Editor's Note: The 2024 European Society for Medical Oncology (ESMO 2024) Annual Meeting will be held from September 13-17 in Barcelona, Spain. At this upcoming ESMO 2024 conference, Dr. Fei Ma from the Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College will present two Mini Oral reports (344MO, 349MO) on the novel Trop-2 antibody-drug conjugate (ADC) ESG401. These two studies not only highlight the significant efficacy of ESG401 in HER2-negative breast cancer with brain metastases but also reveal its broad potential application across different subtypes of metastatic breast cancer. This provides new treatment options for breast cancer patients and opens new directions for the research and development of Trop-2 ADC drugs. Oncology Frontier invited Dr. Fei Ma to introduce the key aspects of these two studies, and we look forward to his exciting presentation at ESMO 2024, contributing Chinese insights and expertise to global breast cancer treatment.

Oncology Frontier: You will be presenting two Mini Oral reports (344MO, 349MO) at the 2024 ESMO conference. Could you please introduce the main content of these two reports?

Dr. Fei Ma: At the upcoming ESMO conference, I will present two Mini Oral reports (344MO, 349MO), both of which are interim reports on the clinical research results of the novel Trop-2 ADC, ESG401.

In report 344MO, we present the safety and efficacy data of ESG401 in HER2-negative breast cancer patients with baseline brain metastases. This analysis included a total of 21 patients with advanced breast cancer and baseline brain metastases, of which 67% had triple-negative breast cancer (TNBC) and 33% had HR+/HER2- breast cancer. The largest brain lesion measured 21 mm. Preliminary results show that among the 17 evaluable patients, 3 achieved complete response (CR) and 4 achieved partial response (PR) for their intracranial lesions, with an intracranial objective response rate (IC-ORR) of 41% and an intracranial disease control rate (IC-DCR) of 76%. The overall response rate (ORR) was 53%, and the overall disease control rate (DCR) was 71%. Importantly, ESG401 showed a safety profile in line with the overall population, even among patients with brain metastases.

Brain metastases are a challenging issue in breast cancer treatment, and to our knowledge, this is the largest exploratory study of Trop-2 ADC drugs that enrolled a significant number of patients with brain metastases and evaluated intracranial responses using objective imaging criteria. The promising efficacy data from this study provide valuable insights for treating HER2-negative breast cancer with brain metastases and for the future development of Trop-2 ADC drugs.

Report 349MO covers the overall trial design and interim safety and efficacy results from the phase Ia/Ib clinical study of ESG401 across different molecular subtypes and lines of treatment in breast cancer patients. So far, 144 patients have been enrolled, including 65 with HR+/HER2- breast cancer, 47 with late-line TNBC, and 28 with treatment-naive metastatic TNBC. The results showed that ESG401 was effective across all three subtypes, with ORRs of 34% for HR+/HER2- breast cancer and 35% for late-line TNBC.

Notably, when used as a first-line treatment for advanced TNBC, ESG401 as a monotherapy achieved a very high response rate, with an ORR of 88% and a DCR of 100%. These response rates surpass those reported for similar ADC drugs in combination with chemotherapy and are also higher than those seen with immune checkpoint inhibitors combined with chemotherapy. Additionally, the favorable safety profile of ESG401 supports its potential for future combination therapy to achieve even higher efficacy and tolerability.

Oncology Frontier: In the 344MO study, ESG401 demonstrated remarkable efficacy in HER2-negative breast cancer with brain metastases. For patients still undergoing treatment, the longest treatment duration has reached 21.3 months. What do you think this data implies for the design of future clinical trials and treatment expectations for patients with brain metastases?

Dr. Fei Ma: With the diversification of breast cancer treatments in recent years, therapeutic outcomes have improved, and patient survival times have been significantly extended. However, the incidence of brain metastases in breast cancer has also increased year by year. Once breast cancer patients develop brain metastases, their survival time is drastically shortened. Although the emergence of new therapies has provided more options for treating brain metastases in HER2-positive breast cancer patients (such as ADC drugs and small-molecule TKIs), progress in treating HER2-negative breast cancer with brain metastases has been slow.

