Trastuzumab deruxtecan (Enhertu) significantly improved progression-free survival compared with pembrolizumab plus platinum-pemetrexed chemotherapy as first-line treatment for patients with unresectable, locally advanced or metastatic HER2-mutant non-squamous non-small cell lung cancer (NSCLC), according to results from the Phase III DESTINY-Lung04 trial.
The findings were presented on September 14 during a Presidential Symposium at the IASLC 2026 World Conference on Lung Cancer (WCLC 2026) in Seoul, South Korea (Abstract PL03.08). Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate developed jointly by Daiichi Sankyo and AstraZeneca.
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Trastuzumab Deruxtecan Reduced Risk of Progression or Death by 37%
In the trial’s primary endpoint analysis, trastuzumab deruxtecan reduced the risk of disease progression or death by 37% compared with pembrolizumab plus chemotherapy, with a hazard ratio of 0.63 (95% CI, 0.50–0.79; p<0.0001).
Median progression-free survival by blinded independent central review was 14.3 months with trastuzumab deruxtecan compared with 8.3 months with pembrolizumab plus chemotherapy, representing an approximately six-month improvement.
The progression-free survival benefit was observed across key prespecified subgroups, including patients with a presence or history of brain metastases, liver metastases, different smoking histories, HER2 exon 19 or exon 20 mutations, and de novo or recurrent disease.
The objective response rate was also higher with trastuzumab deruxtecan, at 70.0%, compared with 44.5% in the pembrolizumab plus chemotherapy arm. Median duration of response was 13.4 months versus 9.7 months, respectively.
Median PFS2, defined as the time from randomization to second disease progression or death, was 22.7 months with trastuzumab deruxtecan and 17.3 months with pembrolizumab plus chemotherapy (HR 0.80; 95% CI, 0.62–1.02).
Julia Rotow, Assistant Professor of Medicine at Dana-Farber Cancer Institute and lead investigator of DESTINY-Lung04, commenting on the findings, said:
“With 70 percent of patients responding and a median progression-free survival of 14.3 months, trastuzumab deruxtecan has the potential to become an important new first-line treatment option for these patients”
Overall Survival Data Remain Immature
At the June 9, 2026 data cutoff, overall survival data were 46.9% mature, and no formal hypothesis testing for OS was performed at this interim analysis.
Median overall survival was 29.3 months with trastuzumab deruxtecan compared with 33.1 months with pembrolizumab plus chemotherapy, corresponding to an HR of 1.15 (95% CI, 0.88–1.52). The companies stated that there was no observed overall survival benefit at this analysis.
Interpretation of the interim OS results may be complicated by differences in subsequent therapies. HER2-directed treatment after progression was received by 48.0% of patients in the pembrolizumab plus chemotherapy arm compared with 23.3% in the trastuzumab deruxtecan arm. Subsequent immunotherapy plus chemotherapy was received by 23.8% of patients initially treated with trastuzumab deruxtecan.
Formal OS testing is planned at the second interim analysis and at the final analysis.
Safety Profile in DESTINY-Lung04
The safety profile of trastuzumab deruxtecan was generally consistent with its known safety profile, with no new safety signals identified.
Despite a longer median treatment exposure of 12.3 months versus 7.1 months, Grade 3 or higher treatment-related adverse events occurred at similar rates: 34.1% with trastuzumab deruxtecan and 33.6% with pembrolizumab plus chemotherapy.
Neutropenia was the most common Grade 3 or higher adverse event occurring in at least 5% of patients, reported in 11.1% of patients receiving trastuzumab deruxtecan and 14.1% receiving pembrolizumab plus chemotherapy.
Interstitial lung disease (ILD) or pneumonitis, a known risk associated with trastuzumab deruxtecan, was reported in 20.8% of patients receiving the drug according to independent adjudication. Most cases were Grade 1 or 2. However, five Grade 3 events, one Grade 4 event and four Grade 5 events, representing 1.8% of patients, were reported.
AstraZeneca and Daiichi Sankyo Comment on DESTINY-Lung04
Susan Galbraith, Executive Vice President, Oncology Haematology R&D at AstraZeneca, commenting on the results, said:
“These results add to the growing body of evidence supporting Enhertu as an important treatment for patients with HER2 alterations.”
She added that the findings underscore the potential role of trastuzumab deruxtecan beginning at metastatic diagnosis, when treatment may have the greatest opportunity to improve outcomes.
John Tsai, Global Head of R&D at Daiichi Sankyo, said:
“The progression-free survival benefit of six months and strong response rates seen in DESTINY-Lung04 reinforce the importance of targeting HER2 directly.”
He said the results support the potential use of trastuzumab deruxtecan in the first-line setting, where delaying disease progression remains an important treatment goal.
About DESTINY-Lung04
DESTINY-Lung04 (NCT05048797) is a global, randomized, open-label Phase III trial evaluating trastuzumab deruxtecan at 5.4 mg/kg against platinum-pemetrexed doublet chemotherapy plus pembrolizumab in patients with unresectable, locally advanced or metastatic non-squamous NSCLC harboring a HER2 exon 19 or exon 20 mutation.
A total of 454 patients were enrolled across sites in Asia, Europe and North America and randomized 1:1 between the two treatment groups. Randomization was stratified according to smoking history and presence or history of brain metastases.
The primary endpoint is progression-free survival assessed by blinded independent central review. Secondary endpoints include overall survival, objective response rate, duration of response, PFS2, pharmacokinetics and safety.
DESTINY-Lung04: Enhertu Improves First-Line PFS in HER2-Mutant NSCLC
HER2-Mutant NSCLC
HER2, also known as ERBB2, is a receptor involved in cell growth and differentiation. HER2 mutations represent a distinct molecular driver in NSCLC and are reported in approximately 2% to 4% of patients with non-squamous NSCLC. They have also been associated with an increased incidence of brain metastases.
Trastuzumab deruxtecan is already approved in more than 80 countries for patients with unresectable or metastatic NSCLC with activating HER2 mutations who have received prior systemic therapy. The DESTINY-Lung04 results evaluate moving HER2-directed treatment into the first-line setting, before prior systemic treatment for metastatic disease.
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