Prof. Grey Gray: From HER2 overexpression to HER2 ultra-low expression, it brings survival benefits to more patients

2024 CSCO YOUNG丨Professor Ge Rui: From the back line to the front line, from HER2 overexpression to HER2 ultra-low expression, the new ADC brings survival benefits to more patients

Editor's note: The 2024 Mid-year Meeting of the Young Expert Committee of the Chinese Society of Clinical Oncology (CSCO YOUNG) will be held in Shanghai on June 28~30. Recently, the results of multiple DESTINY-Breast (DB) studies have been updated and published, bringing additional benefits to HER2-positive, HER2-low and ultra-low HER2 patients. Professor Ge Rui from East China Hospital Affiliated to Fudan University was invited to share the latest research results of the DB series and look forward to the future changes in the treatment landscape in the field of HER2.

#1

Tumor Outlook: Based on the results of the DB-04 study, HER2-low breast cancer has become a new therapeutic category in the field of breast cancer in recent years, and the DB-06 study has extended the application of T-DXd to the ultra-low HER2 expression population. How do you evaluate the role of ADCs in the treatment of HER2-low breast cancer patients and their future directions?

Prof. Gray: Actually, we are very much looking forward to the announcement of the results of the DB-06 study at this year's ASCO conference, because this study not only focuses people's attention again on people with low HER2 expression, but also further expands the field of vision to people with ultra-low HER2 expression. The results of the previous DB-03 study confirmed that the ADC drug T-DXd can bring benefits to the HER2 overexpressing population, and we are very much looking forward to the final OS results of the study. We are also very pleased to see that the results of the DB-04 study and the DB-06 study further confirm that the good efficacy of T-DXd can be further extended to the HER2-low expression population and the ultra-low HER2 expression population. The application of this class of ADC drugs is also very consistent with current clinical practice.

For the traditional treatment mode of HR positive/HER2 negative, endocrine targeted therapy represented by CDK4/6 inhibitors is often chosen for first-line treatment, but there is still no standard answer to the follow-up treatment strategy after the progression of these patients: should we choose traditional chemotherapy, CDK4/6 inhibitor cross-line therapy, or choose drug therapy that includes targeting other endocrine pathways, or choose ADC drug therapy? Of course, a number of clinical explorations have been carried out in the past, and the efficacy observed in these studies is similar to that of endocrine cross-line therapy, mostly about half a year; However, the DB-06 study broke through the PFS of these patients to more than 1 year, and significantly better than the control group (13.2 vs. 8.1 months, P<0.0001). In conclusion, the results of the DB-04 study and the DB-06 study once again confirmed that T-DXd has a good efficacy in people with low HER2 expression, and also provides us with stronger evidence-based evidence.

#2

OS data from the Oncology Outlook :D B-03 study, which set a new standard for second-line treatment of HER2-positive breast cancer, was presented at the 2024 ASCO Congress, showing a median OS of 52.6 months for second-line treatment with T-DXd. What impact do you think the publication of OS study data will have on the treatment and clinical practice of patients in mainland China?

Prof. Grey: Since the DB-03 study was first published at the ESMO Congress, the results have gradually rewritten the ESMO guidelines, ABC6 consensus, and NCCN guidelines, bringing new norms and standards for the second-line treatment of advanced breast cancer. The DB-03 study reported at previous conferences focused more on PFS data and control group analysis, including efficacy-related data and safety data. We are also looking forward to the OS data after the follow-up time is completed, hoping to bring more answers. For patients, perhaps the most important concern is the expected OS outcome after the use of ADC drugs at the time of treatment.

The latest OS results of the DB-03 study were announced at the ASCO meeting, and the median OS of the T-DXd treatment group was 52.6 months (42.7 months better than that of the control group), and the risk of death was significantly reduced by 27% (HR 0.73, 95%CI: 0.56~0.94). The results of the study suggest that treatment with ADC drug T-DXd, especially when applied to advanced second-line therapy, can break through the OS data previously achieved by anti-HER2 therapy in HER2-overexpressing populations.

In addition, another highlight of the study is that 1/3 of the T-DM1-experienced patients in the control group actually cross-treated T-DXd follow-up therapy, and the study also observed the efficacy of ADC re-application in these patients after ADC treatment. In fact, our clinicians will consider that if this effective clinical regimen can be applied earlier and more standardized, it may eventually bring not only phased efficacy benefits to patients, but also overall survival benefits, and the announcement of the OS results of this DB-03 study also gives us more confidence and answers.

#3

Tumor Outlook: T-DXd has also been explored in the first-line treatment of HER2-positive advanced breast cancer. At the 2024 ASCO Congress, the DB-07 study presented the efficacy and safety data of T-DXd + pertuzumab in the first-line treatment of HER2-positive advanced breast cancer for the first time.

Prof. Grey: The DB-07 study also reflects the continuous exploration of the DB series of studies, which has pushed the treatment strategy of T-DXd to a more advanced level. The results of this study are also very much being published. From the follow-up treatment strategy of the previous DB-01 study, to the second-line treatment of the DB-03 study, and now to the DB-07 study, we have been thinking about whether we can push this effective ADC drug to the first-line treatment, so as to optimize the overall lineup and bring better treatment outcomes to patients.

It can be found that the DB-07 study has been very cleverly designed, including both the T-DXd monotherapy group and the T-DXd plus patitrolimab group. PFS data, objective response rate (ORR), safety and tolerability data from the DB-07 study were presented at this year's ASCO Congress. Similar to previous studies, PFS was reported for nearly 30 months, and at a median follow-up of 23.9 months and 25.3 months, 62.7% and 56% of patients in the combination arm continued to receive treatment, respectively. There is a trend of superiority compared to the absolute values of previous late-stage first-line studies. Of course, we also look forward to conducting a head-to-head, randomized controlled clinical study of T-DXd and dual-target-based combination chemotherapy regimens in the first-line treatment of advanced patients in the future, so as to further confirm whether T-DXd can be the preferred or optional strategy for the first-line treatment of advanced disease. We also look forward to more clinical studies, including further follow-up data from the DB-07 study, to provide us with more answers.

Prof. Gray

Deputy Director of Breast Nail Surgery, East China Hospital, Fudan University

Vice Chairman of the CSCO Young Expert Committee of the Chinese Society of Clinical Oncology

Member of the Oncology Committee of the Capacity Building and Continuing Education Center of the National Health Commission and Secretary General of the Breast Cancer Project Team

Member of the Standing Committee of the CSCO Patient Education Committee of the Chinese Society of Clinical Oncology and a member of the Breast Cancer Committee

Member of CBCS of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association

He is a member of the Standing Committee of the Breast Disease Branch of the China Association for the Promotion of International Exchange in Health Care

Deputy head of the Breast Cancer Diagnosis and Treatment Technology Promotion Group of the China National Health Association

Member of the Breast Professional Committee of the Chinese Association of Research Hospitals

Vice Chairman of the Breast Health Science Popularization Committee of Shanghai Science Popularization Volunteer Association

He is a member of the Standing Committee of the Breast Cancer Committee and the Cancer Rehabilitation and Palliative Care Committee of the Shanghai Anti-Cancer Association

Member of the Breast Cancer Group of the Surgical Branch of Shanghai Medical Association

The leader of the professional class of the first medical garden rising star program of Shanghai Health Development Foundation

He is a member of the editorial board of CA Chinese Edition, a member of the Cancer Editorial Board of China Medical Tribune, a reviewer of Frontiers in Oncology and JNCC, and a young editorial board member of the Chinese Journal of Oncology