FDA Approves Enhertu for Unresectable or Pretreated Metastatic HER2-Positive Breast Cancer
On Dec. 20, 2019, the U.S. Food and Drug Administration approved Enhertu (chemical name: fam-trastuzumab deruxtecan-nxki) to treat people diagnosed with unresectable HER2-positive breast cancer or metastatic HER2-positive breast cancer that has been treated with two or more anti-HER2 therapies.
On Dec. 20, 2019, the U.S. Food and Drug Administration (FDA) approved Enhertu (chemical name: fam-trastuzumab deruxtecan-nxki) to treat people diagnosed with:
- unresectable HER2-positive breast cancer
- metastatic HER2-positive breast cancer that has been treated with two or more anti-HER2 therapies
Unresectable means the cancer can’t be removed with surgery.
Metastatic breast cancer is cancer that has spread to parts of the body away from the breast, such as the bones or liver.
Enhertu is a targeted therapy made up of three parts:
- fam-trastuzumab: an anti-HER2 medicine that has the same basic structure as Herceptin (chemical name: trastuzumab)
- a topoisomerase I inhibitor chemotherapy called DXd: topoisomerase I inhibitors work by interfering with the cancer cells’ ability to replicate; this type of chemotherapy is not typically used to treat HER2-positive breast cancers, so researchers believe it is less likely that the cancers will develop resistance to it
- a compound that links the fam-trastuzumab molecule to the topoisomerase I inhibitor chemotherapy molecule
Doctors call Enhertu an antibody-drug conjugate targeted therapy. The combination of the topoisomerase I inhibitor and the linking compound is called deruxtecan. The linking compound attaches (conjugates) the fam-trastuzumab to the topoisomerase I inhibitor chemotherapy.
Enhertu is given intravenously, which means the medicine is delivered directly into your bloodstream through an IV or port. Enhertu usually is given every 3 weeks unless the cancer grows or unacceptable side effects develop.
In earlier studies, Enhertu was called T-DXd and DS-8201.
The FDA’s approval of Enhertu is based on results from the DESTINY-Breast01 study, which were presented on Dec. 11, 2019, at the San Antonio Breast Cancer Symposium and published simultaneously in the New England Journal of Medicine.
- Read the 2019 SABCS abstract of “[Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: A phase 2, multicenter, open-label study (DESTINY-Breast01).”
- Read the NEJM abstract of “Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer.”
Earlier results from the phase I part of the DESTINY-Breast01 study found that 59% of people diagnosed with advanced-stage HER2-positive breast cancer previously treated with Kadcyla (chemical name: T-DM1 or ado-trastuzumab emtansine) had a response to Enhertu. The FDA granted priority review to Enhertu in October 2019.
The phase II part of the study included 184 people diagnosed with metastatic HER2-positive breast cancer. Half the people had received six prior treatments for advanced-stage breast cancer, including anti-HER2 medicines, and half had received fewer prior treatments:
- all the people had been previously treated with Herceptin and Kadcyla
- 65.8% had been previously treated with Perjeta (chemical name: pertuzumab)
- 54.3% had been previously treated with other anti-HER2 medicines
- 99.5% had been previously treated with other chemotherapy medicines
Overall, 60.9% of the 184 people responded to Enhertu:
- 11 people (6%) had a complete response, which means there was no evidence of cancer
- 101 people (54.9%) had a partial response, which means the cancer tumors stopped growing or shrunk
Median progression-free survival was 16.4 months. This means that half the people lived longer than 16.4 months without the cancer growing and half the people lived for shorter periods of time without the cancer growing.
The data cut-off point for this analysis was Aug. 1, 2019, but the study is ongoing:
- 79 people continue to be treated with Enhertu
- 105 people stopped treatment with Enhertu; 28.8% stopped treatment because the cancer grew
“Although HER2-directed therapies such as [Herceptin, Perjeta, and Kadcyla] have led to improved outcomes for patients with HER2-positive advanced breast cancer, resistance to these drugs develops almost inevitably and we do not have a clear standard of care for these patients once resistance occurs,” said Ian Krop M.D., associate chief of the division of breast oncology at Dana-Farber Cancer Institute, at a media presentation about the research at the 2019 San Antonio Breast Cancer Symposium. “Thus, there clearly is an unmet medical need for new and improved therapies for such patients.
“The high rate of durable responses observed with trastuzumab deruxtecan in patients whose cancers had progressed on T-DM1 and other therapies suggests this agent could provide a new treatment option for this patient population,” he added.
Enhertu side effects
In the DESTINY-Breast01 study, 99% of the people treated with Enhertu had side effects; 57% had side effects rated grade 3 (severe) or higher.
Overall, the most common side effects caused by Enhertu were:
- hair loss
- low white blood cell counts
The most troubling severe side effect seen was interstitial lung disease, which happened in 25 people.
Interstitial lung disease is a general term for disorders that cause inflammation and scarring in the lungs. The scarring makes lung tissue stiff, which makes it difficult to breathe.
“[Interstitial lung disease] is a serious concern in patients treated with [Enhertu],” said Krop. “While these events were primarily grade 1 or 2, there were unfortunately four grade 5 interstitial lung-related deaths [during] the study. Because of this potential toxicity, close monitoring for signs and symptoms of [interstitial lung disease] is recommended for early detection. If [interstitial lung disease] is suspected, evaluations should include high-resolution CT [scans], pulmonologist consultation, pulmonary function tests, and other tests. Although data on treatment for [Enhertu]-induced [interstitial lung disease] are limited, if diagnosed, interruption of treatment and prompt intervention with glucocorticoids is recommended.”
Overall, side effects led to:
- a break from Enhertu treatment for 65 people
- a reduction in the dose of Enhertu for 43 people
- stopping Enhertu treatment for 28 people
What this means for you
If you’ve been diagnosed with metastatic HER2-positive breast cancer that has grown while being treated with Herceptin and Kadcyla and you and your doctor are considering next treatments, you may want to talk to your doctor about Enhertu.
If you do decide that Enhertu is right for you and your unique situation, it’s important to know that interstitial lung disease can be a severe side effect of the medicine. You should be closely monitored for signs of interstitial lung disease and tell your doctor right away if you experience:
- shortness of breath
- dry cough
Editor’s Note: This article was updated on Jan. 22, 2020, with additional information to clarify how Enhertu works.
On May 4, 2022, the FDA updated Enhertu’s approval so it can now be used to treat unresectable or metastatic HER2-positive breast cancer in people who have previously received an anti-HER2 medicine:
- for metastatic disease
- before or after surgery for early-stage disease that came back (recurred) within six months of completing treatment
Written by: Jamie DePolo, senior editor
Reviewed by: Brian Wojciechowski, M.D., medical adviser
— Last updated on February 22, 2022, 9:58 PM
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