ADC reshapes breast cancer treatment pattern, what are the thoughts behind

*For medical professionals for reading reference

Analyzing the latest progress of ADC breast cancer, wonderful in the "ADC Pioneer Camp".

In the past 20 years, anti -HER2 therapy drugs have continued to develop, from chemotherapy, monoclonal antibody to small molecular targeted drugs to the current high -profile antibody drugs (ADC), which has greatly improved the prognosis of HER2 positive breast cancer patients Essence Among them, the therapeutic value of ADC drugs in HER2 positive breast cancer is more vividly reflected. It not only completely innovates the selection of anti -HER2 treatment drugs, but also brings the possibility of targeted therapy for HER2 low expression of breast cancer. It can be said that ADC Drugs redefine the treatment of breast cancer, but it has also triggered many thinking and problems. "ADC Pioneer Camp" specially invited a number of big coffees to express his insights on related issues.

01

ADC to reshape breast cancer treatment pattern,

T-DXD becomes HER2 low expression standard selection

With the breakthrough results of Destiny-Breast03 (DB03), ADC drug T-DXD successfully replaced T-DM1 to become a new second-line therapy standard for HER2-positive breast cancer. change. With the 2022 ASCO conference announced the first phase III Destiny-Breast04 (DB04) research results in HER2 low-expression breast cancer people [1], which means that T-DXD completely broke the barrier for previous anti-HER2 treatment. It is expected to become the first anti -HER2 treatment drug for HER2 low -expression breast cancer.

The DB04 research aims to evaluate the efficacy and safety of T-DXD compared to the doctor's selected chemotherapy (TPC) in HER2 low expression of irregularity or metastatic breast cancer (MBC). The number of medium chemotherapy lines is 1 line, and the number of medium endocrine therapy lines is 2 lines. At the same time, HR positive patients must be identified as not to benefit from endocrine therapy. Of the 557 patients who received randomized, 494 (88.7%) were HR positive and 63 cases (11.3%) HR negative. Among patients with HR positive T-DXD treatment, 100%have received chemotherapy and endocrine therapy, 78%have received targeted therapy, and 70%have received CDK4/6 inhibitors in the past.

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In response, Professor Luo Ting of Huaxi Hospital of Sichuan University, Professor Yan Ying of Peking University Cancer Hospital, and Professor Li Qiao of the Cancer Hospital of the Chinese Academy of Medical Sciences said that in the past, patients with HR+/HER2 often accepted CDK4/6 inhibitors combined with endocrine therapy for endocrine therapy However, the treatment of patients after the progress of CDK4/6 inhibitors is limited, mostly chemotherapy, and the overall benefits are not ideal.

For HR-negative patients, it was previously regarded as tri-negative breast cancer (TNBC). Although immunotherapy and PARP inhibitors appear to a certain extent enriched TNBC's treatment options, immunotherapy must meet PD-L1 expression positive, and PARP inhibitory suppression The agent is mainly effective for patients with mutations in the BRCA embryo system, and its applicable surface is not wide. At present, chemotherapy still occupies an important position in the treatment of different lines of TNBC in different lines.

From this point of view, whether it is HR -positive or HR -negative patients, the treatment of backline chemotherapy is very limited. The DB04 research will be targeted at the precisely positioning of such patients, which is of great significance to meet the treatment needs of patients with low HER2 low -expression breast cancer.

In addition, Professor Li Qiao emphasized that the research control group selected Capitaba, Eliblin, Gesatabine, paclitaxel or ginkgo -binding paclitaxel is common chemotherapy drugs for clinical breast cancer, and the single drug is more efficient. This also reflects the rigor of DB04 research design.

From the perspective of efficacy data, in the HR-positive MBC queue, compared with the chemotherapy energy selected by doctors, T-DXD reduces the progress and risk of death of HR positive MBC patients 49% (HR = 0.51; 95% CI, 0.40-0.64; P. <0.001), T-DXD's median PFS is 10.1 months, which is significantly better than 5.4 months of chemotherapy group. In addition, the analysis of each sub-group shows a consistent benefit trend, and the efficacy of T-DXD is not affected by the treatment of CDK4/6 inhibitors.

