real-world study.
[5] Ito K, Hamamichi S, Abe T, et al. Antitumor effects of eribulin depend on modulation of the tumor microenvironment by vascular remodeling in mouse models. Cancer Sci. 2017; 108(11):2273-2280. doi:10.1111/cas.13392
[6] Abbona A, Paccagnella M, Astigiano S, et al. Effect of Eribulin on Angiogenesis and the Expression of Endothelial Adhesion Molecules. Anticancer Res. 2022; 42(6):2859-2867. doi:10.21873/anticanres.15767
[7] Goto W, Kashiwagi S, Asano Y, et al. Eribulin Promotes Antitumor Immune Responses in Patients with Locally Advanced or Metastatic Breast Cancer. Anticancer Res. 2018; 38(5):2929-2938. doi:10.21873/anticanres.12541
[8] Liu J, Wang Y, Tian Z, et al. Multicenter phase II trial of Camrelizumab combined with Apatinib and Eribulin in heavily pretreated patients with advanced triple-negative breast cancer. Nat Commun. 2022; 13(1):3011. Published 2022 May 31. doi:10.1038/s41467-022-30569-0
[9] Mougalian SS, Feinberg BA, Wang E, et al. Observational study of clinical outcomes of eribulin mesylate in metastatic breast cancer after cyclin-dependent kinase 4/6 inhibitor therapy. Future Oncol. 2019; 15(34):3935-3944. doi:10.2217/fon-2019-0537
[10] Yuting Li, et al. Efficacy and safety of eribulin-based chemotherapy in patients with advanced breast cancer: A single-centre retrospective study. J Clin Oncol 42, 2024 (suppl 16; abstr e13121)
[11] Aodi Li, et al. Clinical outcomes of patients with HR-positive advanced breast cancer treated with eribulin: A retrospective multicenter study from China.J Clin Oncol 42, 2024 (suppl 16; abstr e13010)
[12] Lili Wang, et al. Feasibility and tolerability of eribulin-based chemotherapy versus other chemotherapy regimens for patients with metastatic triple-negative breast cancer: A single-centre retrospective study. J Clin Oncol 42, 2024 (suppl 16; abstr e13135)
[13] Peijian Peng,et al. Efficacy and safety of eribulin plus gemcitabine in second-line or beyond for patients with HER2-negative metastatic breast cancer (MBC): A multicenter, open-label, single-arm, phase II study. J Clin Oncol 42, 2024 (suppl 16; abstr e13139)
Prof. Jin Yang
Doctor of Medicine, Chief Physician/Professor, Doctoral Supervisor
Director of the Cancer Center, Director of the Precision Research Center, and Deputy Director of the Department of Oncology of the First Hospital of Xi'an Jiaotong University
Member of the Standing Committee of the Breast Cancer Professional Committee of the Chinese Association of Research Hospitals
He is a member of the Breast Cancer Professional Committee of the National Cancer Quality Control Center
Member of the Breast Cancer Committee of the Chinese Society of Clinical Oncology (CSCO).
Member of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association
Member of the Standing Committee of the Clinical Oncology Committee of the Chinese Women Physicians Association
Member of the Breast Professional Committee of the Oncology Branch of the Chinese Medical Doctor Association
Vice Chairman of the Breast Group of the Tumor Marker Committee of the Chinese Anti-Cancer Association
Deputy head of the Breast Group of the MDT Special Committee on Precision Medicine and Oncology of the Chinese Association of Research Hospitals
Member of the Tumor Integration Heart Committee of the Chinese Anti-Cancer Association
Member of the Standing Committee of the Medical Oncology Branch of Shaanxi Medical Association
Chairman of the Anti-Cancer Drug Professional Committee of Shaanxi Anti-Cancer Association
Chairman-elect of the Biotherapy Professional Committee of Shaanxi Anti-Cancer Association
Chairman of the Tumor Precision Treatment Committee of Xi'an Cancer Rehabilitation Association
美国马里兰大学Marlene and Stewart Greenbaum 肿瘤中心访问学者
Shaanxi Province May Day Women's Pacesetter
He has published more than 50 papers, 47 of which are included in SCI
He has presided over 4 general projects of the National Natural Science Foundation of China
He has won 2 Shaanxi Provincial Science and Technology Progress Awards and 2 University Science and Technology Progress Awards