Based on data from the DESTINY-Breast04 trial, the FDA has granted a priority review designation for the supplemental biologics license application for fam-trastuzumab deruxtecan-nxki.
Based on data from the DESTINY-Breast04 trial (NCT03734029), the FDA has granted a priority review designation for the supplemental biologics license application for fam-trastuzumab deruxtecan-nxki (Enhertu). The agency is expected to decide on the submission for the treatment of adult patients with unresectable or metastatic HER2-low breast cancer who have received 1 prior therapy in the metastatic setting in the fourth quarter of 2022.1
HER2-low status is defined as disease classified as immunohistochemistry [IHC] 1+ or IHC 2+ and in-situ hybridization [ISH]–negative. Investigators hypothesized that by targeting a lower range of HER2 expression, treatments could delay disease progression in patients with metastatic disease.2
DESTINY-Breast04, a randomized, open-label pivotal trial, randomly assigned patients to receive the antibody-drug conjugate at 5.4 mg/kg every 3 weeks (n = 373) or physician’s choice chemotherapy physician’s choice of chemotherapy at locally approved dosing (n = 184). The treatment options included capecitabine (Xeloda), eribulin, gemcitabine, paclitaxel, or nab-paclitaxel (Abraxane).3,4
The primary end point was progression-free survival (PFS) in patients with hormone receptor–positive disease. The median PFS in the primary end point population was 10.1 months (95% CI, 9.5-11.5) with trastuzumab deruxtecan vs 5.4 months (95% CI, 4.4-7.1) with standard of care in patients with hormone receptor–positive, HER2-low metastatic breast cancer (HR, 0.51; 95% CI, 0.40-0.64; P < .0001). The median overall survival (OS) was 23.9 months (95% CI, 20.8-24.8) vs 17.5 months (95% CI, 15.2-22.4), respectively (HR, 0.64; 95% CI, 0.48-0.86; P = .003).3,4
“The data from DESTINY-Breast04 represent the first time a HER2-targeted therapy has shown a survival benefit in patients with HER2-low metastatic breast cancer,” Susan Galbraith, MBBChir, PhD, said in a news release.1 “For more than 2 decades, only patients with HER2-positive breast cancer have been able to benefit from HER2-targeted therapies. If approved, [trastuzumab deruxtecan] will redefine how we classify and treat metastatic breast cancer, enabling patients whose tumors have lower levels of HER2 expression the opportunity to benefit from a HER2-directed therapy.” Galbraith is the executive vice president, oncology research and development at AstraZeneca.
Among all randomized patients the risk of disease progression or death was reduced by 50% with trastuzumab deruxtecan (HR, 0.50; 95% CI, 0.40-0.63). Specifically, the median PFS was 9.9 months (95% CI, 9.0-11.3) vs 5.1 months (95% CI, 4.2-6.8) with chemotherapy, and the median OS was 23.4 months (95% CI, 20.0-24.8) vs 16.8 months (95% CI, 14.5-20.0), respectively (HR, 0.64; 95% CI, 0.49-0.84; P = .001).3,4
The benefit extended to patients with hormone receptor–negative disease. The median PFS was 8.5 months (95% CI, 4.3-11.7) with trastuzumab deruxtecan vs 2.9 months (95% CI, 1.4-5.1) with chemotherapy (HR, 0.46; 95% CI, 0.24-0.89). The median OS in this population was 18.2 months (95% CI, 13.6–not estimable) vs 8.3 months (95% CI, 5.6-20.6), respectively (HR, 0.48; 95% CI, 0.24-0.95).
“The results seen in the DESTINY-Breast04 trial represent a significant advance and reinforce the potential for trastuzumab deruxtecan to become a new standard of care for patients with previously treated HER2-low metastatic breast cancer,” Ken Takeshita, MD, global head of research and development at Daiichi Sankyo, said in a news release.1 He added that the priority review designation highlights the importance of these data. “We look forward to working with the FDA to potentially bring [trastuzumab deruxtecan] to patients with HER2-low metastatic breast cancer as quickly as possible.”
The most common all-grade treatment-related adverse effects for trastuzumab deruxtecan vs chemotherapy were nausea (73% vs 23.8%, respectively), fatigue (47.7% vs 42.4%), vomiting (34% vs 9.9%), neutropenia (33.2% vs 51.2%), and anemia (33.2% vs 22.7%).
In terms of interstitial lung disease, 12.1% of patients (n = 45) experienced an event—5 patients had a grade 3 event, and 3 patients had a grade 5 event. Further, 14 drug-related deaths occurred with trastuzumab deruxtecan (3.8%) vs 5 for physician’s choice of therapy (2.9%).