On September 13-17, 2024, the 2024 Annual Meeting of the European Society for Medical Oncology (ESMO) was officially held in Barcelona, Spain. As one of the most authoritative annual events in the field of oncology, this annual meeting once again gathered global oncology experts and gathered the latest progress in the field.
中国医学科学院肿瘤医院马飞教授在当地时间9月15日转移性乳腺癌简短口头报告专场就“ESG401, a novel Trop2 antibody-drug conjugate (ADC), and its efficacy evidence in HER2-negative metastatic breast cancer with brain metastases（344MO）”研究进行了汇报，并在9月16日的转移性乳腺癌简短口头报告专场2就“Results from a Phase Ia/Ib Study of ESG401, a Novel Trop2 Antibody-Drug Conjugate, in Patients with Different Subtypes of Metastatic Breast Cancer（349MO）”研究进行了汇报。
In response to the above series of studies, China Medical Tribune specially invited Professor Ma Fei to conduct an exclusive interview, and the content of the interview is summarized as follows.
Q1
Could you briefly describe the background of this series of studies and what is special about ESG401?
ESG401 is a Trop2-targeting ADC drug with a small molecule payload of SN-38 and a drug-to-antibody ratio (DAR) of 8. The structural design of ESG401 is innovative, and its stable linker is a prominent feature of the drug. This stable linker is designed to ensure that SN-38 is released after being endocytosed by tumor cells and acts locally in the tumor through the "bystander effect", thereby effectively killing tumor cells. In serum and normal tissues, ESG401 exists in the form of a stable ADC, which avoids toxicity to normal tissues and reduces the occurrence of adverse reactions.
Several preclinical studies were conducted on ESG401 prior to entering clinical trials, including in vitro and in vivo pharmacodynamics, pharmacokinetics and toxicology studies. The results showed that ESG401 had significant effects in inhibiting tumor growth and inducing tumor regression, while demonstrating an excellent safety profile. Following regulatory and ethics committee approvals, ESG401 officially launched its first-in-human trial in September 2021. The study included a Phase Ia dose escalation study and a Phase Ib cohort expansion study. In the Phase Ia study, the Bayesian optimal interval (BOIN) design was used for dose escalation, and the dosage and frequency of ESG401 were fully explored. In the Phase Ib study, based on the results of the dose escalation study, an appropriate dosing regimen was selected in subjects with locally advanced/metastatic triple-negative breast cancer (TNBC) and hormone receptor positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer to evaluate the safety, PK and preliminary anti-tumor activity of ESG401, providing more data for further determination of RP2D and dosing regimen.
Q2
What breast cancer subtypes were covered in the Phase Ia/Ib study of ESG401 in patients with different subtypes of metastatic breast cancer? What are the similarities and differences in response to ESG401 among different subtypes? What are the implications of these findings for subsequent clinical research and treatment strategies?
The study of ESG401 (349MO) included breast cancer patients in three different clinical settings: HR+/HER2- breast cancer patients who have undergone multiple lines of therapy, patients with advanced TNBC who have undergone multiple lines of therapy, and patients with advanced TNBC who have been untreated in metastatic stages.
The results of the study showed that ESG401 had significant efficacy in all three breast cancer patients, with objective response rates (ORR) of 34% and 35% for patients with HR+/HER2- breast cancer and late-line TNBC, respectively. In particular, when ESG401 is used as a first-line treatment for advanced TNBC, it achieves a very high disease control rate (DCR) and ORR with an ORR of 88% and a DCR of 100% as a single agent. ORR is somewhat higher than that reported in comparable ADC and chemotherapy trials, and higher than those reported in immune checkpoint inhibitor and chemotherapy combination trials.
This result is of great significance for understanding the possible differences in the efficacy of Trop2 ADC in different treatment line scenarios, and for analyzing the potential reasons for these differences. It will help us better understand ADC drugs and provide a valuable reference for optimizing their applications in the future. Based on our study data, the difference between ESG401 as a first-line treatment and as a late-line treatment for TNBC patients is significant.
We believe that this difference may be related to the pharmacokinetic profile of the ADC drug. In the structure of ADC, monoclonal antibodies account for more than 90% of its molecular weight, and the PK of different components is greatly affected by monoclonal antibody PK. Proteolytic degradation, as the main elimination pathway for monoclonal antibodies, can be affected by a variety of disease states, including tumors, injury, and chronic inflammation. Late-line and early-line cancer patients had different disease stages, and the systemic protein conversion rate of cancer patients with different disease stages was also different. This results in non-specific proteolytic clearance of monoclonal antibodies that is not constant in patients, but can vary greatly between patients with different disease severity, i.e., that is, the clearance of monoclonal antibodies is related to the course of the disease. As a result, this may result in a relatively small number of ADC drugs being cleared in patients with an earlier line, thus showing a better therapeutic effect; In more advanced patients, it is cleared relatively quickly, and it is difficult to achieve the effect of drug therapy. These are also speculations based on the results of our trials, and we will do more in-depth research in the future.
In addition, the safety profile of ESG401 is also very good, and the most important adverse reactions of grade 3 and above are neutropenia and leukopenia, and the treatment of this type of adverse event (AE) is mature, easy to manage, and has little impact on the quality of life of patients. This also lays a solid foundation for the subsequent combination therapy of ESG401 with other drugs for higher efficacy and tolerability. At present, the follow-up clinical studies of ESG401 will mainly include phase III clinical studies for the late-line treatment of HR+/HER2- breast cancer and first-line treatment of patients with advanced TNBC, and the study of combination therapy with other anti-tumor drugs (such as PD-L1 inhibitors) is also planned.