ESG401 has shown encouraging efficacy in HER2-negative breast cancer patients with brain metastases, achieving a high intracranial ORR of 41%. In clinical research, patients with brain metastases are often excluded due to poor performance status, shortened life expectancy, or increased safety risks. However, given the rising incidence of brain metastases, excluding such patients from clinical trials may lead to results that do not fully reflect the benefit-risk profile of a drug for the broader patient population.

In early clinical trials, ESG401 included patients with brain metastases and yielded excellent results. On one hand, this brings new hope and treatment opportunities for patients with brain metastases. On the other hand, it provides valuable insights for the design of clinical trials for innovative drugs. With a strong theoretical basis, we can explore treatment options for specific subtypes earlier in the clinical trial process, bringing solutions to pressing clinical challenges.

Oncology Frontier: The 349MO study explored ESG401’s efficacy in different subtypes of metastatic breast cancer, and the results showed promising and durable responses across various subtypes. In first-line treatment of TNBC patients, ESG401 showed particularly remarkable efficacy. Based on the current phase Ia/Ib study results, what are your plans for future clinical trials of ESG401? Will you further explore its efficacy and safety in specific patient groups?

Dr. Fei Ma: We have already explored ESG401’s efficacy across various molecular subtypes and lines of treatment in breast cancer patients. Preliminary data show that ESG401 has good safety and manageable adverse effects. Even in heavily pretreated TNBC patients with poor baseline conditions, ESG401 demonstrated favorable efficacy, especially in first-line treatment for advanced TNBC. Therefore, we plan to conduct further exploration in this patient group.

A phase III clinical trial of ESG401 for second-line treatment of HR+/HER2- advanced breast cancer, comparing ESG401 with chemotherapy, has been approved and is actively recruiting participants. Given the encouraging initial results in patients with brain metastases (particularly HER2-negative patients), we also plan to develop a specific treatment for brain metastases in the future, with the goal of addressing these patients’ clinical needs.

Oncology Frontier: How do you view ESG401’s potential position in the treatment landscape of breast cancer? Could it become an important new drug for treating multiple breast cancer subtypes? What future research will your team conduct on this drug?

Dr. Fei Ma: Current research data indicate that ESG401 is a highly effective and well-tolerated Trop-2 ADC, and we have high expectations for it. For second-line treatment of HR+/HER2- advanced breast cancer, we have already launched a nationwide multi-center randomized controlled trial comparing ESG401 with chemotherapy, and we eagerly await the results. Based on ESG401’s outstanding efficacy in first-line treatment of advanced TNBC patients, we are also planning a phase III clinical trial for this group. If the trial yields positive results, it will significantly improve the overall treatment efficacy and survival for patients with advanced TNBC. Brain metastases remain a clinical challenge, but if we can further demonstrate the safety and efficacy of ESG401 with larger sample sizes in clinical trials, HER2-negative brain metastasis patients will gain new treatment options and survival opportunities. We look forward to these related studies.

Dr. Fei Ma

Chief Physician, Professor, PhD Supervisor, Distinguished Changjiang Scholar Director, Department of Medical Oncology, National Cancer Center / Cancer Hospital, Chinese Academy of Medical Sciences Secretary-General, National Committee for Monitoring Clinical Use of Antineoplastic Drugs Vice-Chair, Breast Cancer Subcommittee, National Center for Quality Control of Cancer Secretary-General, Breast Cancer Screening and Early Diagnosis and Treatment Standards Committee, National Cancer Center Expert, Healthy China Action Promotion Committee Vice-Chair, Oncology Pharmacy Committee, Chinese Pharmacists Association Vice-Chair, Integrative Oncology Cardiology Committee, Chinese Anti-Cancer Association Vice-Chair, Multiple Primary and Unknown Primary Tumors Committee, Chinese Anti-Cancer Association Secretary-General, Clinical Research of Antitumor Drugs Committee, Chinese Anti-Cancer Association Vice-Chair, National Committee for Ovarian Protection and Anti-Aging Promotion Executive Secretary, Geriatric Oncology Division, Chinese Society of Gerontology and Geriatrics Vice President, Beijing Society for Breast Disease Prevention and Treatment Chair, Tumor Chemotherapy Subcommittee, Beijing Tumor Treatment Quality Control and Improvement Center Editor-in-Chief, Cancer Innovation Recipient of National Science and Technology Progress Award (Second Prize) and several other honors including “Top Ten Outstanding Young Doctors in the Capital” and “China Cancer Youth Scientist Award”