Editor’s Note: Breast cancer has become the most common malignant tumor globally, with approximately 30% to 40% of early-stage breast cancer patients ultimately progressing to advanced breast cancer.At this year’s ESMO conference,Dr. Tao Sun’s team from Liaoning Cancer Hospital and Dr. Yehui Shi’s team from Tianjin Medical University Cancer Hospital shared their insights on the potential of different combination regimens involving eribulin, providing more treatment options for breast cancer patients.
Oncology Frontier: Can you talk about the initial design and objectives of the IPU study, and how it addresses unmet treatment needs in clinical practice?
Dr. Sun: HER2-positive advanced breast cancer accounts for approximately 15% to 20% of all breast cancer cases and is characterized by high invasiveness, a high risk of recurrence, and poor prognosis. During the diagnosis and treatment of breast cancer patients, many new drugs have emerged and been used in clinical practice, significantly improving the prognosis of HER2-positive advanced breast cancer patients and their quality of life. Currently, the treatment principles for HER2-positive breast cancer are based on a comprehensive treatment model that combines anti-HER2 therapy with chemotherapy. Targeted drugs in the field of anti-HER2 therapy include large-molecule monoclonal antibodies, small-molecule tyrosine kinase inhibitors (TKIs), and antibody-drug conjugates (ADCs). Monoclonal antibodies mainly target the extracellular region, while TKIs mainly target the intracellular region. Therefore, we considered that combining large-molecule monoclonal antibodies, small-molecule TKIs, and chemotherapy could potentially yield better treatment outcomes.
Based on this concept, we initiated the IPU study to validate this idea. Given that large-molecule monoclonal antibodies, such as trastuzumab, are widely used in clinical practice, we chose pertuzumab as the large-molecule monoclonal antibody in the trial’s design. For the TKI, we selected pyrotinib, and for chemotherapy, we chose eribulin, an anti-microtubule inhibitor. Eribulin was selected because it has demonstrated good anti-tumor activity in advanced breast cancer patients and has shown excellent performance in clinical studies in triple-negative breast cancer, HER2-positive breast cancer, and HR-positive breast cancer. Based on these research results and current clinical needs, our team designed a triple combination therapy regimen, including eribulin, pertuzumab, and pyrotinib, to explore the effectiveness and safety of combining eribulin with anti-HER2 targeted therapy in HER2-positive advanced breast cancer patients. During the course of the study, the results of the PHILA study (pyrotinib + trastuzumab + capecitabine) were announced, confirming the position of the combination of anti-HER2 large-molecule and small-molecule TKI therapy with chemotherapy in first-line treatment of HER2-positive advanced breast cancer. This also validated the correctness of our approach.
Oncology frontier: What are the current results of the study, and what guidance does it provide for clinical practice?
Dr. Sun: The study aimed to enroll 94 patients who would receive pertuzumab (initial dose of 8mg/kg on Day 1, followed by a maintenance dose of 6mg/kg, intravenous) + pyrotinib (400mg daily, orally) + eribulin (30mg/m2 on Days 1-5, intravenous) treatment every 21 days per cycle until disease progression or intolerable toxicity occurred. The primary endpoint was the objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.
As of April 1, 2023, we had enrolled 47 patients, of which 29 were evaluable for efficacy. The median treatment cycle was 8 (range 4-20) cycles, and 19 patients (65.5%) had received first-line treatment, while 10 patients (34.5%) had received second-line treatment. Among the 29 patients evaluable for efficacy and safety, 23 patients achieved a partial response (PR), and 4 patients had stable disease (SD). The ORR was 79.3%, and the disease control rate (DCR) was 93.1%. The median PFS had not been reached.
Regarding safety, most treatment-related adverse events (TRAEs) during treatment were Grade 1 or 2, with diarrhea being the main Grade 3 adverse event, consistent with events reported for pyrotinib. Patients’ diarrhea symptoms improved to Grade 1 or 2 after symptomatic treatment during the treatment period. No new treatment-related adverse events occurred, and there were no treatment interruptions or deaths related to treatment during the study.
The IPU study provides new evidence and options for the combination of large-molecule anti-HER2 and small-molecule TKI therapy with chemotherapy. The ORR/DCR of this regimen has reached a high level compared to similar studies, and in patients treated in the 1st and 2nd lines, the ORR (79.3%) is nearly equivalent to that in the PHILA study (82.8%), which only included first-line treatment. This demonstrates the effectiveness of eribulin, which is as effective as docetaxel. In terms of safety, most TRAEs were Grade 1 or 2, in line with eribulin’s profile of being highly effective with low toxicity. Through this study, we further confirmed the efficacy and safety of combining eribulin with targeted therapy, making it a potential alternative chemotherapy choice for patients who have previously received pertuzumab in adjuvant therapy and subsequently experience recurrence or metastasis, providing more treatment possibilities for HER2-positive advanced breast cancer patients.
Oncology Frontier: What are your expectations and prospects for eribulin in the future?
