Japan’s Ministry of Health, Labor, and Welfare has approved trastuzumab deruxtecan for the treatment of adult patients with HER2-positive unresectable or recurrent breast cancer after prior chemotherapy, which includes trastuzumab and a taxane.
Wataru Takasaki, PhD
Japan’s Ministry of Health, Labor, and Welfare (MHLW) has approved fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of adult patients with HER2-positive unresectable or recurrent breast cancer after prior chemotherapy, which includes trastuzumab (Herceptin) and a taxane.1
The approval was based on data from the phase 3 DESTINY-Breast03 trial (NCT03529110), where trastuzumab deruxtecan reduced the risk of disease progression or death by 72% compared with ado-trastuzumab emtansine (T-DM1; Kadcyla; HR, 0.28; 95% CI, 0.22-0.37; P < .000001). The median progression-free survival (PFS) for patients treated with trastuzumab deruxtecan was not reached (95% CI, 18.5-not estimable) vs 6.8 months for T-DM1 (95% CI, 5.6-8.2).
“We are proud of the quality and speed in which we were able to deliver a confirmatory phase 3 trial that demonstrated the superiority of [trastuzumab deruxtecan] in prolonging PFS compared to T-DM1 in patients with previously treated HER2 positive metastatic breast cancer,” Wataru Takasaki, PhD, executive officer, head of R&D Division in Japan, Daiichi Sankyo, stated in a press release. “This approval by the MHLW highlights the importance of the conditional approval system in Japan that allows for early approval of medicines to treat serious conditions such as breast cancer.”
In March 2020, Japan approved trastuzumab deruxtecan for the treatment of patients with HER2-positive unresectable or recurrent breast cancer after prior chemotherapy, limiting its use to patients who are refractory or intolerant to standard treatments.2 That approval was based on findings from the phase 2 DESTINY-Breast01 trial (NCT03248492).
In May 2022, the FDA granted regular approval to the antibody-drug conjugate (ADC) for 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
The regular approval from the FDA was based on data from DESTINY-Breast03, which also supported the European approval of trastuzumab deruxtecan in adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received at least 1 anti–HER2-based regimen.4
The multicenter, open-label, DESTINY-Breast03 trial enrolled patients with HER2-positive, unresectable or metastatic breast cancer that had progressed during or following treatment with trastuzumab and a taxane in the context of advanced or metastatic disease or that had progressed within 6 months following neoadjuvant or adjuvant treatment involving trastuzumab or a taxane.5 Patients with clinically stable, previously treated brain metastases were allowed to enroll.
Key exclusion trial included brain metastases that were symptomatic or required treatment; prior treatment with a HER2-targeted ADC, including trastuzumab emtansine, for metastatic disease; or a history of noninfectious interstitial lung disease (ILD) that required glucocorticoids.
A total of 524 study participants were randomly assigned 1:1 to receive intravenous (IV) trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks (n = 261) or IV T-DM1 at 3.6 mg/kg every 3 weeks (n = 263). Treatment continued until disease progression or intolerable toxicity.
The primary end point of the trial was PFS per blinded independent central review (BICR). Overall survival (OS) served as a key secondary end point, and other end points included overall response per BICR and investigator assessment, investigator-assessed PFS, and safety.
Demographic and baseline disease characteristics were found to be comparable between the 2 treatment arms and were also determined to be largely representative of the overall population of patients with HER2-positive breast cancer.
Regarding safety, the most common adverse effects (AEs) among patients in the trastuzumab deruxtecan arm included nausea, fatigue, vomiting, alopecia, constipation, anemia, and musculoskeletal pain. Serious AEs that were reported in more than 1% of patients included vomiting, ILD, pneumonia, pyrexia, and urinary tract infection.