The European Commission has conditionally approved Enhertu (trastuzumab deruxtecan) for adults in the EU with inoperable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens.
A conditional approval is granted when the benefits of a medication regulators say still requires additional data or testing are found to outweigh its potential risks. Such approval is given for therapies whose immediate availability fulfills an unmet medical need, as in the case of advanced HER2-positive breast cancer.
Enhertu’s full approval in the European Union will depend on further verification of its clinical benefits in the confirmatory Phase 3 study DESTINY-Breast02 (NCT03523585). That ongoing trial is comparing Enhertu to standard treatment in about 600 adults. The study is fully enrolled, with primary completion expected in February 2022.
The decision comes six months after the European Medicines Agency (EMA) validated and granted accelerated assessment to Enhertu’s marketing authorization application. Moreover, it follows one month after the EMA’s Committee for Medicinal Products for Human Use recommended its conditional approval.
“This expedited review underscores the practice-changing potential of Enhertu for patients in the metastatic setting,” Gilles Gallant, PhD, senior vice president and global head of oncology research & development at Daiichi Sankyo, said in a press release.
“Enhertu is the first-ever new medicine to be approved in breast cancer in Europe on the basis of Phase 2 single-arm data, and one of the fastest accelerated assessment procedures for an application in oncology,” Gallant added.
Health authorities in each EU member state will now decide whether to bring Enhertu into their respective public health programs. In such programs, patients can access the treatment at low or no cost.
The conditional approval, which earned Daiichi Sankyo $75 million from AstraZeneca as milestone payment, follows similar rulings in the U.S. and Japan last year.
The therapy “is already transforming outcomes for patients with HER2-positive metastatic breast cancer in the U.S. and Japan, and this approval enables us to bring the benefits of this medicine to patients in the EU,” said Dave Fredrickson, executive vice president of AstraZeneca’s oncology business unit.
Formerly known as DS-8201, Enhertu is an antibody-drug conjugate made up of trastuzumab, an antibody against HER2, bound to the cancer-killing agent deruxtecan, a derivative of exatecan. HER2 is a protein found on the surface of one in five breast cancers and linked to aggressive disease.
As such, the therapy works by delivering deruxtecan directly to HER2-positive cancer cells, improving specificity and reducing off-target effects when compared with conventional chemotherapy.
The conditional approval was based on positive data from the first 184 women with HER2-positive metastatic breast cancer treated with Enhertu (5.4 mg/kg) in the DESTINY-Breast01 Phase 2 clinical trial (NCT03248492).
The international, open-label, single-arm study included adults who had been previously treated with at least two prior HER2 therapy regimens, including the antibody-drug conjugate Kadcycla (ado-trastuzumab emtansine).
Data presented at the 2020 San Antonio Breast Cancer Symposium showed that 61.4% of these women had responded to Enhertu after a median follow-up of 20.5 months (over 1.5 years). Complete responses — meaning cancer elimination — were achieved by 6.5% of participants, while partial responses, or significant tumor shrinkage, were observed in 54.9%.
Treatment responses lasted a median of 20.8 months and women lived without signs of disease progression — called progression-free survival — for a median of 19.4 months. An exploratory analysis also showed that 74% of patients were estimated to be alive at 1.5 years.
These findings are in line with previously reported 11-month data showing a response rate of 60.9%, median response duration of 14.8 months, and a median progression-free survival of 16.4 months.
“The DESTINY-Breast01 trial showed a breadth, depth and durability of response not previously seen in this patient population,” said Fabrice André, MD, PhD, head of research for the department of medical oncology at Gustave Roussy Cancer Campus, in France.
In addition, a pooled safety analysis of 234 patients who received at least one dose of Enhertu in DESTINY-Breast01 and in a prior Phase 1 trial (NCT02564900) indicated that the therapy was generally well-tolerated.
The most common adverse events included nausea, fatigue, vomiting, hair loss, constipation, decreased appetite, anemia, low white blood cell count, diarrhea, low platelet count, cough, and headache.
Lung tissue scarring — called interstitial lung disease, or ILD — or inflammation known as pneumonitis were reported in 15% of patients; 2.6% of them died from ILD.
“We will continue to explore the potential of Enhertu in this setting, as well as in earlier lines of treatment and stages of disease, with the ambition of improving the lives of patients with HER2-targetable breast cancer,” Fredrickson said.
Besides the confirmatory DESTINY-Breast02 trial, Enhertu is being evaluated in other Phase 3 trials.
It’s being tested as a second-line therapy in the DESTINY-Breast03 study (NCT03529110), and for the treatment of HER2-low breast cancer in the DESTINY-Breast04 study (NCT03734029). In the DESTINY-Breast05 study (NCT04622319), it’s being assessed as an add-on treatment for patients with high-risk HER2-positive early breast cancer.
Additional ongoing trials are testing the therapy in combination with other anti-cancer medicines in HER2-positive and HER2-low metastatic breast cancer.