2022 SABCS Professor Wang Shu: Analyze the therapeutic value of novel ADCs in HER2-low expression breast cancer, and look forward to the new pattern of treatment in the future

The new ADC has a wide range of layouts and is expected to fully cover people who benefit from breast cancer
.

With the establishment of the efficacy of antibody-drug conjugates (ADCs) in HER2-low breast cancer patients, novel ADCs have become a new treatment option
for HER2-low advanced breast cancer patients.
As a representative of the new ADC drug, T-DXd was unveiled
at this year's San Antonio Breast Cancer Congress (SABCS) with a number of research data related to HER2 low-expression breast cancer.
For example, DESTINY-Breast04, the first phase III clinical trial in HER2-low breast cancer, published data from subgroup analysis, and the TALENT study of T-DXd's first neoadjuvant treatment of HR-positive HER2 hypo-expressing breast cancer also disclosed the latest results
.
Based on the above background, the Medical Oncology Channel invites Professor Wang Shu of Peking University People's Hospital to deeply interpret the relevant research progress and explain its impact
on the clinical practice of HER2-low expression breast cancer.

Professor Wang Shu: As a "leader" of new ADC drugs, T-DXd has achieved amazing results in the treatment of HER2-positive advanced breast cancer, re-establishing a new standard
for advanced second-line treatment.
It also opens a new era
of anti-HER2 therapy for HER2-low breast cancer.
The DB04 study is a global multicenter unblinded randomized controlled controlled III clinical trial enrolling a total of 557 patients with HER2-low expression unresectable and/or metastatic breast cancer who have previously received 1-2 lines of chemotherapy and are randomly assigned to T-DXd or physician-selected chemotherapy (TPC: capecitabine, eribulin, gemcitabine, paclitaxel, or albumin paclitaxel).

Figure 1.
DB04 study design

The DB04 research results were first presented at the 2022 ASCO Congress and simultaneously published in the New England Journal of Medicine (NEJM).

The results show ^[1]:

For the primary endpoint, the median PFS in the T-DXd group was 10.
1 months, nearly twice as high as in the chemotherapy group, as assessed by a blinded independent central review (BICR), and a 49% lower risk of disease progression or death (HR = 0.
51; 95% CI: 0.
40-0.
64; p<0.
001
).

• In the overall population, the median PFS assessed by BICR in the T-DXd group was 9.
  9 months, significantly better than 5.
  1 months in the chemotherapy group, and the risk of disease progression or death was reduced by 50% (R=0.
  50; 95% CI: 0.
  40-0.
  63; p<0.
  001
  ).
  

• In HR-positive patients, the median OS in the T-DXd group was 23.
  9 months and the risk of death was reduced by 36% compared with 17.
  5 months in the chemotherapy group (HR=0.
  64; 95% CI: 0.
  48-0.
  86; p=0.
  003).
  
  

• In the overall population, median OS was also better in the T-DXd group, at 23.
  4 months and 16.
  8 months (HR=0.
  64; 95% CI: 0.
  49-0.
  84; p=0.
  001).
  
  

Figure 2.
PFS and OS for HR-positive and general population

The results also showed that in the HR positive cohort, the ORR of 52.
6% in the T-DXd group was 52.
6%, which was more than three times that of 16.
3% in the chemotherapy group, and that 12 (3.
6%) patients in the T-DXd group achieved complete response (CR), disease control rate (DCR) of 88%, and median duration of response (DOR) of 10.
7 months
.
In the overall population, the ORR was 52.
3%, the DCR was 87.
1%, and the median DOR was 10.
7 months, similar
to the HR positive cohort results.

Subgroup analysis of DB04 studies was presented at the 2022 SABCS Conference ^[2], including whether CDK4/6 inhibitors were treated and different disease burden states (low: 0-2 metastases; High: 3 or more metastases), whether the disease progressed rapidly (definition of rapid disease progression: disease progression within 6 months after a course of chemotherapy before the end of the end of patients with early-stage breast cancer), and whether there was brain metastasis at baseline, all showed a trend
of benefit consistent with the overall population 。 Among them, the median PFS, T-DXd and TPC groups in the CDK4/6 inhibitor treatment subgroup (HR-positive population) were 10.
0 months and 5.
4 months, respectively, and the ORRs of the two groups were 50.
6% and 13.
0%, respectively.
The median PFS in the high disease burden subgroup was 9.
5 months and 4.
8 months, with ORRs of 51.
1% and 17.
2%,
respectively.
Overall, the T-DXd group showed a clear beneficial advantage
.

