Trastuzumab Deruxtecan Garners Approval in Japan for HER2-Low Metastatic Breast Cancer

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Japan’s Ministry of Health, Labor and Welfare (MHLW) has approved fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of adult patients with HER2-low unresectable or recurrent breast cancer after prior chemotherapy.¹

The indication is for patients with HER2-low disease defined as immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization.

The regulatory decision was supported by data from the phase 3 DESTINY-Breast04 trial (NCT03734029), which showed that the antibody-drug conjugate (ADC) reduced the risk of progression or death by 50% compared with physician’s choice of chemotherapy in patients with hormone receptor–positive or –negative, HER2-low metastatic breast cancer (HR, 0.50; 95% CI, 0.40-0.63; P < .0001).

Patients treated with trastuzumab deruxtecan experienced a median progression-free survival (PFS) of 9.9 months (95% CI, 9.0-11.3) compared with 5.1 months (95% CI, 4.2-6.8) for those given chemotherapy. Additionally, the ADC reduced the risk of death by 36% compared with chemotherapy (HR, 0.64; 95% CI, 0.49-0.84; P = .001)

“For the first time, certain patients in Japan whose tumors have a low HER2 expression have a treatment option available targeted specifically for them,” Wataru Takasaki, PhD, executive officer and head of R&D Division in Japan, Daiichi Sankyo, stated in a news release. “This is the third indication approved within three years in Japan for [trastuzumab deruxtecan] for patients with breast cancer and this medicine has the potential to become standard of care for patients with low HER2 expression.”

In November 2022, the MHLW approved trastuzumab deruxtecan for the treatment of adult patients with HER2-positive unresectable or recurrent breast cancer after prior chemotherapy, which includes trastuzumab (Herceptin) and a taxane.2 In March 2020, the ADC received approval from the MHLW for the treatment of patients with HER2-positive unresectable or recurrent breast cancer who have had prior chemotherapy and are refractory or intolerant to standard treatments.³

In August 2022, the FDA approved trastuzumab deruxtecan for the treatment of patients with unresectable or metastatic HER2-low breast cancer, which was also supported by findings from DESTINY-Breast04.⁴

The global, randomized, open-label, pivotal phase 3 trial evaluated the efficacy and safety of trastuzumab deruxtecan vs physician’s choice of chemotherapy in patients with hormone receptor–positive or –negative, HER2-low unresectable and/or metastatic breast cancer previously treated with 1 to 2 lines of chemotherapy.1

Patients were randomly assigned in a 2:1 fashion to receive 5.4 mg/kg of trastuzumab deruxtecan every 3 weeks or physician’s choice of chemotherapy, which could consist of capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel (Abraxane).

The study’s primary end point was PFS per blinded independent central review (BICR) in patients with hormone receptor–positive disease. Secondary end points included PFS per BICR in all treated patients, overall survival (OS) in hormone receptor–positive patients, OS in the overall population, investigator-assessed PFS, objective response rate, duration of response, and safety.

Regarding safety, findings from DESTINY-Breast04 were consistent with previous clinical trials, and no new safety signals were reported. Notably, 96.2% of all patients treated with trastuzumab deruxtecan experienced any-grade adverse effects. The most common included nausea (73.0%), fatigue (47.7%), alopecia (37.7%), vomiting (34.0%), anemia (33.2%), and decreased neutrophil count (33.2%).

Japan’s approval for trastuzumab deruxtecan includes a warning for interstitial lung disease (ILD). In DESTINY-Breast04, 26.8% of patients from Japan experienced ILD. The ADC should be administered in close collaboration with a respiratory disease expert, and patients should be observed closely during therapy to monitor for early signs or symptoms of ILD, including dyspnea, cough, or fever.

References

1. Enhertu® approved in Japan as the first HER2 directed therapy for patients with HER2 low metastatic breast cancer. News release. Daiichi Sankyo. March 27, 2023. Accessed March 27, 2023. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202303/20230327_E.pdf
2. Enhertu® approved in Japan for patients with previously treated HER2 positive metastatic breast cancer. News release. Daiichi Sankyo. November 24, 2022. Accessed March 27, 2023. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202211/20221124_E.pdf
3. Enhertu® approved in Japan for treatment of patients with HER2 positive unresectable or metastatic breast cancer. News release. Daiichi Sankyo. March 25, 2020. Accessed March 27, 2023. https://www.daiichisankyo.com/media/press_release/detail/index_3154.html

• FDA approves first targeted therapy for HER2-low breast cancer. News release. FDA. August 5, 2022. Accessed March 27, 2023. https://www.fda.gov/news-events/press-announcements/