Adults newly diagnosed with advanced lung cancer driven by a HER2 mutation went a median of 14.3 months before their disease worsened when their first treatment was Enhertu (trastuzumab deruxtecan), compared with 8.3 months on Keytruda plus chemotherapy. The results come from the phase 3 DESTINY-Lung04 trial presented in Seoul at the International Association for the Study of Lung Cancer's 2026 World Conference on Lung Cancer, held Sept. 12 to 15. Enhertu lowered the risk of cancer progression or death by 37%.
The finding applies to a small group that can be identified only through testing. HER2 mutations occur in roughly 2% to 4% of non-squamous non-small cell lung cancers, and AstraZeneca says they are seen mostly in younger women and people who have never smoked. These patients are found through biomarker testing of tumor tissue or blood, and Enhertu is not yet approved in the United States as a first treatment for this cancer.
The results also leave a major question open. At this early analysis, overall survival did not favor Enhertu, and a serious lung inflammation side effect was linked to four deaths.
A Six-Month Gap in Progression in a 454-Patient Trial
DESTINY-Lung04 enrolled 454 previously untreated patients with unresectable, locally advanced, or metastatic non-squamous lung cancer carrying HER2 exon 19 or exon 20 mutations. Half received Enhertu by infusion every three weeks. The other half received Keytruda (pembrolizumab) with platinum chemotherapy and pemetrexed, the global standard first-line regimen for this group. The trial's design is described in its ClinicalTrials.gov record.
As of a June 9, 2026, data cutoff, with a median follow-up of roughly 20 to 22 months, tumors shrank in 70.0% of Enhertu patients, compared with 44.5% in the comparison group. Responses lasted a median of 13.4 months versus 9.7 months. The progression benefit held in patients with and without brain metastases, which AstraZeneca says occur more often in this form of lung cancer.
Julia Rotow, MD, of Dana-Farber Cancer Institute in Boston, the trial's lead investigator, said in a company statement released with the results that under current first-line care, "many patients experience disease progression within a year of starting treatment."
AstraZeneca and Daiichi Sankyo, which jointly develop and sell Enhertu and sponsored the trial, first said the study met its main goal in an AstraZeneca topline announcement in August. The full results were presented at this month's conference.
Survival Data and Lung Safety Temper the Result
Overall survival, the measure that matters most to patients, remains unresolved. The survival data were 46.9% mature, and no formal statistical test was performed. Median survival was 29.3 months with Enhertu and 33.1 months with Keytruda plus chemotherapy, a numerical difference that ran against Enhertu.
An analysis by ADC Review cautioned that this interim result does not establish that Enhertu is worse, because the statistical range was wide and crossed the point of no difference. Treatment after the study regimen also differed sharply. Among patients who stopped their assigned treatment, 48.0% in the comparison group went on to receive a HER2-targeted drug, compared with 22.9% in the Enhertu group, investigators reported. Formal survival testing is planned at a second interim analysis and at a final analysis.
Lung safety is the other concern. Drug-related interstitial lung disease, a form of lung inflammation, occurred in 20.8% of Enhertu patients versus 2.3% in the comparison group. Most Enhertu cases were mild or moderate, but four patients (1.8%) died. Investigators reported that delayed or insufficient steroid treatment was seen in 90% of severe cases, including all four deaths.
In evidence terms, DESTINY-Lung04 is a randomized, open-label phase 3 trial funded by the drugmakers, and its results were presented at a medical meeting before full peer-reviewed publication. It shows that Enhertu delayed progression compared with standard care. It does not yet show that starting with Enhertu helps patients live longer.
Testing, Warning Signs, and Next Steps for Patients
The most practical takeaway for families is testing. Anyone diagnosed with advanced non-squamous lung cancer can ask whether comprehensive genomic testing was completed before treatment began and whether it looked specifically for HER2 mutations. Testing can be done on a tissue biopsy or, for some patients, a blood sample, and the results can change which drugs are options.
The HER2 treatment picture is also shifting quickly. On Sept. 9, the FDA expanded sevabertinib (Hyrnuo), a twice-daily pill, to first-line use for certain HER2-mutant lung cancers, and zongertinib (Hernexeos) received a first-line accelerated approval in February. Both pills are approved for tumors with HER2 tyrosine kinase domain activating mutations, so the right choice depends on the exact test result and a detailed conversation with an oncologist.
Enhertu is already approved for patients whose HER2-mutant lung cancer has been treated before. People receiving it should promptly report a new or worsening cough, shortness of breath, or fever, since early treatment of lung inflammation matters. Severe trouble breathing or chest pain requires emergency care. No one should start, stop, or change cancer treatment based on a news report.
Cost and access can be real barriers. Using Enhertu as a first treatment before any FDA decision on that use would be off-label and may face insurance hurdles. Patients can ask their care team about prior authorization, manufacturer assistance programs, and clinical trials that may fit their situation.
AstraZeneca and Daiichi Sankyo have said the data will be shared with global regulators, but no FDA decision date has been announced. The planned survival analyses will show whether the six-month delay in progression also translates into longer lives.
For now, the trial marks a real advance in delaying progression for a small, genetically defined group. Because survival and lung safety questions remain, the choice of first treatment should be made case by case with an oncologist who has the full test results.
Key Questions Answered
What did the DESTINY-Lung04 trial find? Patients with previously untreated HER2-mutant advanced non-squamous lung cancer went a median of 14.3 months without disease progression on Enhertu, compared with 8.3 months on Keytruda plus chemotherapy.
Who could this result apply to? Only people whose lung tumors carry a HER2 mutation, estimated at about 2% to 4% of non-squamous non-small cell lung cancers. These patients are identified through genomic testing of tumor tissue or blood.
Did Enhertu help patients live longer? That is not yet known. The survival data were immature and were not formally tested, and they numerically favored the comparison group. Investigators noted that more comparison-group patients later received HER2-targeted drugs, which complicates the comparison.
What is the main safety concern? Lung inflammation, called interstitial lung disease, occurred in about one in five Enhertu patients. Most cases were mild or moderate, but four patients died.
Can doctors prescribe Enhertu as a first treatment now? Enhertu is FDA-approved for previously treated HER2-mutant lung cancer, not as a first treatment. Using it first would be off-label and may face insurance barriers.
What symptoms should patients on Enhertu report? A new or worsening cough, shortness of breath, or fever should be reported promptly. Severe breathing trouble or chest pain requires emergency care.
What happens next? The companies plan to share the data with regulators, and formal survival analyses are planned. No FDA decision date has been announced.
