Enhertu Delays Progression in HER2-Mutant Lung Cancer in Phase 3 Trial

Patients with HER2-mutant advanced non-small cell lung cancer (NSCLC) who received Enhertu (trastuzumab deruxtecan) as their first treatment went longer without their disease worsening than those who received immunotherapy plus chemotherapy, according to findings from the phase 3 DESTINY-Lung04 trial.

The findings were presented at the 2026 World Conference on Lung Cancer and included 454 patients with unresectable, locally advanced or metastatic, non-squamous NSCLC with a HER2 exon 19 or exon 20 mutation. Patients were randomly assigned to receive either Enhertu or Keytruda (pembrolizumab) plus platinum-based chemotherapy and pemetrexed, the current global standard of care in this setting.

Patients treated with Enhertu went a median of 14.3 months without their cancer worsening or death, known as progression-free survival, compared with 8.3 months for patients receiving Keytruda plus chemotherapy. This translated to a 37% reduction in the risk of disease progression or death with Enhertu.

Responses were also more common among patients treated with Enhertu. Seventy percent of patients responded to treatment compared with 44.5% of those who received Keytruda plus chemotherapy. Responses lasted a median of 13.4 months with Enhertu versus 9.7 months with Keytruda plus chemotherapy.

The progression-free survival benefit with Enhertu was observed across key groups of patients, including those with a presence or history of brain metastases, different smoking histories, HER2 exon 19 or exon 20 mutations and liver metastases.

What Do the DESTINY-Lung04 Findings Mean for Patients With HER2-Mutant Lung Cancer?

HER2 is a protein involved in cell growth, and certain mutations in the HER2 gene can contribute to cancer growth. HER2 mutations are found in approximately 2% to 4% of patients with non-squamous NSCLC.

Enhertu is an antibody-drug conjugate, a type of treatment designed to target HER2 and deliver cancer-killing medicine to cancer cells. In the United States, Enhertu is already approved for patients with unresectable or metastatic HER2-mutant NSCLC who have previously received systemic treatment. The DESTINY-Lung04 findings evaluated whether the treatment could benefit patients earlier, as their first treatment for advanced disease.

Overall survival, which measures how long patients live regardless of whether their cancer worsens, is not yet mature. At the time of the analysis, 46.9% of the overall survival data were available, and formal statistical testing had not yet been performed. Investigators reported no observed overall survival benefit at this analysis and noted that differences in treatments patients received afterward may make the results difficult to interpret.

What Side Effects Were Reported With Enhertu?

The safety profile of Enhertu was generally consistent with what has previously been reported, with no new safety signals identified. Severe or medically significant treatment-related side effects, classified as grade 3 or higher, occurred in 34.1% of patients receiving Enhertu. The most common was neutropenia, or low levels of infection-fighting white blood cells, which occurred in 11.1% of patients.

Interstitial lung disease (ILD) or pneumonitis, which involves inflammation in the lungs, occurred in 20.8% of patients receiving Enhertu. Most cases were mild or moderate; however, severe and fatal cases occurred. Four patients, or 1.8%, experienced grade 5 ILD, meaning the event was fatal.

Enhertu carries a boxed warning for ILD and pneumonitis. Patients receiving the drug should report symptoms such as a new or worsening cough, shortness of breath or fever to their care team.

The DESTINY-Lung04 findings mark the first phase 3 trial to demonstrate improved progression-free survival with a HER2-directed treatment compared with the current first-line standard of care for patients with HER2-mutant advanced NSCLC. Longer follow-up will be needed to determine whether the progression-free survival improvement translates into an overall survival benefit.

References

1. Daiichi Sankyo. “Enhertu Demonstrated a Median Progression-Free Survival of 14.3 Months as First-Line Therapy in Patients With HER2 Mutant Advanced Non-Small Cell Lung Cancer in DESTINY-Lung04 Phase 3 Trial.” Sept. 14, 2026. Presented at the IASLC 2026 World Conference on Lung Cancer.
2. ClinicalTrials.gov. “DESTINY-Lung04: A Phase 3 Study of Trastuzumab Deruxtecan Versus Pembrolizumab in Combination With Pemetrexed-Platinum in Participants With HER2 Exon 19 or 20 Mutant, Unresectable, Locally Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer.” NCT05048797.
3. Enhertu (fam-trastuzumab deruxtecan-nxki) U.S. Prescribing Information. Daiichi Sankyo and AstraZeneca. Current U.S. indication and safety information for HER2-mutant NSCLC, including the boxed warning for interstitial lung disease and pneumonitis.

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