Prof. Zhimin Shao: A new generation of ADC drugs enables HER2-positive breast cancer treatment to enter a new stage

*Only for medical professionals to read for reference.
The "medical community" hereby invites Professor Shao Zhimin from the Cancer Hospital of Fudan University to analyze the significance and future prospects of DESTINY-Breast03 in the diagnosis and treatment of HER2 breast cancer
.

If you review the most remarkable and amazing clinical research in the field of breast cancer treatment, DESTINY-Breast03 may be one of the important turning points in the history of breast cancer treatment
.

In the just-concluded ESMO2021, due to the greatly improved curative effect and potential changes to the current status of breast cancer treatment, this research has received great attention and has become the most dazzling LBA at this ESMO annual meeting
.

While DB03 brings epoch-making effects, it is of great significance to the development of the new generation ADC drug DS8201 in the treatment of HER2 breast cancer throughout the course of the disease
.

HER2-the scientific legend that changes the fate of breast cancer patients In 1987, Professor Dennis Slamon of UCLA School of Medicine and Dr.
Axel Ullrrich of the Molecular Biology Research Department of Genentech and others reported in Science the correlation between HER2 gene amplification and the prognosis of breast cancer.
It is found that patients with HER2 gene amplification have a higher risk of tumor recurrence and a worse prognosis.
Since then, it has been gradually revealed that the amplification and high expression of HER2 gene are the driving factors for the development of breast cancer in these patients, and the scores of HER2 positive breast cancer have been established.
The basis of type and governance
.

In 1989, Axel Ullrrich and other researchers of Genentech, Michael Shepard, et al.
reported that anti-HER2 (p185HER2) mAb 4D5 had an inhibitory effect on HER2 gene amplification in breast cancer cells in in vitro experiments, and could increase the resistance of these cells to tumor necrosis factor.
Sensitivity
.

Subsequently, Ullrrich and Shepard carried out the humanized transformation of 4D5 to develop trastuzumab, which is like regulan, ushering in the era of HER2 targeted therapy
.

Figure 1.
Winners of the 2019 Lasker Clinical Medicine Research Award, three scientists researching trastuzumab in the treatment of breast cancer.
Before trastuzumab appeared, if a breast cancer patient detects HER2 gene amplification or high expression, This means that the tumor will be more aggressive, more likely to occur tumor metastasis and recurrence, and the prognosis of treatment will be worse
.

With the emergence of targeted drugs for anti-HER2 therapy, the treatment of HER2-positive breast cancer has undergone earth-shaking changes.
HER2 positive has become a sign of targeted and effective treatment, and the survival of the corresponding patients has also been greatly improved
.

Anti-HER2 therapy has changed the fate of patients and also changed the course of this type of disease
.

Figure 2.
The emergence of anti-HER2 therapy significantly improves the prognosis of HER2-positive breast cancer.
With further research and understanding of HER2-positive breast cancer and the maturity of corresponding drug development technologies, many more have been developed after trastuzumab A targeted drug for anti-HER2 therapy.
The combination of these drugs provides a very effective plan for clinical treatment
.

Figure 3.
Continuously innovative anti-HER2 therapeutic drugs, from the era of chemotherapy to the era of monoclonal antibodies, TKI and ADC drugs.
Breast cancer diagnosis and treatment has always been the pioneer of innovation in the treatment of solid tumors, from the first monoclonal antibody for the treatment of solid tumors to subsequent TKIs , And now ADC drugs that target HER2 are all the same
.

Although early anti-HER2 therapies provide very effective treatment options, they are not completely cured.
Breast cancer still has many unmet needs for treatment, such as the existence of primary drug resistance, the occurrence of secondary drug resistance, and advanced breast cancer Incurable reality
.

Therefore, anti-HER2 treatments are constantly being updated, and ADC drugs that target HER2 are the most concerned now
.

DESTINY-Breast03 continues the legend, HER2-positive breast cancer treatment enters the real ADC era.
The 2019 SABCS annual meeting and the New England Journal of Medicine simultaneously released the research data of DESTINY-Breast01, which attracted wide attention from experts in the field of breast cancer, and soon the FDA Approved the listing of related drugs, namely DS8201 (also known as T-DXd, trade name Enhertu)
.

In the DB01 study, DS8201 still achieved an objective response rate of 62%, a median PFS of 19.
4 months, and a median OS of 31.
3 months in patients with advanced breast cancer with a median treatment of 6 lines
.

