FDA Accelerates the Approval of Enhertu for the Treatment of HER2-Low Breast Cancer

October 2022, Vol 13, No 5


On August 5, 2022, the FDA accelerated the approval of fam-trastuzumab deruxtecan-nxki (Enhertu; Daiichi Sankyo), a human epidermal growth factor 2 (HER2)-directed antibody and topoisomerase inhibitor conjugate, for the treatment of unresectable or metastatic HER2-low (immunohistochemistry [IHC]1-positive or IHC2-positive/in situ hybridization–negative) breast cancer in adults who have previously received chemotherapy in the metastatic setting or who have had disease recurzrence during or within 6 months of completing adjuvant chemotherapy. The FDA granted fam-trastuzumab deruxtecan a breakthrough therapy designation for this indication.

Fam-trastuzumab deruxtecan was previously approved for the treatment of adults with unresectable or metastatic HER2-positive breast cancer, locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma, and unresectable or metastatic HER2-positive breast cancer.

This approval was based on the efficacy results of the randomized, multicenter, open-label DESTINY-Breast04 clinical trial that enrolled 557 patients with unresectable or metastatic HER2-low breast cancer, of whom 494 had hormone receptor (HR)-positive disease and 63 had HR-negative disease. The primary efficacy measure was progression-free survival (PFS) in the HR-positive patients, as assessed via RECIST version 1.1. The secondary efficacy measures included PFS and overall survival (OS) in the overall population and OS in the HR-positive patients.

A total of 373 patients received 5.4 mg of fam-trastuzumab deruxtecan intravenously every 3 weeks and 184 patients received the physician’s choice of chemotherapy (ie, eribulin, capecitabine, gemcitabine, nab-paclitaxel, or paclitaxel).

The median PFS in the HR-positive patients was 10.1 months with fam-trastuzumab deruxtecan (95% confidence interval [CI], 9.5-11.5) versus 5.4 months in the chemotherapy arm (95% CI, 4.4-7.1). The median PFS in the overall population was 9.9 months (95% CI, 9-11.3) with fam-trastuzumab deruxtecan versus 5.1 months in the chemotherapy arm (95% CI, 4.2-6.8; hazard ratio, 0.5).

In the HR-positive patients, the median OS was 23.9 months with fam-trastuzumab deruxtecan and 17.5 months with chemotherapy (95% CI, 20.8-24.8 vs 15.2-22.4, respectively; hazard ratio, 0.64). In the overall patient population, the median OS was 23.4 months with fam-trastuzumab deruxtecan and 16.8 months with chemotherapy (95% CI, 20-24.8 vs 14.5-20, respectively; hazard ratio, 0.64).

The most common (≥20%) adverse events with fam-trastuzumab deruxtecan in this study were nausea, fatigue, alopecia, vomiting, anemia, constipation, decreased appetite, diarrhea, and musculoskeletal pain.

Fam-trastuzumab deruxtecan has a boxed warning for the risks for interstitial lung disease and embryo-fetal toxicity.

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