First-line trastuzumab deruxtecan extends progression-free survival in HER2-mutant lung cancer

First-line treatment with trastuzumab deruxtecan (T-DXd) significantly improved progression-free survival compared with pembrolizumab plus platinum-based chemotherapy in patients with advanced or metastatic HER2-mutant non-small cell lung cancer (NSCLC), according to primary results from the global Phase 3 DESTINY-Lung04 trial presented at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer in Seoul, Republic of Korea. Median progression-free survival by blinded independent central review was 14.3 months with single-agent T-DXd versus 8.3 months with pembrolizumab plus chemotherapy, a six-month improvement that corresponds to a hazard ratio of 0.63 (95% CI, 0.50-0.79; P<0.0001). DESTINY-Lung04 is the first global Phase 3 trial to demonstrate a statistically significant and clinically meaningful progression-free survival benefit with first-line single-agent T-DXd against the standard-of-care immunotherapy plus platinum doublet regimen in this patient population.

HER2-mutant NSCLC is an aggressive form of lung cancer associated with poor prognosis, and according to the study investigators many patients do not respond to first-line standard-of-care immunotherapy plus chemotherapy, underscoring the need for effective HER2-directed treatment options. The open-label, randomized Phase 3 trial enrolled treatment-naive patients with unresectable locally advanced or metastatic NSCLC harboring HER2 exon 19 or exon 20 mutations. A total of 454 patients were randomized 1:1 to receive T-DXd at 5.4 mg/kg intravenously every three weeks or pembrolizumab plus platinum chemotherapy and pemetrexed. The primary endpoint was progression-free survival by blinded independent central review, with secondary endpoints including overall survival, objective response rate, progression-free survival 2, duration of response and safety.

T-DXd also produced a higher objective response rate than the comparator regimen, at 70.0% versus 44.5%, with median duration of response of 13.4 months and 9.7 months, respectively. “These results demonstrate substantial improvements in progression-free survival and response with first-line trastuzumab deruxtecan for patients with advanced or metastatic HER2-mutant NSCLC,” said Julia Rotow, MD, of the Dana-Farber Cancer Institute, Boston, Mass. “The findings support T-DXd as a new first-line treatment option for this patient population, for whom more effective HER2-directed approaches are needed.”

Median overall survival, however, was 29.3 months with T-DXd and 33.1 months with pembrolizumab plus chemotherapy (HR 1.15; 95% CI, 0.88-1.52). The investigators noted that subsequent therapies were imbalanced between the treatment groups, primarily involving HER2-directed and immunotherapy-based treatments, which confounded interpretation of the overall survival results. The trial’s primary conclusion therefore rests on the progression-free survival, response rate and durability-of-response findings rather than on an overall survival advantage.

The safety profile of T-DXd was generally consistent with its known profile. Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in 20.8% of patients treated with T-DXd, with most events classified as Grade 1 or 2 (78.7%), compared with 2.3% of patients receiving pembrolizumab plus chemotherapy. Grade 3 or higher drug-related adverse events were reported in 34.1% of patients receiving T-DXd and 33.6% receiving pembrolizumab plus chemotherapy. The investigators concluded that T-DXd improved progression-free survival, response rates and durability of response compared with pembrolizumab plus chemotherapy, supporting T-DXd as a new first-line option for patients with advanced or metastatic HER2-mutant NSCLC.

Subject of Research: First-line trastuzumab deruxtecan versus pembrolizumab plus chemotherapy in HER2-mutant non-small cell lung cancer

Article Title: Phase 3 DESTINY-Lung04 trial shows first-line trastuzumab deruxtecan significantly improves progression-free survival in HER2-mutant NSCLC

Article References: Phase 3 DESTINY-Lung04 trial shows first-line trastuzumab deruxtecan significantly improves progression-free survival in HER2-mutant NSCLC. Original publication (Bibliographic details unavailable.)

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Keywords: HER2-mutant NSCLC, trastuzumab deruxtecan, T-DXd, DESTINY-Lung04, progression-free survival, pembrolizumab, platinum chemotherapy, Phase 3 trial, objective response rate, interstitial lung disease, IASLC, lung cancer