This article sorts out what treatment changes the new generation of ADC drugs bring to HER2-positive breast cancer

*Only for medical professionals to read for reference.
A new generation of ADC drugs brings new hope for treatment of advanced HER2-positive breast cancer
.

Breast cancer is the “number one killer” that affects women’s health worldwide.
Among them, HER2-positive breast cancer accounts for about 15%-20% of all breast cancers.
Its prognosis is poor and it is more likely to metastasize
.

With the emergence of anti-HER2 therapeutic drugs, the survival status of HER2-positive breast cancer has been greatly improved
.

In particular, the emergence of a new generation of antibody-drug conjugates (ADC) has ushered in a new era in the field of HER2-positive breast cancer treatment following chemotherapy, monoclonal antibodies, and small molecule tyrosine kinase inhibitors (TKI)[ 1]
.

Go back to the source and deconstruct the therapeutic basis of DS-8201's potent anti-tumor effect.
DS-8201 (Trastuzumab Deruxtecan, T-DXd) is composed of humanized anti-HER2 immunoglobulin G1 monoclonal antibody (trastuzumab) and Deruxtecan (topoisomerase I inhibitor [DXd]) is coupled by a tetrapeptide-based cleavable linker
.

Compared with the active metabolite SN-38 of irinotecan, the drug-loaded DXd is almost 10 times more potent, and its half maximum inhibitory concentration is only 0.
31 µmol/L
.

At the same time, because DXd is a topoisomerase I inhibitor, it has a different mechanism of action from commonly used chemotherapeutics in the treatment of breast cancer, and can effectively avoid cross-resistance
.

After the DS-8201 linker is optimized, the hydrophobicity is greatly reduced and the stability is enhanced
.

Basic research shows that after 21 days of treatment, the drug release rate of DS-8201 in human plasma is only 2.
1%, while the drug release rate of T-DM1 after 4 days of treatment is 18.
4% [2,3]
.

In addition, DXd has a short half-life (based on animal data, approximately 1.
37 hours in the systemic circulation [4]), which helps minimize the off-target toxicity of DS-8201
.

In addition, the linker is specifically cleaved by the highly expressed lysosomal enzymes (such as cathepsin B and L) in tumor cells, ensuring the stability of DS-8201 in the systemic circulation and limited systemic toxicity [2]
.

In the phase I dose escalation and expansion study, the serum concentration of free DXd was lower [5], which also verified the stability of DS-8201 in the circulation
.

The drug-to-antibody ratio (DAR) of DS-8201 reaches a theoretically high value of 8, which is higher than other ADC drugs currently approved [2,3], which enables DS-8201 to deliver more drug-carrying molecules to tumor cells
.

Due to the cleavable linker and the high membrane permeability of DXd, DS-8201 not only has cytotoxicity against targeted tumor cells, but also exerts a powerful bystander effect, killing adjacent tumor cells [2,3]
.

Based on this, DS-8201 may be effective in treating heterogeneous tumors, and it is also effective against tumor cells with low HER2 expression
.

Focusing on the frontiers, combing the latest research progress in the field of DS-8201 breast cancer.
Phase I DS8201-A-J101 study and Phase II DESTINY-Breast01 study strongly verified the breakthrough efficacy of DS-8201 for the posterior treatment of HER2-expressing breast cancer patients [5- 7]
.

However, the application of DS-8201 is not limited to the back line, and its performance in the field of second-line therapy is even more impressive
.

The DESTINY-Breast03 study, which has announced the latest developments at ESMO in 2021 and SABCS in 2021, is the first randomized controlled, phase III clinical trial of DS-8201, which aims to compare DS-8201 and T-DM1 in the past.
Efficacy and safety in HER2-positive unresectable and/or MBC patients treated with trastuzumab and taxane (n=524, R=1:1), the study included 61% of the PH treated population, with brain metastases The population is 22%, and it is currently the only RCT that includes a large sample of PH dual-target treated population
.

The interim analysis data published by ESMO showed that [8] the median PFS assessed by the blind independent central review committee (BICR) of the DS-8201 group has not yet reached, while the T-DM1 group is 6.
8 months, and the risk ratio (HR) of PFS is only It is 0.
28, P=7.
8 x 10-22, which is unprecedented in previous breast cancer clinical studies
.

The risk of disease progression and death is reduced by 72%
.

The estimated 12-month PFS rates are 75.
8% and 34.
1%, respectively
.

The researchers assessed mPFS with similar benefits (25.
1 months vs 7.
2 months, HR=0.
27, P=6.
5 x 10-24)
.

Overall, DS-8201 showed a statistically and clinically significant improvement in PFS
.

And the ORR of DS-8201 is as high as 79.
7%, of which the complete remission rate (CR) is as high as 16.
1%, compared with T-DM1's ORR of only 34.
2% and CR of only 8.
7%, which also has significant advantages
.

The planned interim analysis showed a strong trend of OS benefit
.

The estimated 12-month OS rate for the DS-8201 group was 94.
1% (95%CI 90.
3%-96.
4%), and the T-DM1 group was 85.
9% (95%CI 80.
9%-89.
7%), HR=0.
5546 (95% CI 0.
3587-0.
8576; P=0.
007172 does not exceed the pre-defined significance boundary)
.

