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It is reported that Merck's blockbuster product pembrolizumab injection (Keytruda, Keytruda ® The new indication was recently approved by China's National Medical Products Administration (NMPA), which is the 10th indication approved in China since pembrolizumab was first approved in China in 2018; This approval makes pembrolizumab the first and only immune checkpoint inhibitor in China for early high-risk triple-negative breast cancer (TNBC) in combination chemotherapy in the adjuvant stage, which will change the treatment pattern
of patients with early TNBC.
We specially invited Professor Shao Zhimin from the Department of Breast Surgery, Fudan University Cancer Hospital, to discuss the significance and impact
of this approval on the clinical practice of TNBC in China based on the current status of TNBC immunotherapy.
Yimaitong: Hello
Professor Shao.
Due to its high heterogeneity and other disease characteristics, TNBC is known as the most dangerous subtype
of breast cancer.
What difficulties and pain points do you think exist in the diagnosis and treatment of TNBC?
Professor Shao Zhimin
According to the latest data from the International Agency for Research on Cancer (IARC), breast cancer has ranked first in the global incidence of female cancer, of which TNBC accounts for about 15%~20%
of all breast cancers.
TNBC is highly malignant and aggressive, and tends to occur in young women
under 40 years of age and before menopause.
With the deepening of TNBC research, we gradually realized that TNBC is a highly heterogeneous hybrid tumor, due to its tumor biological behavior and drug sensitivity, and different patients have different efficacy after using the same drug
.
At present, the difficulties and pain points in clinical diagnosis and treatment are:
First: high
risk of early recurrence.
TNBC has a higher risk of recurrence in the early stage 1~3 years after surgery, and recurrence is more common in visceral metastasis and brain metastasis.
Moreover, once recurrent metastasis occurs, the treatment effect of TNBC patients in the later stage has little
effect.
Second: the treatment method is single, and the prognosis is relatively poor
.
Compared with other breast cancer subtypes, TNBC estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) are negative, endocrine therapy and targeted therapy have limited benefits, and chemotherapy is still used as the main treatment mode in clinical practice.
If there is primary drug resistance and chemotherapy ineffectiveness, the prognosis of patients is often not satisfactory
.
Yimaitong: The team you led proposed the "Fudan classification" of TNBC for the first time, dividing TNBC into four different subtypes, making precise diagnosis and treatment for different subtypes possible
.
Could you please briefly explain the characteristics of the immune mechanism of TNBC in combination with this set of typing theory? What is the current status of TNBC immunotherapy?
Professor Shao Zhimin
In order to match targeted treatment methods for TNBC patients with the same characteristics, our team has systematically built a TNBC database in the past ten years to draw the "world's largest TNBC gene map", and divided it into four subtypes
according to the different gene characteristics of TNBC (IM), luminal androgen receptor type (LAR), basement-like immunosuppressive type (BLIS), and interstitial type (MES).
"Fudan typing" can lay a solid foundation
for further finding key therapeutic targets and establishing precision treatment strategies.
At present, the treatment of TNB C in clinicalpractice is limited, and the emergence of immunotherapy provides new opportunities
for the treatment of TNBC.
Immune checkpoint inhibitors are the most common form of TNBC immunotherapy and target immunomodulatory points such as PD-1 or PD-L1 to reactivate immunity
to tumors.
In the microenvironment of TNBC patients, the expression level of immunotherapy target PD-L1 was high, and PD-L1 was expressed in tumor-infiltrating immune cells, indicating that TNBC patients could benefit from immunotherapy.
Among them, IM-type TNBC patients are enriched with immune-activating cells and immunostimulating factors in the microenvironment, and immunotherapy is the best choice
for this population.
Therefore, clear molecular typing and precision therapy are the keys to improving patient outcomes
.
At present, there are not many studies in the field of immunotherapy, but relevant studies have obtained amazing clinical data
.
Recently, based on the excellent results of the KEYNOTE-522 study, pembrolizumab was approved for early high-risk TNBC patients in China, how do you evaluate this study? What is the current status of pembrolizumab in TNBC immunotherapy?
Professor Shao Zhimin
The KEYNOTE-522 study is the largest study of immunotherapy combined with chemotherapy (new) adjuvant therapy for early-risk high-risk TNBC, and the only study that has achieved all positive results, which is an important milestone
in the history of TNBC treatment.
The traditional TNBC neoadjuvant chemotherapy regimen adopts paclitaxel sequential anthracyclines, and the pathological complete response (pCR) rate of patients is about 44%, and the regimen with platinum drugs is the regimen with the highest pCR rate in TNBC (53.
2%~58%)
.
At this point, the efficacy of neoadjuvant chemotherapy regimens has reached a bottleneck, and pCR cannot be further improved
.
