The Lynx Group

FDA Grants Enhertu Regular Approval for Patients with Unresectable or Metastatic Breast Cancer

June 2022, Vol 13, No 3

On May 4, 2022, the FDA granted a regular full approval for fam-trastuzumab deruxtecan-nxki (Enhertu; Daiichi Sankyo), an HER2-directed antibody and topoisomerase inhibitor conjugate, for the treatment of adults with unresectable or metastatic HER2-positive breast cancer who had received a prior anti–HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and who had developed disease recurrence during or within 6 months of completing therapy.

The FDA granted this approval a priority review, breakthrough designation, and orphan drug designation. In December 2019, fam-trastuzumab deruxtecan-nxki received accelerated approval for the treatment of adults with unresectable or metastatic HER2-positive breast cancer after ≥2 previous anti–HER2-based regimens in the metastatic setting. This accelerated approval was based on a multicenter, open-label, randomized clinical trial of 524 patients with HER2-positive, unresectable, and/or metastatic breast cancer who had received previous trastuzumab and taxane therapy for metastatic disease or developed disease recurrence during or within 6 months of completing neoadjuvant or adjuvant therapy.

Patients were randomized in a 1:1 ratio to receive either intravenous (IV) fam-trastuzumab deruxtecan-nxki or IV ado-trastuzumab emtansine (Kadcyla; Genentech, Inc) every 3 weeks until unacceptable toxicity or disease progression. Randomization was stratified by hormone receptor status, previous treatment with pertuzumab (Perjeta; Genentech, Inc), and history of visceral disease.

The main efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review based on RECIST version 1.1. Key secondary outcomes included overall survival (OS) and confirmed objective response rate (ORR). Median PFS was not reached (95% confidence interval [CI], 18.5-not estimable) in the fam-trastuzumab deruxtecan-nxki arm and was 6.8 months (95% CI, 5.6-8.2) in the ado-trastuzumab emtansine arm. The hazard ratio was 0.28 (95% CI, 0.22-0.37;

P <.0001). At the time of the PFS analysis, 16% of patients had died and OS was immature. The ORR based on the patients with measurable disease assessed by blinded independent central review at baseline was 82.7% (95% CI, 77.4-87.2) in the fam-trastuzumab deruxtecan-nxki arm and 36.1% (95% CI, 30.0-42.5) in the ado-trastuzumab emtansine arm.

The most common (>30%) adverse reactions with fam-trastuzumab deruxtecan-nxki were nausea, fatigue, vomiting, alopecia, constipation, anemia, and musculoskeletal pain.

Fam-trastuzumab deruxtecan-nxki is associated with a risk for interstitial lung disease and embryo-fetal toxicity. Pregnant women should not take this medication.

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