Trastuzumab Deruxtecan in HER2 -Mutant Non–Small-Cell Lung Cancer
- Study type
- Clinical trial
- Study name
- DESTINY-Lung01
- Phase
- Phase 2
- Design
- International multicentre, single-arm phase 2 study
- Sample size
- 91 patients
- Source
- N Engl J Med · 2022
- Trial registration
- NCT03505710
In plain words
In this study, the drug trastuzumab deruxtecan was given to people with advanced lung cancer with a genetic change (mutation) in HER2 for whom earlier treatments had not worked. The tumour shrank in about half of the patients (55%), and half of the patients lived about 17.8 months or longer. The drug has side effects, including inflammation and damage of the lungs (interstitial lung disease), which occurred in 26% of patients and was fatal in two, so it must be used under close medical supervision.
Key results
Treatment arms and regimens
Trastuzumab deruxtecan 6.4 mg/kg IV every 3 weeks (91 patients). Suspected interstitial lung disease (ILD) cases were reviewed by an independent adjudication committee and treated according to the protocol's ILD management guidance (including early initiation of glucocorticoids).
Note: the approved dose differs from the dose in this study. According to the current FDA label (Enhertu), the approved dose in NSCLC with an activating HER2 mutation (after one prior systemic therapy) is 5.4 mg/kg IV every 3 weeks until disease progression or unacceptable toxicity; dose reductions: 4.4 then 3.2 mg/kg. The drug is highly emetogenic and antiemetic prophylaxis is required. Do not substitute with trastuzumab or trastuzumab emtansine. Monitor LVEF and pulmonary symptoms (ILD) during treatment.
Source of the regimen details: Full text of the paper (PMC9066448) and ClinicalTrials.gov NCT03505710; approved dose and dose modifications from the FDA label for Enhertu (DailyMed, 2026 version)
Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.
Study population
Adults with unresectable or metastatic non-squamous NSCLC that had relapsed on or was refractory to standard treatment, with an activating HER2 mutation (local tissue testing); at least one measurable lesion (RECIST 1.1); ECOG 0 or 1. Asymptomatic brain metastases not requiring glucocorticoids or anticonvulsants were allowed.
Key exclusion criteria: prior treatment with an anti-HER2 antibody or antibody–drug conjugate (HER2 tyrosine kinase inhibitors such as afatinib, pyrotinib or poziotinib were allowed); history of non-infectious ILD treated with glucocorticoids, or current/suspected ILD on imaging.
Endpoints
Primary endpoint: objective response by independent central review. Secondary endpoints: duration of response, progression-free survival, overall survival and safety. Biomarkers of HER2 alterations were also explored.
Safety and side effects
Drug-related grade 3 or higher adverse events occurred in 46% of patients; the most common were neutropenia (19%) and anaemia (10%). Drug-related serious adverse events 20%; discontinuation due to a drug-related adverse event 25% (pneumonitis 13% and ILD 5%); dose reduction 34% (mainly nausea and fatigue) and dose interruption 32% (mainly decreased neutrophil count).
Adjudicated interstitial lung disease (ILD): 26% (24 patients: grade 1 in 3, grade 2 in 15, grade 3 in 4 and grade 5 (fatal) in 2 patients); median time to onset 141 days (14 to 462 days). ILD occurred in 8 of 20 patients with prior partial lung resection.
Clinical significance and place in guidelines
This study showed substantial and durable antitumour activity of trastuzumab deruxtecan in previously treated HER2-mutant NSCLC, a disease that previously had no approved HER2-targeted therapy. Given the risk of interstitial lung disease, close monitoring and early detection are essential. The status of drug approvals and clinical guideline recommendations should be checked separately, as the abstract does not address them.
Limitations
This was a single-arm phase 2 study without a control group, so direct comparison with other treatments is not possible. The number of patients was limited (91 patients) and follow-up relatively short (median 13.1 months). The risk of interstitial lung disease, including fatal cases, is an important clinical limitation.
This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.