New advances in ADC therapy for HER2-positive breast cancer brain metastases

*For medical professionals only

The new generation of ADC drugs may become a new treatment option for breast cancer brain metastasis and reshape the treatment strategy
of brain metastasis.

HER2-positive breast cancer brain metastases treatment options are limited,

There is an urgent need to explore new treatments

At present, local therapy is still the main treatment method for breast cancer brain metastasis, including surgery, stereotactic radiosurgery (SRS) and whole-brain radiotherapy (WBRT).
The choice of treatment modality is mainly determined
by the patient's prognosis, the presence of neurological symptoms, the number, size, distribution of metastases, and what kind of treatment has been received in the past.
Topical therapy is more targeted and has a faster onset of action for brain metastases, but adverse effects are also more serious ^[2].

In the systemic treatment of HER2-positive breast cancer brain metastases, studies have shown that monoclonal antibodies can penetrate the damaged blood-brain barrier and thus exert anti-tumor effects, but their low intracranial concentrations may not be sufficient to obtain objective remission
.
Current clinical evidence for trastuzumab in the treatment of brain metastases is mainly from retrospective studies, and although these studies suggest that trastuzumab prolongs overall survival (OS) in patients with HER2-positive breast cancer brain metastases, this benefit may be mainly related to the long-term control of extracranial disease with trastuzumab and weaker
correlation with antitumor activity in intracranial disease.
Trastuzumab and chemotherapy in combination with pertuzumab have been shown to delay the onset of brain metastases and may improve survival in patients with brain metastases at baseline ^[3].

Overall, although monoclonal antibodies have some activity in breast cancer brain metastasis, their overall efficacy is limited ^[4].

Figure 1.
IN THE PATRICIA STUDY, HIGH-DOSE PH DUAL-TARGETED THERAPY HAD A CERTAIN EFFICACY ON BREAST CANCER BRAIN METASTASIS, WITH A CNS ORR OF 11%, A CLINICAL BENEFIT RATE OF 68% AT 4 MONTHS, AND A CLINICAL BENEFIT RATE OF 51% AT 6 MONTHS

Small molecule TKI is a commonly used anti-HER2 therapeutic drug in clinical practice, and the activity of TKI in the treatment of brain metastases has also been explored in a number of clinical studies ^[5].

Initial trials reported an objective response rate (ORR) of the central nervous system (CNS) of lapatinib + capecitabine of 18% to 66%.

Subsequently, the TBCRC022 study evaluated the efficacy of neratinib and neratinib-based combination therapy in brain metastases, and observed that the CNS ORR of patients who had not received lapatinib and lapatinib was 49% and 33%,
respectively.
In the PERMEATE study, the CNS ORR of pyrotinib + capecitabine for patients who had not previously received radiation therapy was 74.
6%, and the CNS ORR of patients treated with radiation therapy was 42.
1%.

Figure 2.
THE PERMEATE STUDY SHOWED THAT PYROTINIB IN COMBINATION WITH CAPECITABINE WAS EFFECTIVE IN PATIENTS WITH BRAIN METASTASES

Among the studies of TKI in the treatment of brain metastases, the most well-known is the HER2CLIMB study, which established the importance of tucatinib in the treatment of HER2-positive breast cancer brain metastases
.
In the HER2CLIMB study, the CNS ORR of 47% in the tucardinib + trastuzumab + capecitabine treatment group was 47% in patients with active CNS metastases with measurable lesions at baseline, significantly better than 20% in the control group, and the median duration of intracranial remission was longer in the tucatinib group (8.
3 months vs.
.
3.
0 months).

And the overall survival (OS) of patients with brain metastases was significant in the tucatinib group, regardless of all 291 patients with brain metastases (21.
6 months vs.
12.
5 months), or 174 patients with active brain metastases (21.
4 months vs.
11.
8 months).

Figure 3.
Tucatinib-based combination regimen in the HER2CLIMB study

Significantly improves OS in patients with brain metastases

Despite this, the existing systemic treatment options for HER2-positive breast cancer brain metastases are still limited, the time for disease control is usually only a few months, and the survival prognosis is still poor, and new therapeutic breakthroughs
need to be explored.