Figure 4.
In the DESTINY-Breast01 study, DS8201 showed amazing ORR, PFS and OS.
In fact, before DS8201 appeared, as early as 2012, anti-HER2 ADC drugs were successful in clinical research in the field of breast cancer.
In 2013, it was approved by the FDA as the first ADC drug approved for the treatment of solid tumors.
This is T-DM1
.

In the ELIMIA study, compared with lapatinib + capecitabine, T-DM1 was used for trastuzumab-treated advanced breast cancer, and the PFS was significantly prolonged.
The PFS of the two groups was 9.
6 vs.
6.
4 months.
And the OS is also extended by 4 months (29.
9 vs.
25.
9)
.

T-DM1 has therefore become the global standard for the second-line treatment of HER2-positive advanced breast cancer
.

Figure 5.
ELIMIA study shows that T-DM1 vs lapatinib + capecitabine significantly prolongs PFS and OS.
Based on DB01 and ELIMIA, DS8201, as a new generation of ADC drugs, needs to prove its efficacy compared with existing standard treatments Advantages, the DESTINY-Breast03 research comes from this
.

The DB03 study compares the efficacy and safety of DS8201 and T-DM1 in the second-line treatment of HER2-positive advanced breast cancer.
It is currently the only phase III clinical trial that has achieved success in advanced second-line head-to-head comparisons of T-DM1 in the world
.

The results showed that DS8201 reduced the risk of disease progression or death by 72% compared with T-DM1.
The 1-year PFS rate was 75.
8% and 34.
1%, respectively.
The median PFS of the T-DM1 group was 6.
8 months, while the DS8201 group was in follow-up The median PFS has not been reached after 16 months
.

DS8201 shows an overwhelming efficacy advantage, which is an improvement in efficacy that has not been seen for many years
.

Figure 6.
DESTINY-Breast03, DS8201 reduces the risk of recurrence or death by 72% compared with T-DM1, and PFS is greatly improved.
Not only that, the secondary endpoint of the DB03 study shows that DS8201 shows a clear trend of OS benefit compared to T-DM1 , The 12-month OS rate was 94.
1% and 85.
9%, respectively
.

The DS8201 group is highly effective, with an ORR of 79.
7% and up to 16.
1% of patients achieving complete tumor remission (CR).
In the first-line THP (dual target combined chemotherapy) treatment, only 5% of patients can achieve CR
.

These data means that DS8201 may bring significant survival benefits, and some patients can obtain long-term disease control
.

Figure 7.
DESTINY-Breast03, DS8201 has an OS benefit trend, with an ORR of nearly 80% and a CR of 16.
1%.
It can be seen that as a new-generation ADC drug, DS8201 has significantly better efficacy than the above after optimization in drug design in many aspects.
A first-generation ADC drug, and will replace T-DM1 as the new advanced second-line standard treatment
.

On the other hand, although T-DM1 has been successful in late second-line and early intensive adjuvant therapy, it has not shown superiority in the head-to-head studies of late first-line and early adjuvant therapy and HP dual targets.
Therefore, T-DM1 does not ADC drugs have not become the mainstream drugs for breast cancer treatment
.

On this basis, DS8201 will have the opportunity to bring breast cancer treatment into the real ADC era
.

DESTINY-Breast03 is a starting point for DS8201, and early cure is still well known.
With everyone’s attention and efforts to early breast cancer screening, about 90% of patients are now diagnosed with early breast cancer at the time of diagnosis, and the goal of early breast cancer treatment is Cure
.

With the continuous development of local treatments such as surgery and systemic treatments such as anti-HER2 treatments, the cure rate of HER2-positive early breast cancer is relatively high, and about 70%-80% of patients can be cured
.

For patients with a high risk of recurrence, how to further reduce the risk of recurrence and increase the cure rate as much as possible when there is a chance of cure is one of the main research directions for early breast cancer
.

DS8201 is the layout of early breast cancer in this kind of population
.

For patients with large tumor burden and lymph node metastasis, receiving neoadjuvant treatment before surgery to shrink the tumor and increase the chance of complete resection is one of the strategies for improving the cure rate of early breast cancer
.

DESTINY-Breast11 research i.
e.
in such scenario Comparative clinical DS8201 and DS8201 sequential neoadjuvant therapy THP and THP ddAC sequential phase III, the pCR primary endpoint, secondary endpoints including 3 years DFS, OS and so on
.

