Enhertu carving out a new space for itself in HER2 low patients. A major-label expansion is likely on the way

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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.

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%) 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.

Read Market Research Reports 2022