Famous coffee meeting room big coffee face to face, from the drug safety to see the "way of using troops" of breast cancer ADC drugs

In recent years, with the deepening of clinical research on breast cancer and the continuous change of therapeutic drugs, the prognosis and survival of breast cancer patients have been continuously improved
.
Chemotherapy, endocrine therapy, immunotherapy, targeted therapy.
.
.
Every innovation in the era of drugs brings more confidence and hope
to clinicians and patients.
At present, the research and application of cytotoxic drugs and antibody drug conjugates (ADCs) conjugated with monoclonal antibodies have become a hot spot in the field of precision treatment of breast cancer, especially the approval of Emmetrituzumab (T-DM1) in China, officially opening a new era
of ADC treatment for breast cancer in China.
With the continuous emergence of various ADC drugs, their safety issues have also received more and more attention
.
Professor Xu Ling of Peking University First Hospital and Professor Wang Tao of the Fifth Medical Center of PLA General Hospital as panelists to discuss the selection and application of breast cancer ADC drugs from the perspective of drug safety
.

Q1: In recent years, a lot of progress has been made in the field of breast cancer treatment, and ADC drugs deserve to become the most potential "stars"
in the history of anti-HER2 therapy.
Could you please talk about the importance of ADC drugs in the treatment of breast cancer based on the mechanism of action, research progress and clinical application of ADC drugs?

Professor Wang Tao: ADC drugs are a class of anti-tumor innovative drugs with a unique mechanism of action, which conjugate target-specific monoclonal antibodies with highly lethal cytotoxic drugs through specific linkers, and rely on monoclonal antibodies as a carrier to accurately and efficiently transport cytotoxic drugs to target cancer cells for "targeted" killing, which is known as "biological missiles"
.
Therefore, ADC drugs have the advantages of targeting, high stability and high anti-tumor activity, which is conducive to the realization of more accurate treatment
of tumors.

We know that compared with other molecular subtypes, HER2-positive breast cancer patients have a relatively worse prognosis, and although traditional anti-HER2 therapeutics, including macromolecular antibody drugs and small molecule tyrosine kinase inhibitor (TKI) drugs, bring significant benefits to HER2-positive breast cancer patients, there are still some patients who will face drug resistance or recurrence, and the emergence of ADC drugs provides more effective treatment options for these patients and fills the unmet
。

In the field of anti-HER2, the ADC drugs currently on the market mainly include T-DM1 and DS-8201, while only T-DM1
is available in China.
T-DM1 is the first ADC drug approved in the field of solid tumors and the first ADC drug
used in anti-HER2 therapy for breast cancer.
As early as February 2013, T-DM1 has been approved by the FDA for marketing
.
In 2020, the indication for HER2-positive adjuvant therapy for early breast cancer was approved in China, and T-DM1 became the first approved ADC drug
in China.
In 2021, T-DM1 was approved for a new indication for second-line treatment of HER2-positive advanced breast cancer
.

In the EMILIA ^study1,2, T-DM1 significantly prolongs median progression-free survival (mPFS, 9.
6 months vs.
6.
4 months, HR=0.
65, P<0.
001) and median overall survival (mOS, 30.
9 months vs.
mOS, 30.
9 months) compared with lapatinib + capecitabine in second-line treatment of HER2-positive advanced breast cancer.
At 25.
1 months, HR = 0.
68, P <0.
001), the risk of death was significantly reduced by 32%.

So, this study establishes the standard position
of T-DM1 in the second-line treatment of HER2-positive advanced breast cancer.
In fact, I think that T-DM1 is more significant in the early stage, because patients are more likely to achieve cure
in early breast cancer treatment.
For such patients with poor prognosis, KATHERINE ^STUDY3 confirmed that T-DM1-adjuvant intensive therapy can significantly improve the non-invasive disease survival (iDFS) of these patients, bringing the chance of cure to more HER2-positive early breast cancer patients.
T-DM1 has also become the standard regimen
for adjuvant intensive therapy for non-pCR patients following neoadjuvant therapy for HER2-positive breast cancer.
At present, for the application of T-DM1, T-DM1 has accumulated very rich experience at home and abroad, whether in HER2-positive advanced breast cancer or HER2-positive early breast cancer, T-DM1 has shown good results
.

Figure 1 PFS results in EMILIA study

FIGURE 2 OS results in EMILIA study

FIGURE 3 iDFS results from the KATHERINE study

Professor Yuan Peng: Professor Wang's views are particularly in line with our clinical practice, ADC drugs play an increasingly important role in the treatment of breast cancer, multi-dimensional to meet part of the clinical needs, I believe that more and more ADC drugs can bring better treatment results for patients
.

