Enhertu shows 14.3-month median progression-free survival as first-line therapy for HER2-mutant lung cancer in DESTINY-Lung04 trial

AstraZeneca and Daiichi Sankyo’s Enhertu produced a statistically significant and clinically meaningful improvement in progression-free survival compared with the global standard of care, a combination of platinum-pemetrexed chemotherapy and pembrolizumab, when used as a first-line treatment for unresectable, locally advanced or metastatic HER2-mutant non-squamous non-small cell lung cancer, according to positive results from the Phase III DESTINY-Lung04 trial.

The data were presented during the Presidential Symposium at the IASLC 2026 World Conference on Lung Cancer in Seoul, South Korea.

On the trial’s primary endpoint, Enhertu monotherapy cut the risk of disease progression or death by 37.0% compared with pembrolizumab plus chemotherapy, with a hazard ratio of 0.63 (95% CI: 0.50 to 0.79, p<0.0001). Median progression-free survival, as assessed by blinded independent central review, reached 14.3 months with Enhertu versus 8.3 months for the standard regimen. The benefit held up favorably across major subgroups, including patients stratified by brain metastases, liver metastases, smoking status, HER2 mutation type (exon 19 or exon 20), and whether the disease was newly diagnosed or recurrent.

Enhertu also produced a higher objective response rate, 70.0% compared with 44.5% for pembrolizumab plus chemotherapy, along with a longer median duration of response, 13.4 months versus 9.7 months.

Julia Rotow, an assistant professor of medicine at Dana-Farber Cancer Institute and the trial’s lead investigator, said HER2-mutant non-small cell lung cancer tends to respond poorly to current first-line standard treatment, with many patients progressing within a year of starting therapy. She said the combination of a 70% response rate and 14.3-month median progression-free survival points to trastuzumab deruxtecan becoming a significant new first-line option for these patients.

Susan Galbraith, AstraZeneca’s executive vice president of oncology hematology R&D, described DESTINY-Lung04 as the first Phase III trial to show superior progression-free survival against the global first-line standard of care in this patient population. She said the results build on existing evidence supporting Enhertu’s role in treating HER2 alterations and highlight its potential value at the point of metastatic diagnosis, when treatment decisions have the greatest impact on outcomes.

John Tsai, global head of R&D at Daiichi Sankyo, noted that Enhertu was the first HER2-directed antibody drug conjugate approved for HER2-mutant non-small cell lung cancer and has since become a standard second-line treatment. He said the six-month progression-free survival advantage and strong response rates seen in DESTINY-Lung04 reinforce the value of directly targeting HER2 in these patients and support moving Enhertu into first-line use, where delaying disease progression matters most.

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Related Topics and Keywords

DESTINY-Lung04 trial, enhertu, HER2-mutant lung cancer, HER2-mutant lung cancer in DESTINY-Lung04 trial, lung cancer