HER2-targeted therapy outperforms chemoimmunotherapy in frontline NSCLC

Clinical takeaway: Test patients with advanced NSCLC for HER2 mutations at diagnosis; trastuzumab deruxtecan could become a first-line option, if approved, but requires close monitoring for interstitial lung disease (ILD)/pneumonitis.

HER2 mutations occur in a small but clinically important subset of non-small cell lung cancer (NSCLC) and are associated with poor outcomes. Although trastuzumab deruxtecan (T-DXd) is already established in previously treated HER2-mutant disease, effective HER2-directed options in the first-line setting have remained limited.

In the global phase 3 DESTINY-Lung04 trial, results of which were presented at the 2026 IASLC World Conference on Lung Cancer and have not yet been peer reviewed, investigators randomized 454 treatment-naive patients with unresectable locally advanced or metastatic NSCLC harboring HER2 exon 19 or exon 20 mutations to receive either single-agent T-DXd or pembrolizumab plus platinum-based chemotherapy.

T-DXd significantly improved median progression-free survival, extending the time before disease progression by 6 months compared with standard chemoimmunotherapy (14.3 vs 8.3 months), representing a roughly 37% reduction in the risk of progression or death. Tumor responses were also more frequent with T-DXd, with 70% of patients responding compared with 44.5% in the pembrolizumab-plus-chemotherapy arm. Responses were more durable as well, lasting a median of 13.4 months versus 9.7 months.

Overall survival data remain immature and were difficult to interpret because of differences in subsequent therapies between study groups. Median overall survival was 29.3 months with T-DXd and 33.1 months with chemoimmunotherapy.

The safety profile was generally consistent with previous experience with T-DXd. Interstitial lung disease (ILD)/pneumonitis occurred in 20.8% of patients receiving T-DXd versus 2.3% with chemoimmunotherapy, although nearly 80% of ILD events were low grade. Rates of grade 3 or higher treatment-related adverse events were similar between groups, occurring in about one-third of patients.

“These results demonstrate substantial improvements in progression-free survival and response with first-line trastuzumab deruxtecan for patients with advanced or metastatic HER2-mutant NSCLC,” said lead investigator Julia Rotow, MD, of Dana-Farber Cancer Institute. “The findings support T-DXd as a new first-line treatment option for this patient population.”

Source: Rotow J, et al. (2026 Sep 14). 2026 World Conference on Lung Cancer. Phase 3 DESTINY-Lung04 trial shows first-line trastuzumab deruxtecan significantly improves progression-free survival in HER2-mutant NSCLC