In fact, the real world research shows that the median PFS of the system treatment after the progress of CDK4/6 inhibitors is usually <4 months [2], which shows that T-DXD brings a large Breakthrough treatment. Among all patients (without considering HR status), the median PFS of the T-DXD group also has a significant advantage, reducing the progress of the disease and the risk of death by 50%(9.9 months vs. 5.1 months, HR = 0.50; 95%CI, 95%CI, 95%CI, 95%CI, and 95%CI, 95%CI, 95%CI, and 95%CI, 95%CI, 95%CI, and 95%CI, 95%CI, and 95%CI. 0.40-0.63; P <0.001).

The test also reached the key secondary end of the OS of HR-positive MBC patients and mid-term analysis. At the HR positive MBC queue, the median OS of the T-DXD and the chemotherapy group was 23.9 months and 17.5 months. The risk of death was reduced by 36% (HR = 0.64; 95% CI: 0.48-0.86; P = 0.003). In all patients (regardless of HR state), the two groups also had significant differences (23.4 months vs. 16.8 months, HR = 0.64; 95% CI: 0.49-0.84; P = 0.001), the risk of death was reduced by 36%. And in the exploration end point, HR negative patients have a significant benefit compared to chemotherapy in PFS and OS in HR negative patients. The two groups of mid-position PFS are 8.5 months and 2.9 months (HR = 0.46, 95% CI, 0.24-0.89), and the median OS is 18.2 months and 8.3 months (HR = 0.48, 95% CI, 0.24 0.24 -0.95). Looking back at the current guidelines recommendation for the late TNBC ≥2 line therapy (chemotherapy and Trop-2 targeted ADC drugs) data, of which the PFS range is only about 1.7 to 5.6 months [3]. Tip T-DXD can provide more effective treatment options for patients with HR negative HER2 low.

In terms of tumor relief, in the HR-positive MBC queue, the objective relief rate of T-DXD (ORR) was 52.6%, which was three times more than 16.3%of the chemotherapy group, and there were 12 (3.6%) and 1 case of the two groups. (0.6%) Patients have reached a complete relief (CR). The two groups of clinical benefits (CBR) were 71.2%and 34.3%, respectively, and the mid -bit relief duration (DOR) was 10.7 months and 6.8 months, respectively.

In general, DB04 studies have confirmed that T-DXD is the first HER2 targeted therapeutic drug with statistical significance and clinical significance in terms of PFS and OS, and is HER2 low expression (IHC 1 +, IHC 1 +, IHC 1 +, IHC 1 +, IHC 2 +/ISH-) MBC provides a solid theoretical basis as a new targeted therapy.

Regarding the heavy results of DB04 research, Professor Luo Ting said that in the past, the lack of targeted treatment for HER2 low-expression breast cancer, and T-DXD will not doubt that it will become the first HER2 low-expression standard for breast cancer patients for backline treatment. And the expansion of indications will also quickly rewrite major guidelines.

It is worth emphasizing that in 2022, the NCCN Guide V4 version has been officially written into T-DXD for HER2 immunohistochemistry (IHC) 1+ or 2+ and in-situ hybridization (ISH) negative tumor and metastatic lesions have accepted at least first-line chemotherapy (If the tumor is HR positive, it is resistant to endocrine therapy) treatment recommendation [4]. These all means that the treatment -oriented advanced breast cancer has officially entered a new era with a special beneficiary of HER2 low expression.

"In China, including 21 centers, including our center, they will be moved to participate and witness this historic step that T-DXD has taken in HER2 low-expression breast cancer."

02

Thinking behind the new pattern of breast cancer treatment

ADC drugs have undoubtedly opened a new chapter in the field of breast cancer treatment, but behind the innovation of treatment, it also brings many thinking and problems.

