Posted: Monday, August 15, 2022
On August 11, the U.S. Food and Drug Administration (FDA) granted accelerated approval to fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for adults with unresectable or metastatic non–small cell lung cancer (NSCLC) whose tumors have activating HER2 mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. This is the first drug approved for HER2-mutant NSCLC. The FDA also approved the Life Technologies Corporation’s Oncomine Dx Target Test (tissue) and the Guardant Health, Inc.’s Guardant360 CDx (plasma) as companion diagnostics for T-DXd.
T-DXd was evaluated at a 6.4-mg/kg dose across multiple trials and at a 5.4-mg/kg dose in a randomized dose-finding trial. Response rates were consistent across dose levels. Increased rates of interstitial lung disease/pneumonitis were observed at the higher dose. The efficacy results of the approved recommended dose of 5.4 mg/kg given intravenously every 3 weeks are from the DESTINY-Lung02 trial, a multicenter, multicohort, randomized, blinded, dose-optimization trial. Eligible patients were required to have unresectable or metastatic HER2-mutant nonsquamous NSCLC with disease progression after prior systemic therapy. Patients were selected for treatment with T-DXd based on the presence of activating HER2 mutations in a tumor specimen.
The major efficacy outcome measures were confirmed objective response rate, as assessed by blinded independent central review using Response Evaluation Criteria in Solid Tumors version 1.1, and duration of response. The confirmed objective response rate was 58% (95% confidence interval [CI] = 43%–71%), and the median duration of response was 8.7 months (95% CI = 7.1 months to not estimable).
The most common (≥ 20%) adverse reactions, including laboratory abnormalities, 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 prescribing information includes a boxed warning on the risk of interstitial lung disease and embryofetal toxicity.