ADC drugs are on the rise,

It is expected to solve the problem of HER2-positive breast cancer brain metastasis

In recent years, ADC drugs represented by T-DXd have risen rapidly in the field of breast cancer, breaking the original treatment pattern of monoclonal antibody, TKI and chemotherapy, and bringing breakthroughs
to the treatment of breast cancer.
The treatment of HER2-positive breast cancer brain metastases has also been actively explored, and there are outstanding manifestations
in stable brain metastases and active brain metastases.

T-DM1 shows potential in the treatment of brain metastases,

Supports the therapeutic possibilities of macromolecular ADC drug brain metastases

T-DM1 is the first ADC drug approved for marketing in breast cancer, and although T-DM1 may have similar limitations (biomacromolecules) to trastuzumab in penetrating the blood-brain barrier, the data show some intracranial activity
.
In the population with baseline brain metastases in the EMILIA ^{study [6]}, the median OS of 26.
8 months in the T-DM1 group was significantly better than that of the lapatinib + capecitabine group at 12.
9 months, although there was no significant difference in median PFS between the two groups (5.
9 months vs.
5.
7 months; P = 1.
000）
。 T-DM1 treatment for brain metastases in the TH3RESA ^{study [7,8]} also showed a survival benefit, with a median OS of 17.
3 months and a median PFS of 5.
8 months
.
IN ADDITION, DATA FROM THE KAMILLA STUDY ^[9] SHOWED THAT 398 PATIENTS WITH BASELINE CONCOMITANT BRAIN METASTASES TREATED WITH T-DM1 (UNTREATED ASYMPTOMATIC BRAIN METASTASES OR PATIENTS WHO RECEIVED RADIOTHERAPY > 14 DAYS PRIOR TO ENROLLMENT AND HAD BRAIN DISEASE UNDER CONTROL WERE ENROLLED) WITH A MEDIAN OS OF 18.
9 MONTHS AND A MEDIAN PFS OF 5.
5 MONTHS
.

Figure 4.
THE KAMILLA STUDY SHOWED THAT T-DM1 HAS A CERTAIN EFFICACY IN THE TREATMENT OF BRAIN METASTASES, WITH AN ORR OF 21.
4%.

T-DXd has significant benefits in stable brain metastasis.

Active brain metastases have also shown therapeutic potential

Advances in T-DXd treatment for stable brain metastases

T-DXd is a new generation of ADC drugs optimized in many aspects, which has a higher drug-antibody ratio (DAR) than T-DM1, and can exert a bystander effect to further enhance the anti-tumor killing effect
.
DESTINY-Breast01 is the first global multicenter clinical study of T-DXd in the field of breast cancer ^[10], in which 24 patients with stable brain metastases were enrolled, with an ORR of 58.
3% and a median PFS of up to 18.
1 months, showing great potential
for stable brain metastases.

DESTINY-Breast03 is the first phase III clinical study of T-DXd [11], and 23.
8% of patients enrolled have stable brain metastases, and the median PFS of these brain metastases patients is ¹⁵ months, significantly better than the 3 months
of T-DM1.
At the same time, T-DXd can significantly shrink intracranial lesions of brain metastases, with ORRs of 63.
9% and 33.
4% in the two groups, respectively, and the complete remission (CR) rate of intracranial lesions in the T-DXd group reached 27.
8% (only 2.
8% in the T-DM1 group
).
The results of this study further indicate that DS-8201 has important clinical therapeutic value
in patients with stable brain metastases.

Figure 5.
Results of subgroup analysis of DESTINY-Breast01 study brain metastases

Figure 6.
DESTINY-Breast03 study brain metastases subgroup PFS analysis results

Figure 7.
DESTINY-Breast03 studies subgroup remission of brain metastases

Exploration of T-DXd in active brain metastasis

Although phase III clinical studies of most agents typically include patients with stable breast cancer brain metastases (eg, previously treated and radiographically stable patients), patients with active breast cancer brain metastases (eg, untreated or locally treated progression) are generally excluded ^[1].

However, T-DXd has also made many explorations
in subsequent brain metastasis studies for patients with active brain metastases.

DEBBRAH is an open-label, multicenter, single-arm, 5-cohort phase II study of T-DXd, where cohort 3 enrolled patients with HER2-positive breast cancer brain metastases progressed, and the latest results show ^[1], 4 of the 9 enrolled patients achieved remission with an intracranial ORR of 44.
4%.

The overall clinical benefit rate (CBR) and disease control rate (DCR) for cohort 3 was 77.
8% and the disease control rate (DCR) was 89.
9%.

