Primary results from DESTINY-Lung04, a global phase 3 registrational trial, were presented at the IASLC World Conference on Lung Cancer 2026 in Seoul, South Korea, evaluating first-line trastuzumab deruxtecan (T-DXd) versus pembrolizumab plus platinum-based chemotherapy in patients with advanced or metastatic HER2-mutant non-small cell lung cancer (NSCLC).
T-DXd demonstrated a statistically significant improvement in progression-free survival (PFS) over the standard-of-care comparator, with a median PFS of 14.3 months versus 8.3 months (HR 0.63; 95% CI, 0.50–0.79; P<0.0001). Overall survival (OS) data did not favor T-DXd at this analysis, though the investigators noted that imbalances in subsequent therapies between arms confound interpretation of the OS results.
Key finding
In the first global phase 3 trial to report this comparison, first-line T-DXd reduced the risk of disease progression or death by 37% versus pembrolizumab plus chemotherapy in HER2-mutant NSCLC, though OS results are difficult to interpret due to imbalanced subsequent therapies across treatment arms.
Study Design
| Trial | DESTINY-Lung04 (NCT05048797); global, open-label, randomized, registrational phase 3 |
|---|---|
| Population | Treatment-naïve patients with unresectable locally advanced or metastatic HER2-mutant (exon 19 or 20) NSCLC; stratified by smoking status and presence/history of brain metastases |
| Treatment | T-DXd 5.4 mg/kg IV every 3 weeks versus pembrolizumab 200 mg IV every 3 weeks plus cisplatin 75 mg/m² or carboplatin AUC 5 and pemetrexed 500 mg/m² IV every 3 weeks (1:1 randomization; 454 patients) |
| Primary endpoint | Progression-free survival per RECIST 1.1 by blinded independent central review (BICR) |
| Key secondary endpoints | Overall survival, objective response rate, duration of response, and safety |
HER2-mutant NSCLC represents an aggressive disease subset with poor prognosis in which a substantial proportion of patients do not respond adequately to first-line immunotherapy-based chemotherapy regimens. DESTINY-Lung04 was designed to assess whether targeting HER2 directly with an antibody-drug conjugate could improve outcomes in this molecularly defined population in the front-line setting.
Results and Safety
At a data cutoff of June 9, 2026, with a median follow-up of 21.6 months in the T-DXd arm and 20.4 months in the pembrolizumab plus chemotherapy arm, T-DXd met its primary endpoint. Median PFS was 14.3 months (95% CI, 12.4–16.5) with T-DXd versus 8.3 months (95% CI, 7.0–9.9) with pembrolizumab plus chemotherapy, representing a 6-month improvement and a hazard ratio of 0.63 (95% CI, 0.50–0.79; P<0.0001). The objective response rate was 70.0% (95% CI, 63.6–75.9) with T-DXd compared with 44.5% (95% CI, 37.9–51.2) with pembrolizumab plus chemotherapy (odds ratio 2.93; 95% CI, 2.00–4.34), and median duration of response was 13.4 months versus 9.7 months, respectively. Median OS 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 cautioned that subsequent therapies, primarily HER2-directed agents in the control arm and immunotherapy-based regimens in the T-DXd arm, were imbalanced between groups, limiting the interpretability of this result.
The safety analysis included 226 patients treated with T-DXd and 220 treated with pembrolizumab plus chemotherapy. Median treatment exposure was 12.3 months with T-DXd and 7.1 months with pembrolizumab plus chemotherapy. Drug-related adverse events of any grade occurred in 90.3% and 89.5% of patients, respectively, and grade 3 or higher drug-related events were reported in 34.1% and 33.6%. Drug-related serious adverse events were more frequent with T-DXd (15.5% vs 10.0%), while treatment discontinuations due to drug-related adverse events occurred at the same rate in both arms (15.9% each). Adjudicated drug-related interstitial lung disease (ILD) or pneumonitis was notably more common with T-DXd, occurring in 20.8% of patients versus 2.3% with pembrolizumab plus chemotherapy. Most ILD or pneumonitis events with T-DXd were grade 1 or 2 (78.7% of affected patients), though grade 5 events occurred in 1.8% of T-DXd-treated patients. Decreases in left ventricular ejection fraction were also more frequent with T-DXd (3.1% vs 0.5%), with grade 3 events reported in 1.3% of T-DXd-treated patients and no grade 4 or 5 events in either arm.
Clinical Context
DESTINY-Lung04 is the first phase 3 trial to demonstrate a statistically significant PFS benefit for a HER2-directed therapy over standard immunotherapy-based chemotherapy in the first-line HER2-mutant NSCLC setting. The magnitude of the PFS improvement and the near-doubling of response rates with T-DXd are clinically meaningful in a population historically underserved by existing front-line regimens. The investigators concluded that these results support T-DXd as a new first-line treatment option for this patient population.
Key questions remain. The OS data are immature and confounded by post-progression treatment imbalances, meaning the ultimate survival benefit of moving T-DXd to the front line, particularly in relation to sequencing with subsequent HER2-directed therapies, is not yet established. The ILD signal, including a 1.8% rate of grade 5 events, will require careful monitoring and risk management in clinical practice. Longer follow-up and real-world data will be needed to fully characterize the benefit-risk profile of first-line T-DXd in this setting.
Sources
- Rotow J et al. “First-Line Trastuzumab Deruxtecan (T-DXd) in Patients With Metastatic HER2-Mutant NSCLC: DESTINY-Lung04 Primary Results.” Conference presentation (IASLC World Conference on Lung Cancer 2026, Seoul, South Korea). Abstract PL03.08. June 2026. https://cattendee.abstractsonline.com/meeting/21487/Session/48
AI disclosure: This article was prepared with assistance from generative AI using the source material cited above. It was reviewed and edited by Danielle M. Blazier, Ph.D., before publication.