Figure 3.
Whether CDK4/6 inhibitors have been treated with PFS in HR-positive patients

Figure 4.
ORR for different subgroups

The DB04 study showed that T-DXd was the first anti-HER2 ADC drug to show unprecedented statistically significant and clinically significant improvements in PFS and OS compared to TPC
.
Trends in benefit were similar
across all subgroups.
The safety profile is consistent with previous reports, and the overall benefits outweigh the risks
.
This study also breaks the limitation that anti-HER2 therapy is only effective for HER2-positive breast cancer, and establishes HER2 low-expression (IHC 1+, IHC 2+/ISH-) metastatic breast cancer as a new targeted therapy population, which has great clinical practical significance
.
T-DXd is expected to become the first standard of care for HER2-low breast cancer, and it is expected to benefit more patients
in the future.

Professor Wang Shu: The R&D and exploration of T-DXd in breast cancer can be described as a wide range of fields, from advanced to early, posterior to front, HER2 positive to HER2 low expression treatment
.
TALENT is a multicenter, unblinded randomized, two-stage, phase II clinical study ^[3] to explore the efficacy and safety
of T-DXd neoadjuvant therapy for HR-positive, HER2-low expression breast cancer.
In the first phase of the study, 58 subjects were randomly divided into 2 groups by 1:1 from September 2020 to October 2022

• 29 patients in group A were given 6-cycle T-DXd monotherapy;

• There were 29 patients in group B, and 6 cycles of T-DXd + anastrozole were treated
  .
  

In February 2022, the study protocol was revised
.
For new patients and those who have not yet undergone surgery, the number of treatment cycles is increased from 6 to 8
.
In addition, both men and premenopausal group B patients were treated
with gonadotropin-releasing hormone (GnRH) agonists.
Stratified factors were HER2 expression level (IHC 1+ or 2+) and menopausal status
.

The primary endpoint was the pCR rate of the breast and lymph nodes at surgery (ypT0/is ypTN0, residual cancer burden index = 0).

Secondary endpoints included ORR, tumor marker analysis (including HER2 changes, Ki67), and safety analysis
.
If the pCR rate is ≤ 5% or less, this method group is not further studied
.

Figure 5.
TALENT study design

SABCS 2022 primarily reports Phase 1 results for the study, as of November 25, 2022:

• The ORR of T-DXd monotherapy group was 68% (17/25), of which 2 (8%) had complete response (CR) and 15 (60%) had partial response (PR).
  

• The ORR of T-DXd combined with endocrine therapy was 58% (14/24), of which 2 (8%) had CR, 12 (50%) had PR, and 2 (8%) patients in the combination group had disease progression (PD).
  
  

From the research data, although the efficacy of endocrine therapy on the basis of T-DXd monotherapy does not seem to be enhanced, this result needs to be interpreted with caution, because the small sample size of the study is difficult to draw convincing conclusions, and further exploration
of the sample size needs to be expanded in the future.
However, overall, the benefits of neoadjuvant therapy are encouraging, whether T-DXd alone or in combination endocrine therapy, and the efficacy is not inferior to previously published data
on HR+/HER2-breast cancer neoadjuvant endocrine therapy.

Figure 6.
ORR of T-DXd monotherapy versus combination group

As the first clinical trial to explore the treatment of HR-positive, HER2-low expression breast cancer with T-DXd neoadjuvant, the release of its results also reflects the leapfrog breakthrough of T-DXd in the field of HER2 low expression breast cancer treatment from late posterior line to early neoadjuvant
.
In the future, whether T-DXd can become a new choice for neoadjuvant therapy for HR-positive and HER2-low expression breast cancer patients is expected to be answered by clinical trials with larger sample sizes
.

Professor Wang Shu: ADC drugs have both the specific targeting of monoclonal antibodies and the potent killing effect of cytotoxic drugs, especially T-DXd as a new ADC drug, its structural design and mechanism of action have been further optimized, not only can accurately target tumor cells, but also thanks to the unique properties of cleavage linker and drug load, and the drug-antibody ratio (DAR) reaches a theoretical high value of 8, T-DXd can also play a strong bystander effect.
It is also effective against HER2-low expression breast cancer ^[4-6], and its excellent strength has also been fully demonstrated
in the DB04 study.

Previous research findings on anti-HER2 therapy in HER2-low breast cancer are unsatisfactory:

• In the NSABP B47 ^{study [7]}, adjuvant trastuzumab did not benefit patients with IHC 1+ or IHC 2+/FISH-, and the benefit of chemotherapy plus trastuzumab was similar to that of IDFS with chemotherapy alone (5-year IDFS rate: 89.
  8% vs 89.
  2%, HR=0.
  98, 95% CI, 0.
  76-1.
  25, P=0.
  85).
  
