The Lynx Group

Enhertu First Drug Approved for HER2-Positive Non–Small- Cell Lung Cancer

October 2022, Vol 13, No 5


On August 11, 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 non–small-cell lung cancer (NSCLC) in adults whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have previously received systemic therapy. The FDA granted fam-trastuzumab deruxtecan a breakthrough therapy designation for this indication.

The FDA concomitantly approved the Oncomine Dx Target Test for tissue (Life Technologies Corporation) and the Guardant360 CDx plasma test (Guardant Health) as companion diagnostics for fam-trastuzumab deruxtecan, with the tumor tissue test used second if no mutation is detected by the plasma test.

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, unresectable or metastatic HER2-low breast cancer, and unresectable or metastatic HER2-positive breast cancer.

This approval was based on the efficacy results of the multicenter, multicohort, randomized, blinded, dose-optimization DESTINY-Lung02 clinical trial that enrolled patients with unresectable or metastatic HER2-positive nonsquamous NSCLC with disease progression after receiving previous systemic therapy. Patients received 5.4 mg of fam-trastuzumab deruxtecan intravenously every 3 weeks until unacceptable toxicity or disease progression.

In the 52 patients in the primary efficacy population of the trial, the major efficacy outcome measures included confirmed objective response rate using RECIST version 1.1, which was 58% (95% confidence interval [CI], 43-71), and duration of response, which was 8.7 months (95% CI, 7.1-not estimable).

The most common (≥20%) adverse events with fam-trastuzumab deruxtecan were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, decreased platelet count, decreased albumin, increased aspartate aminotransferase, increased alanine aminotransferase, fatigue, constipation, decreased appetite, vomiting, increased alkaline phosphatase, and alopecia.

The recommended dose of fam-trastuzumab deruxtecan is 5.4 mg/kg intravenously every 3 weeks in a 21-day cycle until disease progression or unacceptable adverse events. Fam-trastuzumab deruxtecan has a boxed warning for the risks for interstitial lung disease and embryo-fetal toxicity.

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