European Commission Recommends Trastuzumab Deruxtecan for HER2-Low Metastatic Breast Cancer

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for the use of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) monotherapy for adults with unresectable or metastatic HER2-low breast cancer who have received prior chemotherapy in the metastatic setting or who developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.¹

“Enhertu is the first ever HER2-directed medicine to show a survival benefit in patients with HER2 low metastatic breast cancer, confirming the importance of targeting lower levels of HER2 expression in patients previously classified as HER2 negative,” Susan Galbraith, MBBCh, PhD, executive vice president of Oncology R&D with AstraZeneca said in a news release. “The CHMP’s recommendation is encouraging and supports our ambition to evolve the way breast cancer is classified and treated to ultimately improve patient outcomes.”

The FDA approved T-DXd for this population in August 2022 based on results from the phase 3 DESTINY-Breast04 trial (NCT03734029).² The CHMP’s recommendation is also based on those findings. Results presented at the 2022 ASCO Annual Meeting and subsequently published in the New England Journal of Medicine showed that T-DXd induced a statistically significant and clinically meaningful improvement in overall survival (OS) vs chemotherapy.^3,4

A total of 557 patients were enrolled to the trial and received either 5.4 mg/kg of T-DXd every 3 weeks (n = 373) or investigator’s choice of chemotherapy (n = 184). HER2-low was defined as those with an immunohistochemistry score of 1+ or 2+ and a negative result via in situ hybridization. Additionally, 88.7% of patients were hormone receptor positive and 11.3% were negative.

Median progression-free survival (PFS) in the overall cohort was 9.9 months (95% CI, 9.0-11.3) with T-DXd and 5.1 months (95% CI, 4.2-6.8) with chemotherapy (HR, 0.50; 95% CI, 0.40-0.63; P <.001). For patients with hormone receptor–positive disease, the median PFS 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 <.001).

For patients with hormone receptor–negative disease, the median PFS was 8.5 months (95% CI, 4.3-11.7) in the T-DXd arm and 2.9 months (95% CI, 1.4-5.1) in the chemotherapy arm (HR, 0.46; 95% CI, 0.24-0.89). Patients who received prior CDK4/6 inhibitor therapy and were hormone receptor positive had a median PFS of 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).

In the overall population, median OS 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). Patients who were hormone receptor positive had a median OS of 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). Additionally, those who were hormone receptor negative had a median OS of 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).

Updated data presented during the ESMO Congress 2022 further showed that T-DXd provides a quality of life (QOL) benefit for patients with hormone receptor–positive, HER2-low metastatic disease.⁵ Using the EORTC QLQ-C30 assessment, the time to definitive deterioration (TDD) in global health score (GHS) and QOL was 11.4 months (95% CI, 8.8-16.3) with T-DXd compared with 7.5 months (95% CI, 5.9-9.5) with physician’s choice of therapy. The hazard ratio for GHS/QOL TDD was 0.69 (95% CI, 0.52-0.92; P = .0096).

For pain symptoms, the TDD between the experimental and control arms were 16.4 months (95% CI, 13.1-21.5) and 6.1 months (95% CI, 4.2-7.5), respectively. The hazard ratio for pain symptom TDD was 0.40 (95% CI, 0.30-0.54; P <.0001).

References

1. ENHERTU^® recommended for approval in the EU by CHMP for patients with HER2 low metastatic breast cancer. News release. Daiichi-Sankyo. December 19, 2022. Accessed December 19, 2022. https://bit.ly/3YwJav3
2. FDA approves first targeted therapy for HER2-low breast cancer. News Release. FDA. August 5, 2022. Accessed December 19, 2022. https://bit.ly/3BNUxWy
3. 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
4. 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
5. Ueno NT, Jacot W, Yamashita T, et al. Patient-reported outcomes (PROs) from DESTINY-Breast04, a randomized phase 3 study of trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice (TPC) in patients (pts) with HER2-low metastatic breast cancer (MBC). Presented at: ESMO Congress 2022; September 9-13, 2022; Paris, France. Abstract 217O.