T-DXd Significantly Improves PFS in First-Line HER2-Mutant NSCLC

First-line trastuzumab deruxtecan (T-DXd; Enhertu) significantly reduced the risk of disease progression or death compared with pembrolizumab (Keytruda) plus platinum-based chemotherapy in patients with unresectable, locally advanced or metastatic HER2-mutant nonsquamous non–small cell lung cancer (NSCLC), according to results from the phase 3 DESTINY-Lung04 trial presented at the IASLC 2026 World Conference on Lung Cancer.^1,2

The median progression-free survival (PFS) based on blinded independent central review was 14.3 months (95% CI, 12.4-16.5) with T-DXd versus 8.3 months (95% CI, 7.0-9.9) with the pembrolizumab combination, translating to a 37% reduction in the risk of disease progression or death (HR, 0.63; 95% CI, 0.50-0.79; P <.0001).

The objective response rate with T-DXd was 70% compared with 44.5% with pembrolizumab plus chemotherapy. Complete responses were observed in 1.8% of patients in each group, while partial responses were observed in 68.3% and 42.7%, respectively. Stable disease was reported in 26.9% of patients receiving T-DXd compared with 43.2% in the control arm.

The median duration of response was 13.4 months (95% CI, 10.4-17.2) with T-DXd versus 9.7 months (95% CI, 7.0-11.1) with pembrolizumab plus chemotherapy. Median progression-free survival 2 (PFS2) was 22.7 months (95% CI, 20.3-26.3) with T-DXd and 17.3 months (95% CI, 15.6-21.8) with pembrolizumab plus chemotherapy, respectively, corresponding to a hazard ratio of 0.80 (95% CI, 0.62-1.02). PFS2 was defined as the time from randomization to second progression (earliest progression event following first subsequent therapy).

“HER2-mutant non–small cell lung cancer is an aggressive disease with limited responses to current first-line standard of care, and many patients experience disease progression within a year of starting treatment. With seventy per cent 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,” Julia Rotow, MD, assistant professor of medicine at Dana-Farber Cancer Institute and lead investigator of DESTINY-Lung04, stated in a news release.¹

Overall survival (OS) data remained immature at the June 9, 2026, data cutoff, with 46.9% maturity. The median overall survival (OS) was 29.3 months (95% CI, 26.2-33.4) with trastuzumab deruxtecan and 33.1 months (95% CI, 27.7-40.7) with pembrolizumab plus chemotherapy (HR, 1.15; 95% CI, 0.88-1.52).

Safety Profile in DESTINY-Lung04 Trial

The safety profile of T-DXd in DESTINY-Lung04 was consistent with its established profile, with no new safety concerns identified. Although patients remained on treatment longer with trastuzumab deruxtecan, with a median treatment duration of 12.3 months compared with 7.1 months for pembrolizumab plus chemotherapy, grade 3 or higher treatment-related adverse events (TRAEs) occurred at similar rates, in 34.1% and 33.6% of patients, respectively.

Neutropenia was the most common grade 3 or higher TRAE occurring in at least 5% of patients in both groups, affecting 11.1% of patients receiving trastuzumab deruxtecan and 14.1% of those receiving pembrolizumab plus chemotherapy.

Interstitial lung disease or pneumonitis was reported in 20.8% of patients treated with T-DXd based on independent adjudication. Most events were grade 1 or 2, including 7 patients (3.1%) with grade 1 events and 30 patients (13.3%) with grade 2 events. Five patients (2.2%) experienced grade 3 events, 1 patient (0.4%) had a grade 4 event, and 4 patients (1.8%) experienced grade 5 events.

Trial Design and Patient Population

DESTINY-Lung04 was a global, randomized, open-label phase 3 trial that enrolled 454 patients with unresectable, locally advanced or metastatic nonsquamous NSCLC harboring a HER2 exon 19 or exon 20 mutation. Patients were randomized 1:1 to T-DXd at 5.4 mg/kg or standard treatment with pembrolizumab plus platinum-pemetrexed chemotherapy. Randomization was stratified according to smoking history and the presence or history of brain metastases.

The trial enrolled 227 patients to each treatment group across sites in Asia, Europe, and North America. The primary end point was PFS assessed by blinded independent central review, while secondary end points included objective response rate and duration of response assessed by blinded independent central review and investigators, progression-free survival 2, overall survival, pharmacokinetics, and safety.

The June 9, 2026, data cutoff included a median follow-up of 21.6 months in the T-DXd arm and 20.4 months in the pembrolizumab plus chemotherapy arm. At that point, 40 patients (17.7%) receiving T-DXd and 10 patients (4.5%) receiving pembrolizumab plus chemotherapy remained on study treatment. Approximately 75.8% of patients in the T-DXd arm had de novo metastatic disease, while 22.9% had brain metastases at baseline. Patients could have received radiotherapy, chemotherapy, immunotherapy, or targeted therapy for earlier-stage disease.

“DESTINY-Lung04 is the first Phase III trial to demonstrate superior progression-free survival versus the global first-line standard of care in patients with HER2-mutant advanced non-small cell lung cancer. These results add to the growing body of evidence supporting Enhertu as an important treatment for patients with HER2 alterations and underscore its potential role at the time of metastatic diagnosis, when treatment has the greatest opportunity to improve outcomes,” Susan Galbraith, executive vice president, Oncology Haematology R&D, AstraZeneca, said in a statement.¹

References

1. AstraZeneca. Enhertu demonstrated a median progression-free survival of 14.3 months as 1st-line therapy in patients with HER2-mutant advanced non-small cell lung cancer in DESTINY-Lung04 Phase III trial. Published September 14, 2026. Accessed September 15, 2026. https://tinyurl.com/mr2yz2zj

2. Rotow J, Okamoto I, Goto K, et al. First-line trastuzumab deruxtecan (T-DXd) in patients with metastatic HER2-mutant NSCLC: DESTINY-Lung04 primary results. Presented at: International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract PL03.08.