Enhertu carving out a new space for itself in HER2 low patients
1. ASCO 2022: Enhertu Highlights
Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice in patients
with HER2-low metastatic breast cancer (mBC): DESTINY-Breast04, phase III study
On May 05, 2022, the AstraZeneca and Daiichi Sankyo received Enhertu approval
from the FDA for the treatment of adult patients with unresectable or metastatic
HER2-positive breast cancer who have previously received an anti-HER2-based
regimen, either in the metastatic setting, or in the neoadjuvant or adjuvant setting,
and have developed disease recurrence during or within six months of completing
therapy. The Enhertu FDA approval was based on positive results from the Enhertu
DESTINY-03 Phase III trial.
Breast cancer patients are currently grouped into three large categories: HER2-
positive, HR-positive/HER2-negative, and triple-negative. With Enhertu, Daiichi
Sankyo and partner AstraZeneca aimed to open a new group: HER2-low.
The data from the Phase III Destiny-Breast04 trial showed that the Daiichi Enhertu
reduced the risk of disease progression or death by a massive 50% and the risk of
death by 36% in a group of patients with previously treated HER2-low metastatic
breast cancer.
2. At a median follow-up of 18.4 months, Daiichi Sankyo Enhertu extended the
median time patients had lived without disease worsening to 9.9 months, versus
5.1 months for patients who got a physician’s choice of chemotherapy.
In patients with HR-positive disease, which constitutes the trial’s primary endpoint
analysis, Enhertu cut the risk of disease progression or death by 49%. The drug
nearly doubled the median progression-free survival (PFS) to 10.1 months versus
5.4 months for chemotherapy. Among those with HR-negative disease, the size of
the risk reduction on progression-free survival was similar at 55%. The median PFS
between Enhertu and chemotherapy was 6.6 months and 2.9 months, respectively.
In patients who had received prior treatment with a CDK4/6 inhibitor, the
progression-free risk reduction was 45%. For about a quarter of the trial population
who had no prior CDK4/6 experience, that number was 58%.
The only drawback of the DESTINY-Breast04 trial could be that it was not
statistically powered to run subgroup analyses for IHC1+ and IHC2+ patients
separate, and earlier trials did not suggest people with even lower HER2 expression
benefited any less from Enhertu. Hence, a major discrepancy might raise some
eyebrows, but Enhertu showed similar results in IHC 1+ and IHC 2+ subgroups,
cutting the PFS risk by 52% and 45%, respectively.
CONCLUSION
Up to 55% of breast cancer patients fall into that HER2-low definition. These
patients currently are not eligible to receive a HER2-targeted agent, and the
potential demonstrated by Enhertu in Destiny Breast-04 in the 3rd line setting has
provided hope to these patients. The company is expected to make a regulatory
submission in 2022, and it also has Real-Time Oncology Review (RTOR) in addition
to BTD. However, there is one uncertainty because, in the 557-patient Destiny-
Breast04 trial, only 11.3% of the patients were HR-negative. Therefore, the data
might not be enough in the eyes of the FDA for the HR-negative patient subgroup
and possibly limit the approval to the HR-positive patients only.
Moreover, Enhertu (AstraZeneca/Daiichi Sankyo) has also been linked to a
potentially dangerous side effect known as interstitial lung disease (ILD), which
causes scarring of the lungs. According to an independent review committee, in the
Destiny-Breast04 trial, 45 Enhertu her2 low breast cancer patients (12.1%)
3. experienced drug-related interstitial lung disease, including 3 (0.8%) deaths.
Whereas in the chemotherapy arm, only one patient experienced a low-grade 1
case of a lung problem.
The outcome of the DESTINY-Breast04 trial could transform breast cancer
treatment and has made us excited for the DESTINY-Breast06 trial, which will
compare Enhertu with chemotherapy in HER2-low and HER2-ultra-low HR-positive
metastatic breast cancer patients whose disease has progressed on endocrine
therapy (2nd Line). The data from this trial is anticipated in 2023.
In terms of competition in HER2low, there is no major player apart from
Astrazeneca/Daiichi Sankyo in the line at this moment. In fact, majorly active
players include china based pharma companies such as RemeGen, Shanghai
Miracogen, Jiangsu HengRui Medicine, and others. If approved, Enhertu her2 low
breast cancer will be the first targeted drug under this new concept of HER2-low,
which has a large patient population to target.
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