The European Medicines Agency’s Committee for Medicinal Products for Human Use recommended the approval of trastuzumab deruxtecan monotherapy for patients with metastatic HER2-positive breast cancer who have received at least 1 prior anti–HER2-based regimen.
Gilles Gallant, BPharm, PhD, FOPQ
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of fam-trastuzumab deruxtecan-nxki (Enhertu) monotherapy for patients with metastatic HER2-positive breast cancer who have received at least 1 prior anti–HER2-based regimen.1
The recommendation was based on results from the pivotal phase 3 DESTINY-Breast03 trial (NCT03529110), where trastuzumab deruxtecan demonstrated a significant improvement in progression-free survival (PFS) compared with trastuzumab emtansine (Kadcyla; T-DM1). At a median follow-up of 16.2 months (range, 0-32.7) in the investigative arm vs 15.3 months (range, 0-31.3) in the control arm, the median PFS was not yet reached (95% CI, 18.5–not estimable [NE]) in the investigative arm vs 6.8 months (95% CI, 5.6-8.2) in the control arm (HR, 0.28; 95% CI, 0.22-0.37; P < .0001).2
“[The] CHMP opinion provides further validation of the significance of the DESTINY-Breast03 trial results, which for the first time showed superiority of trastuzumab deruxtecan in prolonging PFS in patients previously treated for HER2-positive, metastatic breast cancer as compared to another HER2-directed antibody-drug conjugate [ADC],” Gilles Gallant, BPharm, PhD, FOPQ, the senior vice president and global head, of Oncology Development and Oncology Research and Development at Daiichi Sankyo, stated in a press release. “This positive CHMP opinion is an important step forward in bringing this potentially practice-changing medicine to patients in Europe to use earlier in the treatment of HER2-positive metastatic breast cancer and builds on the recent approval of trastuzumab deruxtecan in the United States.”
In May 2022, the FDA granted regular approval for trastuzumab deruxtecan in 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 6 months of therapy completion.3 That approval also stemmed from results from DESTINY-Breast03.
The multicenter, open-label DESTINY-Breast03 trial enrolled patients with HER2-positive, unresectable or metastatic breast cancer who had progressed during or following treatment with trastuzumab (Herceptin) and a taxane in the advanced or metastatic setting or patients who progressed within 6 months of neoadjuvant/adjuvant treatment with trastuzumab and a taxane.
Patients who had clinically stable, previously treated brain metastases were allowed to enroll. Key exclusion criteria included brain metastases that were symptomatic or required treatment; prior treatment with a HER2-targeted ADC, including T-DM1, for metastatic disease; or a history of noninfectious interstitial lung disease (ILD) treated with glucocorticoids.
The trial enrolled 524 patients who were randomly assigned to 5.4 mg/kg of intravenous (IV) trastuzumab deruxtecan (n = 261) or 3.6 mg/kg of IV T-DM1 (n = 263) every 3 weeks. Treatment continued until disease progression or intolerable toxicity.
The primary end point of the trial was PFS per blinded independent central review (BICR). Secondary end points included overall survival (OS) per BICR and investigator assessment, investigator-assessed PFS, and safety.
Notably, 49.8% and 46.8% of patients in the investigative arm and control arm, respectively, received 1 prior line of treatment for metastatic disease, not including endocrine therapy. Additionally, 62.1% and 60.1% of patients in the experimental arm and control arm, respectively, received prior pertuzumab. The rates of stable brain metastases were 23.8% and 19.8% in the trastuzumab deruxtecan and T-DM1 groups, respectively. Overall, demographic and baseline disease characteristics were comparable between the 2 treatment arms.
Additional data showed that the investigator-assessed median PFS was 25.1 months (95% CI, 22.1-NE) in the trastuzumab deruxtecan arm vs 7.2 months (95% CI, 6.8-8.3) in the control arm (HR, 0.26; 95% CI, 0.20-0.35; P <.001). At 12 months, 75.8% (95% CI, 69.8%-80.7%) of patients in the trastuzumab deruxtecan arm were still alive and free of disease progression compared with 34.1% (95% CI, 27.7%-40.5%) in the T-DM1 arm.
At the May 21, 2021, data cutoff, the 12-month OS rates were 94.1% (95% CI, 90.3%-96.4%) and 85.9% (95% CI, 80.9%-89.7%) in the investigative arm and the control arm, respectively (HR, 0.55; 95% CI, 0.36-0.86; P =.007).
The most common adverse effects (AEs) of any grade in the trastuzumab deruxtecan arm were nausea, fatigue, vomiting, alopecia, constipation, anemia, and musculoskeletal pain. Serious effects that were reported in more than 1% of patients who received trastuzumab deruxtecan included vomiting, ILD, pneumonia, pyrexia, and urinary tract infection.
“This recommendation reflects the transformative progression-free survival benefit seen in the DESTINY-Breast03 trial compared to T-DM1, supporting trastuzumab deruxtecan as a potential new standard of care and setting a new benchmark in the treatment of HER2-positive metastatic breast cancer,” Susan Galbraith, MBBChir, PhD, executive vice President of Oncology Research and Development at AstraZeneca, stated in a press release. “If approved by the European Commission, patients in Europe may be able to benefit from this important medicine earlier in the treatment of their disease, improving their chance for better outcomes.”