FDA Grants Priority Review to T-DXd for Advanced HER2-Low Metastatic Breast Cancer

Trastuzumab deruxtecan was granted priority review by the FDA for patients with unresectable advanced or metastatic HER2-low breast cancer.

The FDA has granted priority review to trastuzumab deruxtecan (T-DXd; Enhertu) for patients with unresectable advanced or metastatic HER2-low breast cancer, according to a press release from AstraZeneca.1

T-DXd was assessed as part of the phase 3 DESTINY-Breast04 trial (NCT03734029) vs investigator choice chemotherapy for patients with HER2-low breast cancer. Priority review was granted under the Real-Time Oncology Review program and Project Orbis, designed to bring forward treatments as soon as possible in a safe and effective way.

The Prescription Drug User Fee Act date has been set for the fourth quarter of 2022.

“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. For more than 2 decades, only patients with HER2-positive breast cancer have been able to benefit from HER2-targeted therapies. If approved, [T-DXd] 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,” Susan Galbraith, executive vice president of Oncology Research and Development at AstraZeneca, said in the press release.

Results from the trial were presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting and subsequently published in the New England Journal of Medicine.2,3 A total of 557 patients enrolled on the trial and received either 5.4 mg/kg of T-DXd every 3 weeks (n = 373) or investigator choice chemotherapy (n = 184).

Patients were determined to be HER2-low if they had an immunohistochemistry score of 1+ or 2+ with a negative in situ hybridization test. In the trial, 88.7% of patients were hormone receptor positive and 11.3% were negative.

Overall, the median progression-free survival (PFS) was 9.9 months (95% CI, 9.0-11.3) in the T-DXd arm and 5.1 months (95% CI, 4.2-6.8) in the chemotherapy arm (HR, 0.50; 95% CI, 0.40-0.63; P <.001). The median PFS for those who were HER2-low was 10.1 months (95% CI, 9.5-11.5) in the T-DXd arm and 5.4 months (95% CI, 4.4-7.1) in the chemotherapy arm (HR, 0.51; 95% CI, 0.40-0.64; P <.0001). For those who were hormone receptor-negative, the median PFS was 8.5 months (95% CI, 4.3-11.7) and 2.9 months (95% CI, 1.4-5.1), between both arms, respectively (HR, 0.46; 95% CI, 0.24-0.89). Of those who were hormone receptor positive and received prior anti CDK4/6 therapies, the median PFS was 10.0 months (95% CI, 8.3-11.4) in the T-DXd arm and 5.4 months (95% CI, 4.0-7.8) in the chemotherapy arm (HR, 0.55; 95% CI, 0.42-0.73).

The overall survival (OS) in the overall population was 23.4 months (95% CI, 20.0-24.8) in the T-DXd group and 16.8 months (95% CI, 14.5-20.0) in the chemotherapy group (HR, 0.64; 95% CI, 0.49-0.84; P = .001). For those who were hormone receptor positive, the median OS was 23.9 months (95% CI, 20.8-24.8) in the T-DXd arm and 17.5 months (95% CI, 15.2-22.4) in the chemotherapy arm (HR, 0.64; 95% CI, 0.40-0.86; P = .003). Of those who were hormone receptor negative, the median OS was 18.2 months (95% CI, 13.6–not estimable) in the T-DXd arm and 8.3 months (95% CI, 5.6-20.6) in the chemotherapy arm (HR, 0.48; 95% CI, 0.24-0.95).

The median treatment duration was 8.2 months in the T-DXd arm and 3.5 months in the chemotherapy arm. Treatment discontinuation because of adverse effects (AEs) occurred in 16.2% of patients vs 8.1%, and dose reductions occurred in 22.6% vs 38.4% in the T-DXd and chemotherapy arms, respectively.

Treatment-emergent AEs (TRAEs) occurred in 99.5% of patients in the T-DXd arm and 98.3% in the investigator choice arm, while serious AEs occurred in 27.8% vs 25.0% of patients, respectively. The most frequent any-grade TRAEs in the T-DXd and chemotherapy arms, respectively, were nausea (73.0% vs 23.8%), fatigue (47.7% vs 42.4%), alopecia (37.7% vs 32.6%), vomiting (34.0% vs 9.9%), neutropenia (33.2% vs 51.2%), and anemia (33.2% vs 22.7%).

Fourteen patients in the T-DXd arm vs 5 in the chemotherapy arm experienced AEs that were associated with death. Grade 3 interstitial lung disease or pneumonitis occurred in 5 patients in the T-DXd arm, and 3 patients had grade 5 disease.

References

  1. Enhertu granted priority review in the US for patients with HER2-low metastatic breast cancer. News Release. AstraZeneca. July 25, 2022. Accessed July 25, 2022. https://bit.ly/3OwoKw3
  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):LBA3. doi:10.1200/JCO.2022.40.17_suppl.LBA3

Modi S, Jacot W, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690