The results suggest that T-DXd remains effective
in patients who progress after treatment for brain metastases.

Figure 8.
In the DEBBRAH study, T-DXd showed intracranial activity in cohorts 1 and 3

The TUXEDO-1 study also demonstrated a significant therapeutic benefit of T-DXd in patients with active brain metastases, including 15 patients with active brain metastases with HER2-positive breast cancer (brain metastases that have not been treated or have progressed after local treatment with new brain metastases or with no immediate topical conditions after trastuzumab and pertuzumab ^{treatment) in} this prospective, single-center, single-arm phase II clinical trial published in August 2022 in Nature Medicine ^[14], 15 patients who received at least one T-DXd treatment were included in the intention-to-treat population, and at a median follow-up of 12 months, the optimal intracranial response rate was 13.
3% (2 cases), the PR rate was 60% (9 cases), the SD rate was 20% (3 cases), and the ORR was 73.
3% (95CI: 48.
1%-89.
1%), meeting the preset primary endpoint
.
The median PFS for patients was 14 months
.
No new safety issues were identified during treatment, and overall quality of life and cognitive function were maintained
.

Figure 9.
The TUXEDO-1 study, RANO-BM criteria assessed patient remission (ORR 73.
3%) and median PFS (14 months).

In addition, preclinical studies and series of clinical case data from Dana-Farber, Duke and MD Anderson at the 2021 SABCS Conference also showed that T-DXd has significant activity
against breast cancer brain lesions.

Figure 10.
Gradual reduction of brain lesions in a patient with brain metastases treated with T-DXd who had previously been treated
with T-DM1, neratinib, and tucatinib presented at the 2021 SABCS Conference.

Ongoing research on T-DXd in the treatment of breast cancer brain metastases

In addition to the above studies, ongoing studies of T-DXd targeting breast cancer brain metastases include DESTINY-Breast12 and HER2CLIMB-04 among others ^[15].

。 DESTINY-Breast12 is a phase IIIb/IV study to evaluate the efficacy and safety of T-DXd for previously treated HER2-positive advanced or metastatic breast cancer with or without brain metastases, dividing 500 patients 1:1 into two cohorts of baseline without brain metastases (cohort 1) and baseline with brain metastases (cohort
2, patients with untreated brain metastases who do not require immediate topical therapy or brain metastases that have been stable or progressed with prior treatment).

Figure 11.
DESTINY-Breast12 study design

HER2CLIMB-04 is a phase II.
clinical study to evaluate the clinical efficacy of tucatinib + T-DXd in patients with HER2-positive unresectable, locally advanced or metastatic breast cancer who have received ≥ two anti-HER2 therapies in the past, in which after the safety verification of the combined application of the two drugs, it is planned to include 60 patients according to 1:1 into the anencephaly metastasis history cohort and the brain metastasis history cohort (brain metastases patients, including active brain metastases)
according to 1:1.
In order to explore the efficacy and safety
of the combination of the two drugs with the greatest potential for brain metastases.

Figure 12.
HER2CLIMB-04 study design

These studies, ranging from single agent to combined application, and comprehensively cover stable brain metastases and active brain metastases, aiming to further explore the therapeutic potential of T-DXd for breast cancer brain metastases, and future results are to be seen
.

Based on the emergence of novel ADC drugs,

Future exploration of breast cancer brain metastasis treatment

Prevention of brain metastasis is an important direction,

It is worth paying attention to whether ADC drugs have relevant effects

At present, there is insufficient evidence to prove that a drug can effectively prevent the occurrence of brain metastasis, and the relevant research and exploration of systemic therapeutic drugs for the prevention of breast cancer brain metastasis, including small molecule TKI, large molecule monoclonal antibody, and ADC drugs, have shown that there may be relevant benefits
。 For example, ExteNET studies reported the possibility of preventing CNS with adjuvant nelatinib therapy, and in a post-hoc analysis of 295 HR-positive/HER2-positive, trastuzumab less than 1 year after treatment with residual disease, the incidence of CNS metastasis was 0.
8% in the neratinib group compared to 3.
6% in the placebo group, suggesting a potential CNS prophylaxis benefit
of neratinib 。 In a post-hoc analysis, the time to new-onset brain metastases or death in the tucatinib group was significantly delayed in all randomized patients enrolled in the HER2CLIMB study, regardless of the presence or absence of brain metastases at baseline (HR=0.
52; p=0.
005) ^[5].

