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2022 SABCS Big Coffee Talk| Professor Lili Zhang: ADC king, continuous breakthrough, consolidate the standard status of second-line treatment of HER2-positive advanced breast cancer

 Last Update: 2022-12-30
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Focus on the frontier of the conference and watch the latest research progress
interpreted by big coffee.

The 45th San Antonio Breast Cancer Congress (SABCS) was successfully held
from December 6 to 10, 2022 local time.
In this conference, many blockbuster studies announced the latest results, bringing many new advances
to the diagnosis and treatment of breast cancer.
In particular, the anti-ADC star drug T-DXd has once again hit the ground, and its blockbuster study DESTINY-Breast02 (DB02) published its findings for the first time in the form of an "oral presentation", and the primary endpoint progression-free survival (PFS) and the key secondary endpoint overall survival (OS) achieved double positive results [1].

The Medical Oncology Channel invited Professor Lili Zhang to give her insights
on related research.

Q1: Based on the significant efficacy of the DESTINY-Breast01 (DB01) study, T-DXd accelerated approval for the late-line treatment
of HER2-positive advanced breast cancer.
The DB02 study, a confirmatory, randomized controlled phase III clinical trial for this indication, was first presented in the "Oral presentation" session of the 2022 SABCS conference.

Prof.
Lili Zhang: The DB01 study showed that the objective response rate (ORR) of T-DXd treatment reached 61% and the median PFS reached 19.
4 months in patients who had previously received median 6-line therapy [2].

Based on this impressive efficacy, the FDA conditionally accelerated approval of T-DXd in December 2019 for the treatment
of patients with unresectable or metastatic HER2-positive breast cancer who have received at least two anti-HER2 anti-HER2 cancers.
However, the fly in the ointment is that the study is a single-arm phase II study, so the randomized controlled phase III.
clinical trial DB02 continues to be conducted to verify the benefit
of T-DXd in the late-line treatment.

The DB02 study is a randomized, multicenter, open-label phase III trial that compares the efficacy and safety
of T-DXd with a physician-selected treatment (TPC, trastuzumab/capecitabine, or lapatinib/capecitabine) in patients with HER2-positive advanced breast cancer who have previously received T-DM1.
Stratification
is based on hormone receptor status (positive or negative), prior pertuzumab therapy, and history of visceral disease.
The primary endpoint was PFS
for blinded independent central assessment (BICR).
The key secondary endpoints were OS, other secondary endpoints included ORR, duration of response (DoR), PFS, and safety, and exploratory endpoints were clinical benefit rate (CBR) and PFS2
.

Figure 1.
The trial design
of the DB02 study included a total of 406 patients in the T-DXd group and 202 patients in the TPC group
.
The enrolled patients were HER2-positive advanced breast cancer
who had previously received T-DM1 treatment and had received 2 or more lines of treatment in the advanced stage.
The median number of previous treatment lines in enrolled patients was second-line, almost all patients received trastuzumab and T-DM1, and nearly 80% received pertuzumab
.

The results of the study presented at the SABCS conference showed that the DB02 study met the primary endpoint
.

Compared with the TPC group, the median PFS assessed by BICR in the T-DXd group was extended by 10.
9 months (17.
8 versus 6.
9 months), reducing the risk of disease progression or death by 64%;
The PFS assessed by the investigators had the same trend, 16.
7 versus 5.
5 months
, respectively.
In the preset subgroup, PFS was significantly longer
in the T-DXd group compared with the TPC group, regardless of age, hormone receptor status, previous pertuzumab therapy, visceral or brain metastases, and number of previous treatment lines.

Figure 2.
The key secondary endpoints assessed by the BICR
of the DB02 study showed median OS of 39.
2 months and 26.
5 months, respectively, and a significant 12.
7-month increase in the T-DXd group compared with the TPC group, reducing the risk of death by 34%.

Although 25.
7% of patients in the TPC group cross-received T-DXd after progression, the T-DXd group achieved a substantial OS benefit advantage
.

Figure 3.
The T-DXd group also showed significant benefit in terms of key secondary endpoint OS outcomes
and other secondary and exploratory endpoints of the DB02 study.

The ORRs in both groups were 69.
7% and 29.
2%,
respectively.
14% of patients in the T-DXd group achieved a complete response (CR), compared with only 5%
in the TPC group.
It is worth mentioning that PFS2 in the T-DXd group was also significantly longer than in the TPC group (35.
8 months vs 15.
8 months).

