On 11 August 2022, the US Food and Drug Administration (FDA) granted accelerated approval to fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo, Inc.) for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumours have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. This is the first drug approved for HER2-mutated 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 Enhertu. If no mutation is detected in a plasma specimen, the tumour tissue should be tested.

Enhertu was evaluated at a 6.4 mg/kg dose (n=152) across multiple studies and at a 5.4 mg/kg dose (n=102) in a randomised dose-finding study. 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 multicentre, multi-cohort, randomised, blinded, dose-optimisation study. Eligible patients were required to have unresectable or metastatic HER2-mutated non-squamous NSCLC with disease progression after prior systemic treatment. Patients were selected for treatment with Enhertu based on the presence of activating HER2 (ERBB2) mutations in a tumour specimen. Patients received Enhertu 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 to 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 (ORR) as assessed by blinded independent central review using RECIST v1.1 and duration of response (DoR). The confirmed ORR was 58% (95% confidence interval [CI] 43, 71) and the median DoR 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 haemoglobin, 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 embryo-foetal toxicity.

Full prescribing information for Enhertu is available here.

This application used advice from the FDA Oncology Center of Excellence (OCE) Project Optimus to conduct a dose randomisation study, which led to a lower dose being approved. For more information regarding the OCE’s efforts to modernise 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 and breakthrough designation.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate.