First FDA-Approved Drug for HER2-Mutant Lung Cancer: Trastuzumab Deruxtecan

For adults whose tumours are HER2-mutation positive, who have received prior systemic treatment and have metastatic or unresectable non-small cell lung cancer (NSCLC), fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo, Inc.) received accelerated FDA (US Food and Drug Administration) approval on 11 August 2022. This is the first drug approved for HER2-mutant NSCLC.

Trastuzumab deruxtecan combines a chemotherapy agent with a monoclonal antibody against the HER2 receptor, forming an  antibody–chemotherapy conjugate.

The FDA also approved Life Technologies Corporation's Oncomine™ Dx Target Test on tumour tissue and Guardant Health, Inc.'s blood-based Guardant360® CDx as companion diagnostics to detect HER2 mutations and establish Enhertu eligibility. If no mutation is found in blood, tumour tissue should be tested (see genetic testing in cancer).

Approximately 3% of NSCLCs carry a mutation in the HER2 gene

Approximately 3% of non-squamous NSCLCs carry a HER2 mutation, associated with female sex, never smoking and a poor prognosis.

HER2-targeted treatments – particularly trastuzumab deruxtecan – had previously received FDA approval for breast and gastric cancers. Such drugs had not previously been FDA-approved for HER2-mutant NSCLC.

FDA Approval Based on DESTINY-Lung02

Enhertu was evaluated at 6.4 mg/kg in multiple trials (n=152) and at 5.4 mg/kg in a randomised dose-finding trial (n=102). Response rates were consistent across doses, but more interstitial lung disease/pneumonia occurred at the higher dose. Efficacy results for the approved recommended dose of 5.4 mg/kg intravenously every 3 weeks are described below.

Accelerated approval efficacy was based on DESTINY-Lung02, a multicentre, multicohort, randomised, blinded dose-optimisation trial. Eligible patients had unresectable or metastatic HER2-mutant non-squamous NSCLC progressing after previous systemic treatment. They were selected for Enhertu based on activating HER2 (ERBB2) mutations in a tumour sample. Patients received Enhertu 5.4 mg/kg by intravenous infusion every 3 weeks until unacceptable adverse effects or disease progression.

Results

The first DESTINY-Lung02 cohort included 52 patients with a median age of 58 (range 30 to 78); 69% were women, 79% Asian, 12% White and 10% of other races.

The main efficacy outcomes were objective response rate, assessed by blinded independent central review using RECIST v1.1, and duration of response.

The confirmed objective response rate was 58% (95% CI: 43, 71), and median response duration was 8.7 months (95% CI: 7.1, not estimable [NE]).

The most common adverse effects (≥20%), including laboratory abnormalities, were nausea, reduced white blood cells, reduced haemoglobin, reduced neutrophils, reduced lymphocytes, reduced platelets, reduced albumin, increased AST, increased ALT, fatigue, constipation, reduced appetite, vomiting, ALP and hair loss. The prescribing information contains a Boxed Warning advising healthcare professionals of the risks of interstitial lung disease and embryo-fetal toxicity.