  

• A phase II study of pertuzumab ^[8] enrolled 78 patients with IHC 0, 1+, or IHC 2+/FISH-advanced late-line breast cancer with an overall objective response rate (ORR) of only 2.
  5%.
  
  

• A combined analysis of two phase III clinical studies of lapatinib EGF100151 and EGF30001 showed ^that patients with IHC >0 and FISH- did not benefit from lapatinib (PFS in combination with lapatinib versus chemotherapy alone, p=0.
  8823, HR=0.
  97).
  
  

• The two phase II single-arm studies of T-DM1 (4258 g and 4374 g) were included as investigators diagnosed HER2-positive, with 21 and 15 HER2 negative, respectively
  , by central laboratory tests.
  In the single-arm, phase II study TDM4258g ^[10], the objective response rate (ORR, 4.
  8% vs 33.
  8%) and median progression-free survival (PFS, 2.
  6 versus 8.
  2 months) of patients with low HER2 expression were significantly lower than those of HER2-positive patients
  .
  Similarly, in the phase II study of T-DM1, TDM4374g ^[11], exploratory subgroup analysis yielded similar results, with significant differences in ORR (20.
  0 versus 41.
  3 percent) and median PFS (2.
  8 versus 7.
  3 months).
  
  

Figure 7.
Attempts at pertuzumab, T-DM1, and lapatinib in HER2-low breast cancer have all failed

With T-DXd as a milestone, it breaks the dilemma that HER2 low-expression breast cancer is ineffective against HER2 treatment and opens up a new situation
.
As early as the phase I DS8201-A-J101 ^{study [12]}, 54 patients with low HER2 expression (IHC1+, IHC2+/ISH-) were included in T-DXd treatment, and after previous treatment with a median of 7.
5 lines, the ORR assessed by the independent review committee was as high as 37%, and the disease control rate (DCR) was as high as 87%.
The median duration of response (DOR) and median PFS were up to 10.
4 and 11.
1 months, respectively, with benefit
observed in all subgroups.
At the same time, the DAISY study data released by SABCS in 2021 showed ^{that the} optimal response rate (BOR) of T-DXd in the overall population was 48.
6%, the median DOR was 8.
5 months, and the median PFS was 7 months
.
In the HER2 high-expression, low-expression and HER2 0 cohorts, BOR was 70.
6%, 37.
5%, and 29.
7%, respectively, and the median PFS was 11.
1 months, 6.
7 months, and 4.
2 months
, respectively.
The results of the study further verify the therapeutic efficacy
of T-DXd for HER2-low expression breast cancer.

The DB04 study broke the traditional situation of effectively defining HER2-positive breast cancer according to trastuzumab treatment, and the era of the HER2 trichotomy of breast cancer has fully begun
.
And the 2022 SABCS conference also announced neoadjuvant therapy data, from the early stage of the late layout, T-DXd performance is still bright
.
In the future, T-DXd, as the "protagonist" of the new era of breast cancer, will always lead the development of
a new track for HER2 low-expression therapy.

Professor Wang Shu: Based on a series of amazing efficacy data, T-DXd has brought many conceptual updates and thoughts to the field of breast cancer treatment, and also provided new treatment options
with great clinical application prospects.

In the field of HER2-positive breast cancer treatment, based on the breakthrough results of DB03 research, T-DXd has established its status as a second-line standard treatment for advanced stage.
In the future, based on DB09 research, it will impact the late first line
.
In addition, DB11 study and DB05 study also explored the application value of T-DXd in the field of neoadjuvant and adjuvant therapy for early breast cancer, and look forward to the early release of the research results, which can further enrich the clinical treatment strategies
of early breast cancer.

HER2 low expression has become a hot spot in the field of breast cancer diagnosis and treatment in recent years, the traditional HR+/HER2- breast cancer and triple-negative breast cancer (TNBC) have covered a certain proportion of HER2 low expression breast cancer patients, in the past breast cancer treatment strategy according to molecular typing, and with the establishment of the efficacy of the new ADC drug T-DXd in HER2 low expression breast cancer patients, a new treatment-oriented breast cancer treatment pattern is gradually taking shape
.

• In the field of endocrine-refractory HR+/HER2- advanced breast cancer treatment, based on DB04 research, T-DXd may become the mainstream treatment option for the second line and later (HER2 low expression)
  in the future.
  

• In the field of TNBC therapy, based on DB04 research, T-DXd may become the preferred regimen for second-line and later (HER2 low expression).
  
  

In short, T-DXd will fully cover the people who benefit from breast cancer, and continue to try new exploration directions in order to maximize
the benefits of patients.