Figure 4.
In general, as a confirmatory study of DB01, DB02 reproduces the results of DB01 and verifies the effectiveness of T-DXd as
a third-line or higher treatment regimen for HER2-positive advanced breast cancer in phase III.

Q2: At this SABCS conference, the latest follow-up data
of the DESTINY-Breast03 (DB03) study was also published.
Based on these research progress, please talk about the application value
of T-DXd in HER2-positive advanced breast cancer.
Prof.
Lili Zhang: The DESTINY-Breast03 study is a randomized, open-label, multicenter phase III study designed to compare the efficacy
of T-DXd with T-DM1 in patients with HER2-positive advanced second-line breast cancer who have previously received trastuzumab and taxan therapy 。 The results of this study were first reported at the 2021 ESMO Conference, and the HR of the primary endpoint PFS was only 0.
28, showing a significant statistical difference and clinical benefit of T-DXd compared with T-DM1, while the key secondary endpoint OS was not assessable due to the low number of events and low data maturity, and the HR was 0.
56, and T-DXd had a clear benefit trend, but did not reach a pre-set threshold of statistical difference [3].

。 This SABCS meeting further updated the results of the second overall survival interim analysis of DB03 [4]:

The median OS of T-DXd and T-DM1 was not reached (although still NR), but HR=0.
64, p=0.
0037, and pre-designed statistical difference thresholds (HR=0.
652, p=0.
013)
were reached.
In terms of PFS, the T-DXd group was 28.
8 months, which was 4.
2 times that of the T-DM1 group, and the HR was 0.
33
.
Moreover, the ORR of the T-DXd group was as high as 78.
5%, and 1/5 of patients achieved CR.

Figure 5.
The latest
follow-up data from the DB03 study not only showed that T-DXd had an ultra-long PFS (28.
8 months) in second-line therapy, but also a significant difference in OS benefit compared with T-DM1, demonstrating that the PFS benefit of T-DXd can be translated into overall survival benefit, further consolidating the second-line position of T-DXd in HER2-positive advanced breast cancer
。
The results of DB02 studies showed that T-DXd significantly improved PFS and OS compared with existing standard treatments in HER2-positive advanced breast cancer treated with T-DM1, which further confirmed the excellent efficacy of DB01 study and was the preferred treatment for patients with third-line and above T-DM1 treatment
.
Based on the above DB02 and DB03 research results, it can be said that T-DXd occupies a very important position
in the treatment of HER2-positive advanced breast cancer.

It is worth mentioning that T-DXd also laid out the DESTINY-Breast09 study to evaluate the efficacy and safety of T-DXd alone or in combination with pertuzumab compared with the current first-line standard treatment regimen (THP, tropa+ chemotherapy), which is the first phase III study
to challenge the first-line standard treatment of THP 。 Based on the innovative structural advantages of T-DXd and the breakthrough benefits of previous DB01, DB02, and DB03 studies, we believe that T-DXd will also be successful in the first-line treatment of HER2-positive advanced breast cancer, further enriching first-line drug options
.
In addition, the DESTINY-Breast11 (neoadjuvant) and DESTINY-Breast05 (adjuvantary) studies, which aim to explore the value of T-DXd in HER2-positive early-stage breast cancer, are very exciting
.

Q3: Drug safety is an important factor to consider in treatment, combined with previous research progress, please talk about the overall safety of T-DXd
.
Professor Lili Zhang: The available clinical research data show that the common adverse reactions of T-DXd are mainly
gastrointestinal, hematology, fatigue, hair loss and other general adverse reactions.
For clinicians, accurate identification and effective management of these adverse reactions can be said to be very familiar and
experienced.

Interstitial lung disease (ILD) was the main adverse effect of particular concern when receiving T-DXd, which occurred in 15.
8 percent of patients in the T-DXd group in the DB01 study, with most grades 1 to 2 and 3.
3 percent occurring in grade 3 to 5 [2].

Compared with DB01, fewer ILD events were observed in the DB02 study, with an overall ILD event rate of 10.
4%, mostly grade 1-2, and a incidence of 1.
2% in grade 3-5[1].

Recent data from the DB03 study show that the incidence of ILD increased from 10.
5 percent to 15.
2 percent with longer follow-up, but all new ILD events were grade 1 to 2, and only two patients developed grade 3 ILD (0.
8 percent incidence), and no grade 4 or 5 ILD events [4].

