Japanese Regulatory Approval Sought for Trastuzumab Deruxtecan in HER2-Low Metastatic Breast Cancer

A supplemental New Drug Application (sNDA) has been submitted to Japan’s Ministry of Health, Labour, and Welfare seeking approval for use of fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of adult patients with HER2-low unresectable or recurrent metastatic breast cancer following chemotherapy.¹

The sNDA is based on findings from the phase 3 DESTINY-Breast04 trial (NCT03734029), which showed that trastuzumab deruxtecan doubled progression-free survival (PFS) and reduced the risk of death by 36% compared with physician's choice of chemotherapy for patients with HER2-low, hormone receptor–positive metastatic breast cancer.²

Breast cancer is the most common cancer in Japanese women, and approximately half of all patients have tumors with a HER2 immunohistochemistry (IHC) score of 1+, or a HER2 IHC score of 2+ in combination with a negative in-situ hybridization (ISH) test. These patients are not eligible for HER2-targed therapy.

“The positive DESTINY-Breast04 results represent the first time ever that a HER2-directed therapy has demonstrated a survival benefit in patients with HER2-low metastatic breast cancer, offering the potential to redefine how we classify and treat approximately half of all metastatic breast cancers,” Wataru Takasaki, PhD, executive officer, head of the Research and Development Division at Daiichi Sankyo in Japan, said in a news release.

In the trial, investigators randomly assigned 557 patients 2:1 to trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks (n = 373) or physician’s choice of chemotherapy at locally approved dosing (n = 184). Chemotherapy consisted of capecitabine (Xeloda; 20.1%), eribulin (Halaven; 51.1%), gemcitabine (10.3%), paclitaxel (8.2%), or nab-paclitaxel (Abraxane; 10.3%).^2,3

Low expression of HER2 was defined as an IHC score of 1+ or 2+ with a negative in situ hybridization (ISH) test. Overall, 88.7% of patients were hormone receptor–positive and 11.3% were negative.

In findings presented at the 2022 ASCO Annual Meeting and simultaneously published in the New England Journal of Medicine, trastuzumab deruxtecan elicited a median PFS of 10.1 months (95% CI, 9.5-11.5) compared with 5.4 months (95% CI, 4.4-7.1) for chemotherapy (HR, 0.51; 95% CI, 0.40-0.64; P < .0001) in patients with hormone receptor–positive, HER2-low metastatic breast cancer. The median overall survival (OS) was 23.9 months (95% CI, 20.8-24.8) in the experimental arm compared with 17.5 months (95% CI, 15.2-22.4) for chemotherapy (HR, 0.64; 95% CI, 0.40-0.86; P = .003).

Across all patients enrolled in the study, including those with hormone receptor–negative disease, the median PFS was 9.9 months (95% CI, 9.0-11.3) with trastuzumab deruxtecan, compared with 5.1 months (95% CI, 4.2-6.8) with chemotherapy (HR, 0.50; 95% CI, 0.40-0.63). The median OS was 23.4 months (95% CI, 20.0-24.8) with trastuzumab deruxtecan vs 16.8 months (95% CI, 14.5-20.0) for chemotherapy, representing a 6.6-month improvement in survival with the antibody-drug conjugate (ADC; HR, 0.64; 95% CI, 0.49-0.84; P = .001).

In those with hormone receptor–negative disease, the median PFS was 8.5 months (95% CI, 4.3-11.7) with trastuzumab deruxtecan and 2.9 months (95% CI, 1.4-5.1) for chemotherapy (HR, 0.46; 95% CI, 0.24-0.89). The median OS in the hormone receptor–negative cohort was 18.2 months (95% CI, 13.6–not estimable) with trastuzumab deruxtecan vs 8.3 months (95% CI, 5.6-20.6) with chemotherapy (HR, 0.48; 95% CI, 0.24-0.95).

Furthermore, investigators observed fewer grade 3 or greater adverse effects (AEs) were reported with the ADC (52.6%) compared with chemotherapy (67.4%).

In December 2019, the FDA granted an accelerated approval to trastuzumab deruxtecan for adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting. This accelerated approval received full regulatory approval in May 2022.⁴

The prescribing information includes a box warning on the risk of interstitial lung disease. In DESTINY-Breast04, ILD occurred in 45 (12.1%) patients in the trastuzumab deruxtecan arm, including 5 patients with a grade 3 event and 3 with a grade 5 event.

References

1. Trastuzumab deruxtecan supplemental new drug application submitted in Japan for patients with HER2 low metastatic breast cancer. Daiichi Sankyo. News release. June 27, 2022. Accessed June 27, 2022. https://bit.ly/3NnHflY
2. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): results of DESTINY-Breast04, a randomized, phase 3 study. J Clin Oncol. 2022;40 (suppl 17):abstr LBA3. doi:10.1200/JCO.2022.40.17_suppl.LBA3
3. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. Published online June 5, 2022. doi:10.1056/NEJMoa2203690
4. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. News release. FDA. May 4, 2022. Accessed June 27, 2022. https://bit.ly/3ybhZLL