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1

HER2 low expression has proposed a new one for the pathology department

Requirements, definition and testing all need to be innovated

DB04 Study established HER2 low expression as a new position as a new breast cancer, which put forward new requirements for pathological doctors. The most critical problem with HER2 low expression is the solidification of its concept. Professor Liu Yueping of Hebei Cancer Hospital said that in the past, the anti -HER2 drug was only effective in HER2's expressions. "Positive" or "negative"; with the emergence of new ADC drugs, especially T-DXD, it has promoted the transition from the two-point method of mammalcinic cancer HER2 from two-point method to high expression, low expression, and negative [5]. Professor Yang Jin, the First Affiliated Hospital of Xi'an Jiaotong University, also pointed out that DAISY Studies [6] indicates that T-DXD has incomplete, weak cell membrane staining in the existing IHC 0 (non-dyed or ≤10%of infiltrating cancer cells) It is also valid (orr30%), which indicates that the lower limit of HER2's low expression is not particularly clear, and more research data is yet to be confirmed. The Destiny-Breast06 Study [7] will provide new evidence-based on patients with HER2 extremely low, and further explore the need to re-define the lower limit of HER2 low expression.

Secondly, the previous clinical and pathologists only pay attention to HER2 positive (IHC 3+ and IHC 2+ and FISH positive), but the distinction of IHC 0 and 1+ lacks attention. When it is strong, it should be judged as HER2 IHC 0 or IHC 1+. It is currently not specified and controversial. Therefore, it is necessary to strengthen the accuracy of the interpretation of this specimen in the future. In addition, in view of the expression of HER2 is a continuous variable in breast cancer, whether it may be the same as the current ER and PR scores in the future, the continuous score (0-100%) of HER2 will need to be further explored. Looking forward to cooperating with each other clinical and pathological, pushing more accurate clinical treatment strategies through pathological testing, and the development of clinical treatment to promote the improvement of pathological testing capabilities, with a view to the maximum benefit of patients with breast cancer. ""

2

ADC needs to balance the efficacy and security,

Adverse reaction management has gradually improved

For the treatment of drugs, the efficacy and safety must be balanced. ADC drugs combine the precise targetedness of monoclonal antibodies and the powerful killing effect of small molecular cytotoxic drugs, realizing the targetedness of cytotoxic drugs, and is a type of high -efficiency and low toxic new anti -tumor therapy drug. Among them, the effect of the new generation of ADC drug T-DXD is undoubted, and it is precisely because of its wonderful manifestations in a series of heavy clinical studies that clinicians have greatly paid attention to its safety.

This year's ASCO conference announced the security update data of the longer follow-up time of DB03 [8], Professor Li Wei, Jiangsu Provincial People's Hospital pointed out in the analysis of the study that T-DXD and T-DM1 groups are ) The incidence is similar, but the incidence of correction (EALR) of the T-DXD group TeaE is lower than the T-DM1 group. Both groups of drugs related to TEAE are mainly blood-learning and gastrointestinal adverse reactions. Among them, the T-DXD group is nauseous and the incidence of early vomiting is higher, but it is extended over time, and the cumulative risks have not risen. And the incidence of level ILD has not increased, mostly 1 or 2, and most of them have been relieved.

At the same time, it is worth mentioning that in DB04 research, the security of T-DXD is also reassuring. Its safety characteristics are consistent with previous clinical trials. No new security signals are found, and the overall security is better than healing. Among them, the incidence of ILD is consistent with the results observed in the clinical trials of T-DXD in HER2-positive breast cancer.

Not only that, the ESMO BC conference in 2022 also announced the end of the patient's report of DB03 research [9], further verifying the good security characteristics of T-DXD. Professor Wang Lei Ping of the Cancer Hospital affiliated to Fudan University pointed out that from the perspective of the patient, the assessment of the impact on the quality of life due to treatment is of great significance. It is gratifying that the end of the report of the DB03 patient's report shows that the quality of life during T-DXD treatment is maintained and the deterioration time in the pre-stipulated meter table (compared to T-DM1), especially in terms of emotional function and pain symptoms T-DXD has improved significantly, which shows that T-DXD not only has the encouraging clinical effects, but also has good tolerance during the treatment. It can also improve the quality of life to a certain extent and have a high risk of benefit.

