Recently, the FDA approved fam-trastuzumab deruxtecan-nxki (T-DXd), which is marketed as Enhertu, for two new indications in HER2-postive, early-stage breast cancer in adults1:
- T-DXd followed by taxane, trastuzumab, and pertuzumab (THP) for the neoadjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) Stage II or III breast cancer, as determined by an FDA-authorized test
- T-DXd for the adjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) breast cancer who have residual invasive disease following neoadjuvant treatment with trastuzumab (with or without pertuzumab) and taxane-based treatment
Clinical trial results
The approval comes after significant results from two clinical trials: DESTINY-Breast05 and DESTINY-Breast11. In the phase 3 DESTINY-Breast05 trial, patients who received T-DXd (n=818) achieved a 3-year invasive disease-free survival rate of 92.4% (95% CI, 89.7%-94.4%) compared with 83.7% (95% CI, 80.2%-86.7%) among those who received ado-trastuzumab emtansine (T-DM1; n = 817; HR, 0.47; 95% CI, 0.34-0.66; P<.0001).2 Based on these results, T-DXd has been included in the National Comprehensive Cancer Network Guidelines as a Category 1 recommended treatment in the adjuvant setting for eligible patients.3
In DESTINY-Breast11, which compared an Enhertu-based sequence against the traditional doxorubicin and cyclophosphamide (ddAC) followed by THP, results demonstrated that the improved outcomes with Enhertu and half the rate of serious toxicities compared to the older standard.4 The primary objective was to measure the pathological complete response (pCR) rate—the total absence of invasive cancer in the breast and lymph nodes at the time of surgery—and patients receiving the Enhertu sequence achieved a 67.3% pCR rate, significantly higher than the 56.3% seen in the traditional chemo-based arm.4
While these clinical trial results demonstrate that Enhertu is highly effective, the treatment does have a boxed warning for interstitial lung disease (ILD) and pneumonitis. This was a point of concern for researchers moving the drug into an early-stage, potentially curable population.
However, the rate of ILD in the clinical trial was less than 5%. Another benefit in terms of the safety profile of Enhertu compared to the standard of care is on heart health. The global standard for high-risk HER2-positive patients involved an ACT regimen (anthracycline, cyclophosphamide and a taxane), which is known for potentially serious cardiac toxicities. This new approval expands treatment options that limit these risks for cardiac health, as the rate of left ventricular dysfunction was significantly lower, occurring in about 1% of patients taking Enhertu compared to 6% in the traditional arm.4
How the standard of care may change
Antibody-drug conjugates (ADCs) have already been reshaping HER2-positive metastatic breast cancer and HER2-low disease treatments, firstly by redefining how these patients are classified—there is more than just HER2-positive or HER2-negative breast cancer, and these new developments highlighted HER2 low and the benefit of treatment for patients.3
Since those first approvals and new definitions of disease types, the standards of care will potentially change in major ways for patients with high-risk localized disease in both neoadjuvant and adjuvant settings, with a curative-intent setting in mind. These trials expand momentum for ADCs in breast oncology, specifically as investigators move highly active metastatic therapies into earlier-stage disease.3 Notably, the expanded early-stage breast cancer indications strengthen AstraZeneca’s broader oncology strategy around precision therapeutics and ADC platforms, but also highlight an area that will continue to see investment across pharma companies.5
Conclusion: more treatment choices for patients
For patients facing a diagnosis of HER2-positive stage 2 or 3 breast cancer, this approval provides a powerful new option to treat their disease before surgery. And for patients looking to manage disease post-surgery, the approval provides an option to treat residual invasive disease that can help reduce the risk of cancer recurring. With the FDA also approving companion diagnostic tests to help accurately identify patients who are HER2-positive and eligible for this treatment, the treatment landscape will continue to become more personalized and determine which patients will specifically benefit from the various regimens that may be available to them.
There’s no question that these approvals will continue to redefine perspectives about HER2 breast cancer types and ways of treating disease. With varying opinions and perspectives on what these approvals mean for day-to-day care, it can be helpful to speak to a clinical expert directly and get their opinion. With NoeticInsight, you can get actionable health care insights on demand by connecting with experts wherever, whenever, as soon as the need arises via our exclusive, virtual health insights platform. Learn more about how our services can help with your specific needs, and contact us today to get started.
Sources:
- https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-two-separate-indications-fam-trastuzumab-deruxtecan-nxki-her2-positive-early-stage
- https://www.onclive.com/view/dr-mccann-on-the-expanding-role-of-t-dxd-in-her2-breast-cancer-management
- https://www.ajmc.com/view/fda-approves-enhertu-for-two-new-indications-for-patients-with-her2-positive-early-breast-cancer
- https://www.curetoday.com/view/fda-approves-enhertu-regimen-for-her2-positive-early-breast-cancer
- https://www.biopharminternational.com/view/fda-expands-enhertu-into-early-her2-positive-breast-cancer-with-dual-new-indications