It can be seen that with the advance of the number of treatment lines, the incidence of ILD events, especially the incidence of grade 3-5, shows a decreasing trend
.

In general, with the improvement of relevant awareness and the accumulation of medication experience, the adverse reactions related to T-DXd are preventable and controllable
.
In clinical work, we should be vigilant about ILD, identify high-risk groups early, and achieve early prevention, early detection and early treatment, which will help reduce the incidence and mortality rate of ILD, improve the prognosis of patients, and improve their quality of life
.

Q4: What do you think of the PFS2 data published in the DESTINY-Breast03 study? And, what do you think about the alignment of different ADC drugs? Professor Lili Zhang: In the DB03 study, the updated data show that T-DXd achieves a significant difference in OS prolongation compared with T-DM1, demonstrating its long-term survival benefit
.
In addition, PFS2 in the T-DXd and T-DM1 groups was 40.
5 versus 25.
7 months, respectively, suggesting that T-DXd was used in first-line therapy without harming the benefit
of late-line treatment.
The updated results of the DB03 study confirm the standard of
standard for T-DXd in second-line treatment.

Previously, based on the early results of the DB03 study, T-DXd second-line treatment of HER2-positive advanced breast cancer significantly improved the survival benefit compared with T-DM1, and international authoritative guidelines such as ESMO, ABC6, NCCN and ASCO all recommended T-DXd as the preferred regimen for second-line treatment of HER2-positive advanced breast cancer, replacing T-DM1 as the new standard of second-line treatment in the world
。 How to choose the follow-up treatment plan after the progress of second-line T-DXd treatment will be an important issue in clinical practice
.
In the follow-up treatment analysis of the DB03 study, the subsequent treatment received by the T-DXd group included trastuzumab, T-DM1, pertuzumab, anti-HER2 TKI, etc
.
Among them, 35.
2% of patients received T-DM1 treatment after disease progression, indicating that T-DM1 may be one of the options after T-DXd treatment progression, although the treatment benefit of this subgroup of patients is not clear, which is very worthy of further study
.
For patients treated with T-DM1, the DB02 study results showed a significant benefit of T-DXd, so T-DXd can be used as the preferred treatment
for patients treated with T-DM1.

The arrangement of ADC drugs can be considered
according to the respective composition, mechanism of action, clinical research results, drug accessibility, safety and drug resistance mechanism of different ADC drugs.
In the future, more ADC drugs will come out, and the formation is not static, and it is necessary to continuously explore the best treatment mode
in the clinic.

Expert profiles

Professor Lili Zhang

Chief physician, master tutor, ward director of the Department of Internal Medicine, Jiangsu Cancer Hospital
Member of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association
Member of the Breast Cancer Expert Committee of the Chinese Society of Clinical Oncology
Chairman of the Breast Cancer Quality Control Expert Committee of Jiangsu Provincial Cancer Quality Control Center
Deputy leader of the Breast Cancer Group of the Cancer Chemotherapy and Biological Therapy Branch of Jiangsu Medical Association
Member of the Breast Cancer Group of the Oncologist Branch of the Chinese Medical Doctor Association
Member of the Standing Committee of the Breast Professional Committee of the Chinese Association of Women Physicians
Member of the Breast Cancer Expert Committee of Jiangsu Cancer Prevention and Control Alliance
Mainly engaged in the clinical, scientific research and teaching of breast cancer, good at the internal medicine diagnosis and treatment of breast cancer, presided over and participated in a number of breast cancer-related scientific research projects
He has undertaken a number of international and domestic multi-center clinical studies of new drugs and new solutions related to breast cancer

References:

[1] Krop I,Yeon H.
Park YH,Kim SB,et al.
Trastuzumab deruxtecan vs physician’s choice in patients with HER2+unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine:primary results of the randomized,phase 3 study DESTINY-Breast02.
2022 SABCS.
GS2-01.

[2] Modi S,Saura C,Yamashita T,et al.
Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer.
N Engl J Med.
2020 Feb 13; 382(7):610-621.

[3] Cortés J,Kim S,Chung W,et al.
Trastuzumab deruxtecan(T-DXd)vs trastuzumab emtansine(T-DM1)in patients(Pts)with HER2+metastatic breast cancer(mBC):Results of the randomized phase III DESTINY-Breast03 study.
2021 ESMO.
LBA1.

[4] Hurvitz SA,Chung WP,Im SA,et al.
Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer:Updated survival results of the randomized,phase 3 study DESTINY-Breast03.
2022 SABCS.
GS2-02

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