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At the 2022 ASCO Annual Meeting, Professor Modi from New York shared the results of the Phase 3 clinical study of T-DXd, a new anti-cancer drug, for "HER2 low-expression" breast cancer.
The results of this study directly change the clinical classification and treatment standards of breast cancer, and will also open a new era, that is, the era
of precision treatment of "HER2 low expression" breast cancer.
Why is T-DXd attracting so much attention?
Why is T-DXd attracting so much attention?T-DXd（Trastuzumab deruxtecan）（DS-8201； ENHERTU®)
It is a new HER2-targeted ADC
developed by Daiichi Sankyo in collaboration with AstraZeneca.
T-DXd was approved in 2019 and has shown significant antitumor activity
in patients with refractory HER2+ metastatic breast cancer.
HER2 belongs to the four tyrosine kinases of the human epidermal growth factor receptor (HER) family and regulate key cellular processes, including proliferation, motility, and survival
.
Amplification of the HER2 locus is an early event
of cancerous changes in breast cancer.
Before the introduction of T-DXd, breast cancer patients were usually divided into two categories, "HER2-positive" and "HER2-negative", according to the HER2 protein expression of tumors, of which positive patients accounted for about 20% and negative accounted for about 80%.
In 80% of HER2-negative breast cancer patients, it can be specifically subdivided into: (1) there is no HER2 protein at all, which is really "negative"; (2) Express some HER2 proteins, but the expression is low
.
To be precise, they are "HER2 low-expression" breast cancers
.
Previous HER2-targeted drugs such as trastuzumab, pertuzumab, emmetrituzumab, pyrotinib, lapatinib, etc.
, are mainly effective in HER2-positive patients, but not in HER2-negative patients
.
But now T-DXd has changed that result, and studies have found that T-Dxd in breast cancer patients with "low HER2 expression" is significantly better than the current standard of care: chemotherapy
.
.
T-DXd has multiple unique advantages in structural design and pharmaceutical mechanisms
T-DXd has multiple unique advantages in structural design and pharmaceutical mechanismsFirst, compared with traditional anti-HER2 monoclonal antibodies and small molecule tyrosine kinase inhibitors (TKIs), the mechanism of T-DXd killing tumors is not only blocked by the HER2 signaling pathway
.
Moreover, the anti-tumor effect of T-DXd is significantly stronger and longer-lasting, and it is more effective
against heterogeneous tumors.
against heterogeneous tumors.
In terms of ADC structure, T-DXd is composed of trastuzumab, cleavable tetrapeptide linker and topoisomerase I inhibitor (Dxd), and its uniqueness is mainly reflected in the following points
.
(1) The highly active drug DXd confers T-DXd with a more potent anti-tumor effect, which can avoid the secondary resistance of tubulin inhibitors
.
(2) Highly stable tumor-specific digestion tetrapeptide linker, chemical optimization to achieve a drug-antibody ratio (DAR) of up to 8:1, greatly enhancing the tumor killing effect
of T-DXd.
(3) The cleavage tetrapeptide linker is structurally stable in blood circulation, which avoids early release of drug loading, and the drug shedding rate is low, thereby reducing toxic side reactions
.
(4) T-DXd has high efficiency
The "bystander effect" not only further enhances the efficacy, but also makes its anti-tumor effect not limited to HER2 high-expression tumors, but also effective
for HER2-low expression and HER2 heterogeneous tumors.
For a variety of tumors, T-DXd shines
For a variety of tumors, T-DXd shinesThe study found that T-DXd has achieved significant success
in treating tumors expressing HER2.
Multiple clinical trials of T-DXd, either as monotherapy or in combination with novel cancer drugs, are currently underway
.
in treating tumors expressing HER2.
In the Phase 2 DESTINY-Breast01 trial, patients with HER2-positive metastatic breast cancer were evaluated for T-DXd activity (patients who had received ≥ 2 anti-HER2 drugs, including TDM-1).
The results showed that the ORR was 60.
9% and the DCR was 97.
3%.
The median DOR was 14.
8 months and the median PFS duration was 16.
4 months
.
The median OS was not reached, but the estimated OS was 93.
9% at 6 months and 86.
2%
at 12 months.
The evaluation of T-DXd in patients with HER2-positive gastric cancer who had received at least two treatments, including trastuzumab, had an ORR of 42.
9% vs.
a control group of chemotherapy
12.
5%, DCR 85.
7% vs 62.
5%; The median DOR was 11.
3 vs 3.
9 months; The median PFS was 5.
6 months vs
3.
5 months
.
T-DXd significantly lengthened OS, with a median OS of 12.
5 vs 8.
4 months and a 12-month OS of 52.
1% and 28.
9%.
With the advent of T-DXd, HER2 may become an important therapeutic target for NSCLC and colorectal cancer patients
.
Although T-DM1 has obtained good response rates ranging from 20% to 50% in different studies, it is not the same as the response rate (ORR) observed with T-DXd
61.
9%), which is still low
.
Even in patients with HER2-positive colorectal cancer, single-agent T-DXd showed an ORR of more than 50%, while trastuzumab in combination with lapatinib or pertuzumab had an ORR of only 30%.
Overall, preliminary evidence suggests that T-DXd is actively changing the treatment paradigm
for HER2-positive tumors.
for HER2-positive tumors.
Overall, preliminary evidence suggests that T-DXd is actively changing the treatment paradigm
for HER2-positive tumors.
In the face of T-DXd, how can domestic ADCs catch up
In the face of T-DXd, how can domestic ADCs catch upUp to now, there are three ADC drugs approved for use in China, namely emmetrituzumab targeting HER2, vedicitumab and vebutuximab
targeting CD30.
As T-DXd continues to gain new progress, emmetrastuzumab and vedicitumab bear the brunt
.
Now Remegen Biotech (09995.
HK) is a domestic flat version
of T-DXd.
Emmetrastuzumab reduced its price by more than 50% before T-DXd was declared in China, which is close to the average price reduction in medical insurance negotiations
.
This is because on current trends, T-DXd is likely to suppress emmetrtuzumab in all
directions.
According to CITIC Securities Research Report data, by the end of 2021, HER2 was invested in research in China
There are as many as 22 ADCs
.
And most of them are modeled on emmetrastuzumab, and the goal is to become a replica or advanced product
of emmetrastuzumab.
However, due to the emergence of T-DXd, the advantage of emmetrastuzumab no longer exists, and HER2 has been invested in domestic research
ADCs are under even more pressure
.
How to highlight the encirclement has become the current challenge
of domestic ADCs.
As there is room for improvement in the safety of T-DXd: a comprehensive analysis of T-DXd was conducted in 234 patients with HER2-positive breast cancer, and the most common adverse events (≥20%) included: nausea, fatigue, vomiting, hair loss, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough, and thrombocytopenia
.
So perhaps finding a new way to find new innovation points is the best choice
that domestic ADCs can make.
directions.
How to highlight the encirclement has become the current challenge
of domestic ADCs.
How to highlight the encirclement has become the current challenge
of domestic ADCs.
Since T-DXd still has room for improvement in terms of safety, T-DXd still has room for improvement in terms of safety, so it may be the best choice
that domestic ADCs can make at present.
So perhaps finding a new way to find new innovation points is the best choice
that domestic ADCs can make.