It should be emphasized that adverse reactions are inevitable. In order to improve the treatment compliance of patients and ensure that patients can benefit from the treatment of ADC drugs, effective adverse reaction management is particularly important. The main adverse reactions of ADC drugs are mostly related to blood science and gastrointestinal tract, which is similar to traditional chemotherapy. Therefore, to a certain extent, it can learn from the management of adverse reactions related to chemotherapy. And with the in -depth development of ADC drugs, the management experience of special adverse reactions such as ILD has been rich, and a series Essence In the future, the application of clinicians on ADC drugs will be more handy.

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3

HER2 -positive advanced breast cancer brain metastasis treatment

The treatment is still difficult, the ADC may become a new

Treatment selection

HER2 -positive breast cancer brain metastasis has always been a clinical treatment problem. At present, the treatment of breast cancer brain metastasis is more limited. Local treatment has stronger targetedness and faster effects on brain metastases, but adverse reactions are more serious. Separational treatment can reach tumor cells that can reach all parts of the body with blood circulation and kill multiple parts of multiple parts, which plays an important role in the control of systemic diseases. In recent years, the whole body treatment of breast cancer brain metastasis has made many progress. In 2022, the ESMO BC conference announced a TUXEDO-1 research results of TUXEDO-1 for patients with active brain metastases of HER2-positive breast cancer. [10] Professor Xu Fei, a university tumor prevention center, said that the intracranial ORR of the intention treatment (ITT) crowd in the study is as high as 73.3%, the CBR is as high as 86.7%, and the median PFS is as long as 14 months. The median OS has not been achieved. The data is pleasing. And based on a series of research results, T-DXD has been recommended by the 2021 ESMO guide as a treatment option for patients with brain metastases. In addition, Destiny-Breast12 Study [7] includes patients with a base line companion/non-brain metastases, I believe that T-DXD will provide more evidence-based evidence for brain metastatic treatment in the future. In the exploration of breast to metastasis in the past, many drugs for the primary stove of breast cancer cannot be discharged through the blood brain barrier (BBB). Bring challenges. However, T-DXD, as a macromolecular ADC drug, shows a large potential of brain metastasis. Professor Chen Zhanhong, an affiliated tocotic hospital (Zhejiang Cancer Hospital) affiliated to the Chinese Academy of Sciences, also has some thinking about the relevant mechanism: on the one hand, it is the on the one hand: on the one hand, it is on the one hand. Because the brain metastases of breast cancer, the BBB has been destroyed, and a new hemiflox barrier (BTB) is generated, which enhances the permeability of the brain lesions [11]. And the pathological effects of omnidirectional radiotherapy on the blood brain barrier may also increase the permeability of drug molecules [12]. In addition, the T-DXD has a powerful drug, its drug antibody ratio (DAR) is as high as 8, and it can play the effect of bystanders, greatly improve the anti-tumor killing effect, and has a significant effect on brain metastases. These are possible mechanisms for T-DXD to treat breast cancer brain metastasis [13-15].

In short, the treatment of breast cancer brain metastasis is becoming more and more complicated, and local treatment is still the cornerstone of its treatment. Organic integration of local treatment with systemic treatment is still an urgent problem. In addition, the existence of the blood -brain barrier makes the central nervous system a refuge of tumor cells, while new ADC drugs and tyrosine kinase inhibitors (TKI) may improve the prognosis of this type of patients. In the future, further study the mechanism of brain metastases, find the way to penetrate the blood -brain barrier, and even prevent the occurrence of brain metastases may bring greater hope to patients.

03

Future outlook

ADC drugs break the situation of conventional anti-HER2 targeting HER2 expression or genetic amplification. The success of the field of targeted therapy in HER2 lowers the beneficiaries may be expanded to 60%-70%of all breast cancer patients [5]. The treatment of breast cancer treatment has been reshaped and the further development of clinical diagnosis and treatment will be promoted.

At present, as far as HER2-positive breast cancer is concerned, many ADC drugs such as T-DXD, T-DM1, SYD985, and RC48 have performed well. With the continuous deepening of ADC drug research, its target target is more diversified. In addition to the establishment targets of HER2, Trop-2, HER3, ADC drugs are also trying more development of targets. In addition, the efficacy of ADC drug single drugs is undoubted, and the clinical research of various drugs such as immunization, chemotherapy, endocrine, TKI and other drugs is constantly being promoted. Essence

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