Dr. Sun: Both the IPU study we designed and the ICU study initiated by Professor Yan Min’s team explore the treatment of HER2-positive advanced breast cancer patients. The ICU study investigates the efficacy of eribulin in combination with anti-HER2 targeted therapy and immunotherapy in later-line HER2-positive patients, while the IPU study explores the efficacy of the eribulin combination with anti-HER2 targeted therapy in front-line HER2-positive patients. Both studies have shown excellent treatment outcomes and have enriched the treatment options for HER2-positive advanced breast cancer. In terms of safety, no Grade 3 or higher serious adverse events occurred in either study, highlighting the safety and effectiveness of clinical research initiated by investigators. In the future, different mechanisms of action, such as epothilone-like microtubule inhibitors like eribulin, can be considered for patients who have failed immunotherapy, anti-HER2 therapy, or HR+ endocrine therapy. This will allow Chinese regimens to catch up with international standards.
Oncology Frontier: Can you discuss the current status of breast cancer brain metastasis treatment and the diagnostic and therapeutic needs it faces?
Dr. Shi: Breast cancer is the most common malignancy in women, and the incidence of breast cancer brain metastasis is increasing year by year. Currently, the standard approach for brain metastasis primarily involves local treatments, such as radiation therapy or surgery, with drug therapy as a complementary option. In terms of drug therapy, due to the presence of the blood-brain barrier, systemic treatments are not effective in reaching the brain. In recent years, the introduction of small-molecule TKIs has provided new options for HER2+ breast cancer brain metastasis patients. However, overall, the drug treatment outcomes for breast cancer brain metastasis are not ideal. There is a significant unmet need for systemic treatments. Therefore, in this context, finding new drugs and treatment methods has become an urgent task.
Oncology Frontier: Can you introduce the rationale and design of the UTOBIA-BM study?
Dr. Shi: The initiation of the UTOBIA-BM study was based on our understanding of new drugs. Early research on eribulin showed that it maintained high drug concentrations in brain tissue, significantly higher than traditional taxane-based chemotherapy drugs. Eribulin is produced through genetic engineering and microbial fermentation, with a molecular weight of only 491.68 kDa, and it does not bind to the P-glycoprotein that causes multidrug resistance on cancer cell membranes. These characteristics indicate its potential for preventing and treating breast cancer brain metastasis. Bevacizumab has been proven to be the standard accompanying drug for brain metastasis treatment. Based on these data, our team designed the UTOBIA-BM study (eribulin combined with etoposide and bevacizumab) to control brain edema and reduce intracranial tumors through the combination of eribulin with bevacizumab and achieve a new treatment approach for breast cancer brain metastasis. We aimed to explore the potential for drugs to play a primary role in the treatment of breast cancer brain metastasis, not merely as an adjunct treatment for symptom relief.
The study enrolled HER2-negative breast cancer brain metastasis patients and used a Simon’s two-stage optimal trial design. If three or more of the 13 patients achieved central nervous system (CNS) responses, an additional 30 patients would be recruited. The treatment regimen included eribulin (30mg/m2, intravenous on Days 1-5) + etoposide (100mg/m2, intravenous on Days 1-3) + bevacizumab (10mg/kg, intravenous on Day 1) every 21 days per cycle for a total of 6 cycles, followed by continued eribulin and bevacizumab maintenance therapy until disease progression or intolerable toxicity occurred. The primary endpoint was CNS objective response rate (CNS-ORR), and secondary endpoints included CNS clinical benefit rate (CNS-CBR), CNS progression-free survival (CNS-PFS), non-CNS-ORR, non-CNS-CBR, ORR, PFS, clinical benefit rate (CBR), overall survival (OS), and safety.
Oncology Frontier: What are the results of the UTOBIA-BM study, and what insights does it bring to the treatment of brain metastases?
Dr. Shi: From August 11, 2022, to March 22, 2023, a total of 17 patients were enrolled in the study. The median age of the patients was 48 years (range 34-67), and all were female. As of May 5, 2023, the median follow-up period was 6 cycles (range 2-8). Sixty-five percent (11/17) of patients were evaluable for efficacy, and the CNS-ORR was 73% (8/11), while the CNS-CBR was 91% (10/11). At present, the median PFS and OS have not been reached, and all patients are still undergoing treatment, meeting the criteria for entering the second stage of the trial.
In terms of safety, most treatment-related adverse events were Grade 1 or 2 and were manageable and reversible. The incidence of Grade 3 chemotherapy-induced peripheral neuropathy (CIPN) was 9% (1/11). One patient experienced eribulin-related dose adjustments, and there were no treatment-related deaths.
The preliminary results of the UTOBIA-BM study confirmed the original intent of the study. For the first time, through clinical trials, we demonstrated the anti-tumor activity and safety of eribulin in breast cancer brain metastasis patients. The CNS-ORR reached 73% in the study’s results. Based on the data from the patients we enrolled, it is clear that the combination of eribulin with anti-angiogenic agents has achieved excellent results for the treatment of breast cancer brain metastasis, likely outperforming existing treatment options. Overall, the safety of the patients was also good. Therefore, in future studies, it will be necessary to increase the number of cases and provide more data to offer the strongest evidence for future clinical treatment. For patients with solid tumor brain metastases, treatment based on eribulin could become a promising direction for future development. Continued research and exploration of eribulin’s application in brain metastasis treatment will provide more treatment options and hope for patients in this field.
Professor Sun Tao
Liaoning Cancer Hospital
Professor Shi Yehui
Tianjin Medical University Cancer Hospital