And based on the results of the Phase III DESTINY-Breast03 research, the ESMO MBC diagnosis and treatment guidelines, the 6th International Consensus on Advanced Breast Cancer (ABC6), and the 2022 version of the National Comprehensive Cancer Network (NCCN) breast cancer guidelines all recommend DS-8201 as HER2 positive The preferred second-line treatment of breast cancer after treatment with taxanes and trastuzumab
.

It can be described as the pursuit of victory.
After only three months, SABCS released the subgroup data of the study in 2021 [9]
.

The results showed that DS-8201 compared T- DM1 showed sustained efficacy benefits in all subgroups, and both PFS and ORR were similar to the general population
.

It is worth mentioning that for patients with brain metastases at baseline, the median PFS of the two groups were 15 months and 3 months, respectively; the determined ORRs were 67.
4% and 20.
5%, respectively
.

In addition, DS-8201 has a lower disease progression rate than T-DM1, which was 48.
8% vs 69.
2% in the two groups
.

Studies also suggest that DS-8201 treatment can bring potential intracranial relief and reduce central nervous system (CNS) diseases.
The intracranial complete remission rates of DS-8201 compared with T-DM1 are 27.
8% and 2.
8%, respectively, while intracranial The progress rate of DS-8201 vs.
T-DM1 was 2.
8% and 22.
2%, respectively
.

This subgroup of data confirms that DS-8201 is associated with the remission of intracranial lesions and the reduction of central nervous system diseases.
1/4 of patients have complete remission of intracranial lesions, and suggest that DS-8201 as a macromolecular drug is still significant for patients with stable brain metastases.
Curative effect
.

In addition, the overall safety of DS-8201 is manageable and tolerable.
Among them, there is no difference between the incidence of interstitial lung disease (ILD)/pneumonia in Asian (10.
9%) and non-Asian populations (10.
0%), and there is no grade 4 Or Grade 5 ILD/pneumonia event
.

There are also a series of ongoing phase III clinical trials, covering the late stage to the first line to the early stage of HER2-positive breast cancer, and active exploration has been carried out for people with low HER2 expression
.

The results of these trials are expected to further reveal the good benefits that DS-8201 brings to breast cancer patients
.

Figure 1.
DESTINY-Breast series research layout conclusion DS-8201 has unique properties in terms of structural composition and mechanism of action.
It can precisely target tumor cells and exert a powerful anti-tumor effect
.

DS-8201 showed unprecedented activity in the phase II DESTINY-Breast01 clinical trial for patients with advanced HER2-positive breast cancer who had previously received multiple lines of treatment
.

Based on the results of this clinical trial, DS-8201 was approved for the treatment of advanced HER2-positive breast cancer in the United States, Japan and Europe
.

Based on the results of the DESTINY-Breast03 clinical trial, ESMO, ABC6, and NCCN have all recommended DS-8201 as the second-line standard treatment for HER2-positive breast cancer
.

And the FDA again granted DS-8201 breakthrough therapy designation
.

This means that DS-8201 redefines the second-line treatment standard for HER2-positive advanced breast cancer, which is a general trend.

.

The ongoing series of phase III clinical studies will also provide a large amount of evidence-based medicine support for DS-8201 to be more widely used in clinical practice
.

References[1] Perez J, Garrigós L, Gion M, et al.
Trastuzumab deruxtecan in HER2-positive metastatic breast cancer and beyond.
Expert Opin Biol Ther.
2021 Jul;21(7):811-824.
[2] Ogitani Y, Aida T, Hagihara K, et al.
DS-8201a, a novelHER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1.
Clin Cancer Res.
2016;22(20) :5097–5108.
[3]Nakada T, Sugihara K, Jikoh T, et al.
The latest research and development into the antibody-drug conjugate, [fam-] trastuzumab deruxtecan(DS-8201a), for HER2 cancer therapy.
Chem Pharm Bull.
2019;67(3):173–185.
[4]Nagai Y, Oitate M, Shiozawa H, et al.
Comprehensive preclinicalpharmacokinetic evaluations of trastuzumab deruxtecan(DS-8201a), a HER2-targeting antibody-drug conjugate, in cynomolgus monkeys.
Xenobiotica.
2019;49(9):1086–1096.
[5]Tamura K,Tsurutani J, Takahashi S, et al.
Trastuzumab deruxtecan(DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion,phase 1 study.
Lancet Oncol.
2019;20(6): 816 –826.
[6]Modi S, Park H, Murthy RK, et al.
Antitumor activity and safety oftrastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase Ib study.
J ClinOncol.
2020;38( 17): 1887–1896.
[7]Modi S, Saura C, Yamashita T, et al.
Trastuzumab deruxtecan inpreviously treated HER2-positive breast cancer.
N Engl J Med.
2020;382(7): 610–621.
[ 8]Cortés J, Kim SB, Chung WP, et al.
Trastuzumab deruxtecan (DS-8201) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): Results of the randomized phase III DESTINYBreast03 study.
2021 ESMO.
LBA1.
[9]Trastuzumab Deruxtecan (T-DXd) vs Trastuzumab Emtansine (T-DM1) in Patients (Pts) With HER2+ Metastatic Breast Cancer: Subgroup analyses from the Randomized Phase 3 DESTINY-Breast03 Study.
2021SABCS.
GS3-01.
*This article It is only used to provide scientific information to medical professionals and does not represent the views of this platform