Q2: While ADC drugs bring efficacy and survival benefits, their safety issues have also attracted much attention
.
We know that paying attention to the management of adverse reactions can improve patient compliance, effectively improve the survival prognosis of patients, and escort ADC treatment
.
What are the adverse effects of ADC drugs that clinicians need to be concerned about? How to deal with these adverse reactions, and what are the specific coping strategies?

Professor Xu Ling: As a new type of targeted drug, ADC drug not only brings tangible clinical benefits to patients, but also the overall adverse reactions are preventable and controllable
.
The adverse response spectrum of different ADC drugs is not completely consistent, mainly because:

(1) Use different antibodies for conjugation against different receptors;

(2) Carrying different chemotherapy drugs;

(3) The connection method of the linker is different;

(4) The ratio of antibodies/drugs, homogeneity, etc.
are different
.

At present, the ADC drug with the best access in China is T-DM1, and there will be DS-8201, Trop2 and so on
in the future.
IN THE CASE OF T-DM1, THE MOST COMMON ADVERSE REACTION WAS THROMBOCYTOPENIA, AND EARLY KATHERINE STUDY3, AND LATE EMILIA ^{STUDY1,2,2 TH3RESA STUDY4} AND KAMILLA STUDY ⁵ PROVIDED A LOT OF RELEVANT DATA
.
Overall, the incidence of T-DM1 thrombocytopenia is about 29%~31%, but the incidence of grade 3 thrombocytopenia in ≥ is relatively ^low6
.
In the treatment of thrombocytopenia, there is currently an "expert consensus on the clinical management of thrombocytopenia associated with tumor treatment^{" 7} can be referenced, according to the guideline recommendations, for patients with thrombocytopenia above grade 2, the use of platelet-raising drugs, such as interleukin-11, TPO and TPO receptor agonists, etc.
, so that the trough of the patient's platelets is not too low, and the body can recover faster.
So as to ensure the treatment cycle of ADC drugs, improve the treatment compliance of patients, and ensure the efficacy
of drugs.
In addition to thrombocytopenia, the adverse reactions of T-DM1 also include liver function damage, infusion-related reactions, etc.
, for these common adverse reactions, clinicians have relatively rich experience to deal with and deal with
.

Fig.
4 Routine symptomatic management of thrombocytopenia associated with ADC treatment6

For other ADC drugs, we need to pay attention to different types of adverse reactions, such as interstitial pneumonia caused by DS-8201, and ADC drug studies have found the occurrence of ocular adverse ^reactions7,8
.
It is believed that with the increasing number of clinical trial data related to ADC drugs, the accessibility will become better and better, we will have a deeper understanding of the adverse reactions of different ADC drugs, and we will get more guidance
in the clinical drug process.

Professor Yuan: As Professor Xu said, the overall adverse reactions of ADC drugs are much
lighter than those of conventional chemotherapy drugs.
In the EMILIA study1,2, T-DM1 had fewer adverse reactions such as gastrointestinal reactions, rash, and neutropenia than lapatinib + capecitabine, so T-DM1 had controllable adverse reactions and better safety
than conventional chemotherapy 。 In addition, for other ADC drugs, clinicians should also actively pay attention to special adverse reactions, especially some ocular toxicity, interstitial pneumonia, etc.
, clinicians to do a good job in the monitoring and management of adverse reactions, to improve the patient's treatment compliance, to ensure the treatment efficacy is very important
.

Q3: With the increasing application of ADC drugs in the field of breast cancer, the safety management of ADC drugs has received more and more attention
.
We know that the "Chinese Expert Consensus on the Safety Management of Breast Cancer Antibody Drug Conjugates" has just been published in the Chinese Journal of Oncology in September, can you please talk about the background, purpose and main content of this consensus, and what new guidance will it bring to clinicians?

Professor Xu Ling: First of all, ADC drugs are different from individual antibodies and different from separate cytotoxic drugs, and their adverse reaction spectrum is different from conventional drugs, so we need to understand the adverse reactions
of such new drugs.
Secondly, as Professor Wang mentioned, the efficacy of such drugs is remarkable, the future application space is very broad, as the accessibility of ADC drugs is getting better and better, the good management of adverse drug reactions is also the content that clinicians need to master, based on this background, Academician Xu Binghe and Professor Yuan Peng led and organized relevant experts at home and abroad to sort out the adverse reactions of ADC drugs, forming the "China Breast Cancer Antibody Drug Conjugate Safety Management Expert Consensus" ⁶
。