These studies together suggest that small molecule TKIs may play a positive role
in the prevention of breast cancer brain metastases.

The CLEOPATRA trial reported that tripa double-targeted chemotherapy delayed the development of brain metastases (median time to CNS metastasis, 11.
9 months vs.
15.
0 months; HR=0.
58；p=0.
0049）； However, the overall incidence of CNS as the site of initiation of disease progression was similar between groups (12.
6% in single-target versus 13.
7% in dual-target group).

THE RELEVANT DATA OF ADC DRUGS NEED TO BE FURTHER ENRICHED, FROM THE EXISTING STUDIES, IN THE KATHERINE TRIAL, MORE THAN HALF OF THE DISTANT RECURRENCES IN THE T-DM1 GROUP WERE OBSERVED TO BE CNS RECURRENCES; In EMILA studies comparing the clinical benefit of lapatinib + capecitabine with T-DM1, no significant differences in
CNS progression were observed.
In addition, only 1.
3% of patients with baseline brainless metastases in the DESTINY-Breast01 study developed new brain metastases
after treatment with T-DXd.
These results suggest that ADC drugs have a certain role in preventing the occurrence of breast cancer brain metastasis, but further clarification is needed, and relevant data
are expected to be available in the future.

Considering the treatment of brain metastases,

Line-up strategy for HER2-positive advanced breast cancer

New anti-HER2 drugs are emerging, and TKI and ADC drugs have become the most promising treatments for breast cancer brain metastases
.
From the current research progress, TKI has shown good effects in patients with active brain metastasis, and the relevant evidence is relatively sufficient
.
ADC drugs such as T-DXd have excellent clinical benefit in breast cancer patients with or without stable brain metastases, while efficacy data in patients with active brain metastases are relatively limited
.
Given that a significant proportion of patients eventually develop brain metastases, TKI should be considered as a solution to brain metastases rather than preferred as a frontline systemic therapy
.
For example, the 2021 ESMO guidelines recommend the selection of T-DXd in the stage of anencephaly or stable brain metastasis, and as the disease progresses, it seems to be a more reasonable choice
to choose tucatinib treatment after patients have active brain metastases.
In 100 percent of patients enrolled in the HER2CLIMB study who had previously received T-DM1, tucatanib significantly prolonged PFS and OS in patients with active brain metastases after ADC ^{treatment [16}
].
It is believed that with the further development of ADC drugs in the future, the treatment mode of ADC sequential TKI will also be more widely used
.

Overcome the problem of brain metastasis treatment,

The ADC combination therapy model is worth looking forward to

One of the reasons why it was previously believed that patients with breast cancer brain metastases had poor drug treatment was that macromolecular drugs could not penetrate the blood-brain barrier
.
Intracranial radiotherapy is the standard treatment for patients with brain metastases, and some researchers have found that HER2-positive brain metastases treated with trastuzumab have an increased concentration of trastuzumab in cerebrospinal fluid after whole-brain radiotherapy
.
It suggests that intracranial radiotherapy has an effect on the blood-brain barrier and can increase drug permeability
.
This theoretically confirms that patients with HER2-positive breast cancer brain metastases may benefit
from subsequent biomacromolecular drugs after receiving intracranial radiotherapy.
Since then, more and more studies have confirmed that whole-brain radiotherapy and anti-HER2 therapy in patients with HER2-positive breast cancer with brain metastases can significantly improve the prognosis of patients with brain metastases ^[17].

How to organically integrate ADC drug-based system therapy with intracranial radiotherapy in the future is also worth exploring
.

In terms of drug combination, ADC drugs have shown great therapeutic potential in the field of HER2-positive breast cancer, and TKI drugs have shown good efficacy in brain metastases and intracranial lesions, and the combination of the two drugs may bring greater therapeutic benefit
.
In fact, T-DXd combined with tucatatinib (HER2CLIMB-04 study) and T-DM1 combined with tucatinib (CompassHER2 RD) and other related studies as mentioned above are actively being carried out
.

summary

Brain metastasis is a common complication of HER2-positive advanced breast cancer, and the development of anti-HER2 therapy drugs provides some options for improving the poor prognosis of breast cancer brain metastasis patients, among which ADC drugs represented by T-DXd have been explored through a series of studies, which has subverted the traditional cognition that small molecule drugs are more effective in treating brain metastases, and is expected to provide new ideas
for the treatment of breast cancer brain metastases.

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