Figure 8.
DESTINY-Breast11, DS8201 is used for neoadjuvant treatment of early high-risk HER2-positive breast cancer.
Another study of DS8201 in early-stage breast cancer is to compare T-DM1 for HER2-positive breast cancer patients with high risk of recurrence while receiving neoadjuvant Intensive adjuvant treatment without reaching pCR after treatment, the primary endpoint is iDFS assessed by the investigator
.

Figure 9.
DESTINY-Breast05, DS8201 is used in the neoadjuvant treatment of non-pCR HER2-positive breast cancer adjuvant treatment.
It is hoped that DS8201 can also show breakthrough effects in these early breast cancer studies, thereby improving the cure of HER2-positive breast cancer Rate, and further redefine the standard treatment for HER2-positive breast cancer
.

The next breakthrough after DESTINY-Breast03, to expand the personalized and precise treatment of HER2 low-expressing breast cancer.
The standard for HER2 positivity comes from whether trastuzumab is effective, and it has gradually developed into HER2 with IHC 3+ and IHC2+ and ISH+ as the standard.
Criteria for positive judgment
.

Patients with IHC1+ and IHC2+ and ISH- (that is, HER2 low expression) actually have HER2 expression, but the expression level is not so high.
Past studies have found that traditional anti-HER2 treatment is basically ineffective in this part of the population, so they are treated as HER2 negative
.

More and more related studies have found that breast cancer with low HER2 expression is different from HER2 pure-negative breast cancer in terms of disease biological characteristics, response to drug treatment, and prognosis; especially DS8201 in its phase I study Demonstrated effectiveness for people with low HER2 expression, allowing clinical experts to renew attention to this patient population, which may become a new molecular type of breast cancer
.

For breast cancer with low HER2 expression, DS8201 currently has two ongoing phase III clinical trials worthy of attention.
If it succeeds, it will be another breakthrough in breast cancer treatment
.

Figure 10.
DS-8201-A-J101 study, DS8201 showed efficacy in patients with a median of 7 lines of HER2 low expression, ORR 37%, mPFS 11.
1 months DESTINY-Breast04 is an exploration DS8201 has received ≥1 line in the metastatic stage A phase III clinical study of the efficacy and safety of chemotherapy-induced HER2 low expression breast cancer compared with the chemotherapy selected by the investigator
.

The primary study endpoint was PFS assessed by an independent blind review committee
.

Figure 11.
DESTINY-Breast04 trial design.
DESTINY-Breast06 is a HER2 low-expressing breast cancer that has received two-line endocrine therapy.
It compares the efficacy and safety of DS8201 with the chemotherapy selected by the investigator
.

The primary study endpoint was the PFS of the HR+/HER2 low expression population evaluated by the independent blind review committee, and the secondary endpoints included PFS, OS and ORR of the OS and ITT population
.

Figure 12.
DESTINY-Breast06 experimental design DESTINY-Breast03, as the first phase III clinical study of DS8201, has shown revolutionary efficacy.
This not only redefines the standard for second-line treatment of HER2-positive advanced breast cancer, but also indicates that it is HER2-positive Both advanced first-line and early breast cancer related studies may surpass existing standard treatments; on the other hand, the expansion of people with low HER2 expression may provide a personalized and precise treatment plan for people with low HER2 expression
.

From these perspectives, the success of DESTINY-Breast03 means that the exploration of HER2 breast cancer treatment has entered a new stage
.

Expert profile Professor Shao Zhimin, the first batch of distinguished professors of the Ministry of Education, Changjiang Scholars, National Outstanding Youth, Fudan Distinguished Professor, Fudan University Cancer Institute Director, Breast Cancer Institute Director General Surgery Director and Breast Surgery Director Honorary of the Chinese Anti-Cancer Association Breast Cancer Professional Committee Chairman, Director of the Targeted Therapy Professional Committee of the Chinese Anti-Cancer Association Director of the Chinese Society of Clinical Oncology (CSCO), Vice Chairman of the Chinese Medical Association Oncology Branch, Chairman of the Breast Cancer Professional Committee of the Chinese Medical Doctor Association Clinical Precision Medicine Committee Chairman of the Shanghai Anti-Cancer Association Honorary Chairman of the Breast Cancer Specialty Committee Honorary Chairman of the Oncology Specialty Committee of the Shanghai Medical Association Scan the code to follow the ADC Academy Online official account *This article is only used to provide scientific information to medical professionals and does not represent the views of this platform