Enhertu extends progression-free survival in HER2 lung cancer

In the phase 3 DESTINY-Lung04 study, Enhertu (trastuzumab deruxtecan) delayed disease progression more than the standard first-line regimen of Keytruda plus chemotherapy for adults with advanced HER2-mutant non-small-cell lung cancer.

First-line trial shows longer progression-free survival

The trial enrolled 454 participants with unresectable, locally advanced or metastatic non-squamous disease carrying an exon 19 or exon 20 HER2 mutation. Patients were randomly assigned to receive either Enhertu or pembrolizumab combined with a platinum agent and pemetrexed, the current global standard.

Median progression-free survival was 14.3 months for the antibody-drug conjugate arm, compared with 8.3 months for the chemo-immunotherapy group. That difference represents a 37 % reduction in the risk of disease progression or death.

Response rates and durability

Objective responses occurred in 70 % of patients treated with Enhertu, versus 44.5 % in the comparator cohort. The median duration of response was 13.4 months for the former and 9.7 months for the latter.

Benefit was consistent across subgroups, including those with brain metastases, varying smoking histories, exon 19 versus exon 20 alterations, and liver involvement. The data suggest the regimen works regardless of these clinical factors.

Safety profile and adverse events

Grade 3 or higher treatment-related adverse events were reported in 34.1 % of patients receiving Enhertu. Neutropenia was the most frequent severe event, affecting 11.1 % of the cohort.

Interstitial lung disease (ILD) or pneumonitis occurred in 20.8 %, most cases being mild or moderate. Fatal ILD was observed in 1.8 % (four patients). The drug carries a boxed warning for ILD, and clinicians are advised to monitor for new cough, shortness of breath, or fever.

Implications and next steps

Overall survival data are not yet mature; only about 47 % of the endpoint is available, and formal statistical testing has not been completed.

Compared with earlier HER2-targeted agents that required prior lines of therapy, the data suggest that moving the antibody-drug conjugate to the front line may close a gap that has limited options for this small patient subset.

The findings represent the first phase 3 trial to show a progression-free survival advantage for a HER2-directed treatment against the current first-line standard in this population. Continued follow-up will determine whether the observed benefit translates into longer overall survival.