Q3
What is the efficacy of ESG401 in patients with HER2-negative metastatic breast cancer with brain metastases? What is the importance of this to improve the prognosis of these patients?
In this study of ESG401 (344MO), a total of 21 patients with HER2-negative breast cancer with brain metastases at baseline were included, of whom 67% were TNBC and 33% were HR+/HER2- breast cancer. The largest brain lesion reached 21 mm. The results of the study showed that among the 17 patients who received ES401 treatment, 3 patients achieved complete response (CR) of intracranial lesions, 4 patients achieved partial response (PR), and the intracranial objective response rate (IC-ORR) reached 41%, and the intracranial disease control rate (IC-DCR) reached 76%. The overall efficacy response in these patients was also consistent with the intracranial response, with an overall ORR of 53% and an overall DCR of 71%. The latest data show that the median duration of PFS in these patients has reached 5.7 months, and the maximum duration of treatment has reached 21.8 months.
For a long time, brain metastasis is a clinical treatment problem, and breast cancer is the second most common malignant tumor with central nervous system metastasis, and the incidence of metastatic breast cancer brain metastasis can reach 20%~30%. In recent years, although the treatment of HER2+ breast cancer brain metastases has been improved due to the use of effective drugs for HER2, the treatment effect of HER2- breast cancer brain metastases is still unsatisfactory, with an intracranial ORR of about 14% and a DCR of about 53% in such patients. The overall ORR was about 4% and the DCR was 44%; The duration of PFS is only about 2.8 months. It can be expected that the number of patients with HER2- brain metastases will also increase with the improvement of HER2- breast cancer treatment.
Therefore, there is a huge unmet clinical need for HER2- breast cancer brain metastases. The excellent data of ESG401 in the treatment of HER2- breast cancer brain metastases are of great significance for the treatment of these patients and for the development of Trop2 ADC drugs. In the follow-up clinical study of ESG401, we will also continue to conduct further research on the treatment of brain metastases.
Q4
What do you think are the unsolved clinical challenges for patients with metastatic breast cancer?
Breast cancer is the most common malignancy in women and one of the leading causes of death in women. With the continuous improvement of diagnosis and treatment methods, breast cancer has become an obvious trend of chronic disease in recent years. For early-stage breast cancer, the current treatment methods are very abundant, and the efficacy is stable. However, for advanced breast cancer, due to its special biological behavior, it is still a challenge for oncologists and patients, especially triple-negative breast cancer.
TNBC has always been a difficult problem in the treatment of breast cancer, with poor prognosis, high risk of recurrence, and limited treatment methods. Therefore, TNBC has been a hot spot in the research and development of new treatments. These treatments include immunotherapy (such as PD-L1 inhibitors, CTLA-4 inhibitors, cellular immunotherapy, etc.), tumor vaccines, oncolytic viruses, and ADC drugs mentioned in our previous studies (including multiple targets, such as Trop2, B7-H4, etc.), which are all worth looking forward to.
HR+/HER2- breast cancer accounts for 65%~70% of all breast cancers and is the most common subtype in advanced breast cancer. Although the combination of CDK4/6 inhibitors and endocrine therapy has greatly improved the treatment level of these patients, it is still very difficult to treat patients who are resistant or relapse after treatment failure, and there are few treatment options. For such patients, Trop 2 ADC will also break the treatment dilemma, provide new treatment ideas, and bring new hope to patients.
In addition, brain metastases from metastatic breast cancer are also a major pain point in treatment. Once a patient has brain metastases, survival is significantly shortened. Although the incidence of brain metastases in HER2- breast cancer is lower than that in patients with HER2+ breast cancer, patients with HER2- brain metastases usually have a shorter median survival time than patients with HER2+ brain metastases due to the lack of more effective treatments. Therefore, we also look forward to more and more effective systemic treatment options, which can provide more new options for this part of the patient, so as to improve the prognosis, improve the quality of life, and prolong the survival outcome of patients with brain metastases.
Expert Profile
Professor Ma Fei
Director of the Department of Internal Medicine, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences
Professor, Doctoral Supervisor, Changjiang Scholar Distinguished Professor
Secretary-General of the National Special Committee for Monitoring the Clinical Application of Anti-tumor Drugs
Vice Chairman of the Breast Cancer Committee of the National Cancer Quality Control Center
Secretary-General of the National Cancer Center Norms Committee for Breast Cancer Screening, Early Diagnosis and Early Treatment
Expert of the Healthy China Action Promotion Committee
Vice Chairman of the Oncology Pharmacist Branch of the Chinese Pharmacists Association
Vice Chairman of the Integrated Oncology and Cardiology Branch of the Chinese Anti-Cancer Association
Vice Chairman of the Multi-Primary and Unknown Primary Tumor Special Committee of the Chinese Anti-Cancer Association
Secretary-General of the Oncology Drug Clinical Research Committee of the Chinese Anti-Cancer Association
Vice Chairman of the National Female Ovarian Protection and Anti-Aging Promotion Project Committee
Director General of the Geriatric Oncology Branch of the Chinese Society of Gerontology and Geriatrics
Vice President of Beijing Society for the Prevention and Treatment of Breast Disease
Chairman of the Tumor Chemotherapy Quality Control Committee of Beijing Cancer Treatment Quality Control and Improvement Center
Cancer Innovation主编
He has won the second prize of the National Science and Technology Progress Award, and the honorary titles of "Top Ten Outstanding Young Doctors in the Capital" and "China Young Oncology Scientist Award".
Review | Ma Fei, Cancer Hospital, Chinese Academy of Medical Sciences
Finishing | China Medical Tribune Gui Jingjing
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