First-line trastuzumab deruxtecan reduced the risk of progression or death by 37% compared with pembrolizumab plus chemotherapy in HER2-mutant non–small cell lung cancer.
First-line fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), a HER2-directed antibody-drug conjugate (ADC), reduced the risk of disease progression or death by 37% compared with pembrolizumab (Keytruda) plus platinum-based chemotherapy and pemetrexed in patients with unresectable, locally advanced, or metastatic HER2-mutant nonsquamous non–small cell lung cancer (NSCLC), according to data from the phase 3 DESTINY-Lung04 trial (NCT05048797) presented in a presidential symposium at the
At a data cutoff of June 9, 2026, with a median follow-up of 21.6 months (range, 0.4-51.1) in the T-DXd arm and 20.4 months (range, 0.1-52.0) in the chemoimmunotherapy arm, the median progression-free survival (PFS) by blinded independent central review (BICR) was 14.3 months (95% CI, 12.4-16.5) with T-DXd vs 8.3 months (95% CI, 7.0-9.9) with pembrolizumab plus chemotherapy (HR, 0.63; 95% CI, 0.50-0.79; P < .0001).
“DESTINY-Lung04 is the first phase 3 trial to demonstrate the benefit of a HER2-directed therapy vs global standard of care as upfront treatment for patients with HER2-mutant NSCLC,” lead study author Julia Rotow, MD, stated in the presentation. Rotow is the clinical director of the Lowe Center for Thoracic Oncology, director of clinical research, and an assistant professor of medicine at Harvard Medical School at Dana-Farber Cancer Institute in Boston, Massachusetts.
DESTINY-Lung04 is a global, randomized, open-label, multicenter trial that enrolled 454 patients with treatment-naive, unresectable locally advanced or metastatic nonsquamous NSCLC harboring a HER2 exon 19 or 20 mutation, with WHO/ECOG performance status of 0 or 1, and at least 1 measurable lesion per RECIST 1.1; asymptomatic or stable brain metastases were permitted.
Patients were randomly assigned 1:1, stratified by brain metastases history and smoking status, to T-DXd monotherapy at 5.4 mg/kg intravenously every 3 weeks (n = 227) or pembrolizumab at 200 mg intravenously every 3 weeks plus investigator's choice of platinum chemotherapy and pemetrexed for up to 4 cycles followed by maintenance pemetrexed (n = 227). The primary end point was PFS by BICR; secondary end points included overall survival (OS), objective response rate (ORR) and duration of response (DOR) by BICR, investigator-assessed second PFS (PFS2), and safety.
HER2 mutations occur in approximately 2% to 4% of nonsquamous NSCLCs and carry a poor prognosis. T-DXd is already approved in the second-line setting for HER2-mutant metastatic NSCLC; DESTINY-Lung04 is the first global randomized phase 3 trial testing a HER2-directed therapy against standard-of-care chemoimmunotherapy in the first-line setting. AstraZeneca first announced topline PFS results from the trial in August 2026, ahead of the full presentation at WCLC.2,3 The findings add to an evolving debate over sequencing HER2-directed ADCs and oral tyrosine kinase inhibitors in the frontline HER2-mutant NSCLC setting.4
The confirmed ORR by BICR was 70.0% (95% CI, 63.6%-75.9%) with T-DXd vs 44.5% (95% CI, 37.9%-51.2%) with pembrolizumab plus chemotherapy (odds ratio, 2.93; 95% CI, 2.00-4.34), including partial responses in 68.3% vs 42.7% of patients.1 The median DOR by BICR was 13.4 months (95% CI, 10.4-17.2) with T-DXd vs 9.7 months (95% CI, 7.0-11.1), and investigator-assessed median PFS2 was 22.7 months (95% CI, 20.3-26.3) vs 17.3 months (95% CI, 15.6-21.8; HR, 0.80; 95% CI, 0.62-1.02).
The PFS benefit with T-DXd was consistent across prespecified subgroups, including patients with and without brain metastases (HR, 0.62 and 0.65, respectively), those with exon 20 vs exon 19 mutations (HR, 0.65 and 0.46, respectively), and those with liver metastases at baseline (HR, 0.41) vs without (HR, 0.67).
At this first interim analysis (46.9% OS data maturity, no formal hypothesis testing performed), OS did not favor T-DXd. OS events occurred in 115 patients (50.7%) in the T-DXd arm and 98 patients (43.2%) in the pembrolizumab plus chemotherapy arm; median OS was 29.3 months (95% CI, 26.2-33.4) with T-DXd vs 33.1 months (95% CI, 27.7-40.7) with pembrolizumab plus chemotherapy (HR, 1.15; 95% CI, 0.88-1.52). Investigators noted the trend may partly reflect an imbalance in subsequent therapy: among patients who discontinued study treatment, similar proportions received any subsequent anticancer therapy (71.5% vs 72.4%), but more patients in the pembrolizumab plus chemotherapy arm went on to receive subsequent HER2-directed therapy than those in the T-DXd arm (48.0% vs 22.9%). Formal OS testing is planned at a second interim and final analysis.
Investigator-assessed drug-related adverse effects (AEs) of any grade occurred in 90.3% of patients treated with T-DXd (n = 226) and 89.5% of patients treated with pembrolizumab plus chemotherapy (n = 220); grade 3 or higher drug-related AEs occurred in 34.1% and 33.6% of patients, respectively, and serious drug-related AEs occurred in 15.5% vs 10.0%. Drug-related AEs led to treatment discontinuation in 15.9% of patients in both arms and to death in 4 patients (1.8%) in the T-DXd arm (all pneumonitis) vs 1 patient (0.5%) in the pembrolizumab plus chemotherapy arm (sepsis). The most common drug-related AEs (≥15% in either arm) included nausea, fatigue, neutropenia, alopecia, decreased appetite, anemia, constipation, diarrhea, increased transaminases, leukopenia, vomiting, thrombocytopenia, stomatitis, and rash.
Adjudicated drug-related interstitial lung disease (ILD) or pneumonitis occurred in 20.8% of patients treated with T-DXd vs 2.3% with pembrolizumab plus chemotherapy, including grade 5 events in 4 patients (1.8%) vs none with T-DXd and chemoimmunotherapy, respectively. Most ILD/pneumonitis cases in the T-DXd arm were grade 1 or 2 (78.7%) and resolved (66.0%); investigators noted that delayed or suboptimal steroid dosing was observed in 90% of grade 3 or higher ILD cases, including all 4 grade 5 cases. Left ventricular dysfunction of any grade occurred in 3.1% of patients treated with T-DXd vs 0.5% with pembrolizumab plus chemotherapy. Investigators concluded that the safety profile of each regimen was generally consistent with its known profile.
