WILMINGTON, DE — AstraZeneca (NYSE: AZN) and Daiichi Sankyo’s Enhertu extended median progression-free survival by six months versus pembrolizumab plus chemotherapy in a Phase III trial of first-line treatment for advanced HER2-mutant non-small cell lung cancer, potentially expanding the drug’s role earlier in the disease.
The DESTINY-Lung04 trial showed Enhertu, or fam-trastuzumab deruxtecan-nxki, reduced the risk of disease progression or death by 37% compared with platinum-pemetrexed chemotherapy plus pembrolizumab. The hazard ratio was 0.63, with a 95% confidence interval of 0.50 to 0.79 and p<0.0001.
Median progression-free survival was 14.3 months with Enhertu compared with 8.3 months for the standard-of-care regimen, based on blinded independent central review.
The trial enrolled patients with unresectable, locally advanced or metastatic HER2-mutant non-squamous non-small cell lung cancer receiving first-line treatment. Results were presented at the International Association for the Study of Lung Cancer’s 2026 World Conference on Lung Cancer in Seoul, South Korea.
The objective response rate was 70% with Enhertu compared with 44.5% for pembrolizumab plus chemotherapy. Median duration of response was 13.4 months and 9.7 months, respectively.
Progression-free survival numerically favored Enhertu across key subgroups, including patients with brain or liver metastases, different smoking histories, exon 19 or exon 20 HER2 mutations, and newly diagnosed or recurrent disease.
“With seventy percent of patients responding and a median progression-free survival of 14.3 months, trastuzumab deruxtecan has the potential to become an important new 1st-line treatment option for these patients,” said Julia Rotow, an assistant professor of medicine at Dana-Farber Cancer Institute and lead investigator of the trial.
Overall survival data were 46.9% mature at the time of the analysis, and no formal hypothesis testing was performed. The companies said no overall survival benefit had been observed at that point.
Interpretation of the survival data may be complicated by differences in subsequent treatment between the two groups, according to the companies. HER2-directed therapies were used after study treatment in 48% of patients initially receiving pembrolizumab plus chemotherapy, compared with 23.3% of those initially receiving Enhertu.
Subsequent immunotherapy plus chemotherapy was used in 23.8% of patients in the Enhertu arm.
The safety profile was generally consistent with previous experience with Enhertu, with no new safety concerns identified, according to the companies.
Grade 3 or higher treatment-related adverse events occurred in 34.1% of patients receiving Enhertu and 33.6% of those receiving pembrolizumab plus chemotherapy, despite longer median treatment exposure with Enhertu of 12.3 months versus 7.1 months.
Neutropenia was the most common Grade 3 or higher adverse event occurring in at least 5% of patients in both groups, affecting 11.1% of Enhertu-treated patients and 14.1% of those receiving pembrolizumab plus chemotherapy.
Interstitial lung disease or pneumonitis occurred in 20.8% of patients treated with Enhertu, according to independent adjudication. Most cases were Grade 1 or Grade 2, though the trial recorded five Grade 3 cases, one Grade 4 case and four Grade 5 events.
Enhertu is already approved for previously treated metastatic non-small cell lung cancer with activating HER2, or ERBB2, mutations and for certain previously treated HER2-positive solid tumors.
The HER2-directed antibody-drug conjugate was discovered by Daiichi Sankyo (TSE: 4568) and is jointly developed and commercialized with AstraZeneca.
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