FDA Grants Accelerated Approval to Trastuzumab Deruxtecan for HER2-Mutant NSCLC

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On August 11, 2022, the U.S. Food and Drug Administration (FDA) granted accelerated approval to fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for adult patients 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.

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. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.

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 described below.


Efficacy for accelerated approval was based on DESTINY-Lung02, 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. Patients received T-DXd at 5.4 mg/kg by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression.

Of the 52 patients in the primary efficacy population DESTINY-Lung02, the median age was 58 years (range = 30–78); 69% were female; 79% were Asian, 12% were White, and 10% were of other races.

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–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 advising health professionals of the risk of interstitial lung disease and embryofetal toxicity.

This application used advice from the FDA Oncology Center of Excellence (OCE) Project Optimus to conduct a dose-randomization study, which led to a lower dose being approved. For more information regarding the OCE’s efforts to modernize dose selection for oncology products, refer to Project Optimus.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. This application was granted Priority Review, Breakthrough Therapy designation, and Orphan Drug designation.