KEYNOTE-522 RESEARCH RESULTS SHOW:
The whole population benefited from the intention-to-treat (ITT) group, and the pembrolizumab group showed excellent pCR rate (64.
8% vs 51.
2%), and EFS at 36 months was significantly higher than that in the chemotherapy group alone (84.
5% vs 76.
8%, HR=0.
63), and the safety was generally manageable and controllable.Based on the excellent data of KEYNOTE-522, China has also been approved for the use
of pembrolizumab in specific populations of TNBC.
In the PD-L1-positive [composite positive score (CPS)≥20] subgroup, pembrolizumab in combination with chemotherapy neoadjuvant therapy followed by 8 courses of pembrolizumab monotherapy for 9 courses also achieved dual benefits of pCR and event-free survival (EFS):• The pCR rate in the pembrolizumab group increased by 18.
5 percentage points from 63.
2% to 81.
7%.• The EFS risk ratio decreased by 59% in the pembrolizumab group, and the EFS rate in 24-month follow-up data increased from 86.
5% to 95.
1%, an improvement of 8.
6 percentage points;
It is worth noting that non-pCR patients in the pembrolizumab combined with chemotherapy group were also significantly better than those in the chemotherapy alone group, regardless of pCR status, and the survival efficacy of immunotherapy combined with chemotherapy was beneficial
.
Data from the KEYNOTE-522 study showed that pembrolizumab combined with chemotherapy significantly prolonged event-free survival in TNBC patients compared with traditional neoadjuvant chemotherapy, and the addition of pembrolizumab before and after surgery reduced the risk of distant recurrence in patients, significantly improved the survival benefit of patients, and opened up a new situation
for immunotherapy of early TNBC.
This treatment has great potential to change the existing treatment landscape and is worthy of more attempts and explorations
in the future.
Yimaitong: In your opinion, how is the operation of this new indication approval different from the previous indication, and is there a breakthrough innovation? How do you see the future application prospects of pembrolizumab in China?
Professor Shao Zhimin
In the past, when seeking a breakthrough in the efficacy of new drugs, most plans chose to start with late-line treatment in the advanced stage of the disease
.
The layout of pembrolizumab in the early TNBC is completely different, starting directly from the most difficult neoadjuvant and adjuvant treatments, and with the unique attributes of the product, it has achieved a double endpoint positive result of pCR and EFS rates, which can be described as unique
.
It is worth mentioning that the excellent results of KEYNOTE-522 research have been published twice in the top international journal "New England Journal of Medicine (NEJM)
".
At present, although some large hospitals in China have begun to use pembrolizumab combined with chemotherapy neoadjuvant and adjuvant therapy for early TNBC, looking at the national medical environment, the proportion of neoadjuvant therapy for patients with early TNBC receiving pembrolizumab combined with chemotherapy is still low, and some doctors and patients still have insufficient
understanding of the drug sensitivity effect and long-term survival benefits of this program.
With the approval of pembrolizumab, there is a new mode of neoadjuvant and adjuvant therapy for TNBC patients, and it is believed that the new regimen of pembrolizumab combined with chemotherapy can bring hope to patients and pull the cure rate of early TNBC to a new height
.
brief summary
Since pembrolizumab was first approved for marketing in China in 2018, it has obtained ten indications in just a few years, and has been deployed
in multi-tumor types and multiple tracks.
As the first and only immune checkpoint inhibitor approved for early TNBC in China, pembrolizumab has a strong position in the treatment of TNBC in China
.
The neoadjuvant-adjuvant regimen of pembrolizumab combined with chemotherapy may become the standard regimen in the future, helping TNBC enter a new era of immunotherapy and promoting the standardization of early TNBC immune system therapy in China
.
Expert profiles
Professor Shao Zhimin
Department of Breast Surgery, Fudan University Cancer Hospital
Fudan Distinguished Professor, the first batch of Education Minister Jiang Scholar Distinguished Professor
Director of the Cancer Institute and the Institute of Breast Cancer of Fudan University
Director of General Surgery and Director of Breast Surgery, Fudan University Cancer Hospital
Honorary Chairman of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association
Chairman of the Tumor Targeted Therapy Professional Committee of the Chinese Anti-Cancer Association
Vice Chairman of Oncology Branch of Chinese Medical Association
Chairman of the Breast Group of the Oncology Branch of the Chinese Medical Association
Honorary Chairman of the Breast Cancer Professional Committee of Shanghai Anti-Cancer Association
Chairman of the Oncology Specialty Committee of Shanghai Medical Association
President of the 8th Asian Breast Cancer Association
Member of the Expert Council of the St.
Gallen Breast Cancer Congress
Edited by Serena
Reviewer: Kino
Typesetting: Babel
Execution: Uni
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