January 20, 2021 - The antibody-drug conjugate trastuzumab deruxtecan has been granted conditional approval in the European Union for use as a single agent in the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received 2 or more HER2-based regimens.
The antibody-drug conjugate (ADC) trastuzumab deruxtecan (Enhertu) has been granted conditional approval in the European Union for use as a single agent in the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received 2 or more HER2-based regimens.1,2
The regulatory decision follows the recommendation for approval issued by the European Medicines Agency’s Committee for Medicinal Products for Human Use.
The approval was based on data from the phase 2 DESTINY-Breast01 trial (NCT03248492), in which the ADC demonstrated clinically meaningful and durable anticancer activity in patients with HER2-positive metastatic breast cancer who had received 2 or more prior HER2-based treatments.3
At a median follow-up of 20.5 months, the ADC elicited a confirmed objective response rate (ORR) of 61.4% (95% CI, 54.0%-68.5%); this comprised a complete response rate of 6.5%, a partial response rate of 54.9%, and a stable disease rate of 35.9%. Moreover, 1.9% of patients experienced disease progression. The median duration of response (DOR) with trastuzumab deruxtecan was 20.8 months in this population.
“One in five women with breast cancer have HER2-positive disease and those with previously treated metastatic disease often progress quickly,” Fabrice André, MD, PhD, head of research in the Department of Medical Oncology of Gustave Roussy Cancer Campus, stated in a press release. “One of the biggest challenges in this setting has been identifying treatments that produce a durable response. The DESTINY-Breast01 trial showed a breadth, depth and durability of response not previously seen in this patient population.”
The open-label, international, multicenter, phase 2 DESTINY-Breast01 trial enrolled a total of 184 heavily pretreated patients with HER2-positive breast cancer; these patients had received ado-trastuzumab emtansine (T-DM1; Kadcyla) and other HER2-targeted agents. In part 1 of the trial, investigators evaluated the pharmacokinetics of the agent in 65 patients and set out to identify the recommended phase 2 dose (RP2D; n = 25). The RP2D of the ADC was determined to be 5.4 mg/kg.
The primary end point of the trial was ORR per independent central review, while secondary end points comprised disease control rate, DOR, and progression-free survival (PFS). To be eligible for enrollment, patients had to be at least 18 years of age, have unresectable and/or metastatic breast cancer, HER2 positivity, and have previously received T-DM1. Those who had a history of significant interstitial lung disease were not included. However, those with stable, treated brain metastases were permitted.
All participants were female, and the median age was 55 years; 55% were white and 38% were Asian. Fifty-three percent of patients had hormone receptor–positive disease, while 45% were HR negative. The median number of previous treatment regimens received at baseline was 6 (range, 2-27); these treatments included trastuzumab (Herceptin; 100%), T-DM1 (100%), pertuzumab (Perjeta; 65.8%), other HER2-targeted antibodies or ADCs (6.0%), other HER2-targeted TKIs (50.5%), hormonal treatment (48.9%), and other previous systemic therapy (99.5%).
At a median follow-up of 20.5 months, 20.1% of patients were still on treatment. Just under half, or 43.4% of patients were on treatment for longer than 1 year and 6.0% continued on the ADC for over 2 years. With increased maturity of the data DORs increased, 65.2% of participants were censored.
Additional data presented during the 2020 San Antonio Breast Cancer Symposium showed that the estimated 12-month OS rate with trastuzumab deruxtecan was 85% (95% CI, 79%-90%); the estimated OS rate at 18 months was 74% (95% CI, 67%-80%). Moreover, the median PFS was 19.4 months (95% CI, 14.1–not estimable [NE]) with the ADC. Although still immature, the preliminary median OS with the agent was 24.6 months (95% CI, 23.1-NE).
A pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who were given at least 1 dose of the ADC at 5.4 mg/kg in trials showed that the most frequently reported toxicities included nausea (79.9%), fatigue (60.3%), vomiting (48.7%), alopecia (46.2%), constipation (35.9%), reduced appetite (34.6%), anemia (33.8%), neutropenia (32.5%), diarrhea (30.8%), thrombocytopenia (23.1%), cough (21.4%), leukopenia (20.5%), and headache (20.1%).
“This expedited review underscores the practice-changing potential of [trastuzumab deruxtecan] for patients in the metastatic setting,” Gilles Gallant, BPharm, PhD, FOPQ, senior vice president and global head of Oncology Development, Oncology R&D, of Daiichi Sankyo, stated in a press release. “[Trastuzumab deruxtecan] is the first-ever new medicine to be approved for 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.”
In December 2019, the FDA approved trastuzumab-deruxtecan for use in adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more previous anti–HER2-based regimens in the metastatic setting. The decision was based on earlier data from DESTINY-Breast01.