Clinical Summary: 

• Design/Population: The phase 3 DESTINY-Lung04 trial compared first-line trastuzumab deruxtecan with pembrolizumab plus platinum chemotherapy and pemetrexed in patients with treatment-naïve, unresectable locally advanced or metastatic HER2-mutant non-small cell lung cancer (NSCLC).
• Key Outcomes: Trastuzumab deruxtecan significantly improved progression-free survival (PFS), reducing the risk of disease progression or death by 37%. Trastuzumab deruxtecan also produced a higher objective response rate and longer duration of response. Overall survival did not favor trastuzumab deruxtecan at the reported analysis, although interpretation was complicated by imbalances in subsequent therapies between treatment arms.
• Clinical Relevance: These findings provide phase 3 evidence supporting HER2-directed therapy in the first-line setting and position trastuzumab deruxtecan as a new treatment option for advanced HER2-mutant NSCLC. Interstitial lung disease/pneumonitis remains an important toxicity requiring monitoring and management.

Results from the phase 3 DESTINY-Lung04 trial demonstrated that trastuzumab deruxtecan significantly improved progression-free survival (PFS) compared with pembrolizumab plus chemotherapy as first-line treatment for patients with advanced or metastatic HER2-mutant non-small cell lung cancer (NSCLC).

These results were presented in a plenary session at the World Conference on Lung Cancer by Julia Rotow, MD, Dana-Farber Cancer Institute, Boston, Massachusetts. 

In this open-label trial, 454 previously untreated patients with unresectable locally advanced or metastatic NSCLC harboring HER2 exon 19 or 20 mutations were randomized 1:1 to receive either 5.4 mg/kg of trastuzumab deruxtecan every 3 weeks or 200 mg of pembrolizumab every 3 weeks plus either 75 mg/m² of cisplatin or carboplatin at an AUC of 5 and 500 mg/m² of pemetrexed every 3 weeks. Patients were randomized based on smoking status and the presence or history of brain metastases.

The primary end point was PFS by blinded independent central review according to RECIST version 1.1. Secondary end points included overall survival (OS), objective response rate (ORR), duration of response, and safety.

At analysis, median PFS was 14.3 months in the trastuzumab deruxtecan arm and 8.3 months in the pembrolizumab plus chemotherapy arm. Trastuzumab deruxtecan reduced the risk of disease progression or death by 37% compared with pembrolizumab plus chemotherapy (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.50 to 0.79; P < .0001).

Trastuzumab deruxtecan also produced a higher ORR, at 70% compared with 44.5% with pembrolizumab plus chemotherapy. Median duration of response was 13.4 months and 9.7 months, respectively.

Median OS was 29.3 months in the trastuzumab deruxtecan arm and 33.1 months in the pembrolizumab plus chemotherapy arm. According to the investigators, interpretation of the OS findings was confounded by imbalances in subsequent treatment between the study groups, particularly the use of HER2-directed and immunotherapy-based therapies.

Overall, the safety profile of trastuzumab deruxtecan was generally consistent with its known safety profile. Interstitial lung disease (ILD)/pneumonitis remained an important safety consideration with trastuzumab deruxtecan. Adjudicated drug-related ILD/pneumonitis occurred in 20.8% of patients receiving trastuzumab deruxtecan compared with 2.3% receiving pembrolizumab plus chemotherapy. Most ILD/pneumonitis events in the trastuzumab deruxtecan arm were grade 1/2. All events reported in the control arm were grade 1/2.

DESTINY-Lung04 represents the first global phase 3 trial to demonstrate a significant PFS benefit with first-line trastuzumab deruxtecan compared with pembrolizumab plus chemotherapy in advanced or metastatic HER2-mutant NSCLC. The improvement in PFS, response rate, and response durability supports moving HER2-directed therapy into the frontline setting, although longer-term survival findings and the risk of ILD/pneumonitis remain important considerations.

Source: 

First-line trastuzumab deruxtecan (T-DXd) in patients with metastatic HER2-mutant NSCLC: DESTINY-Lung04 primary results. Presented at the World Conference on Lung Cancer; September 12-15, 2026. Seoul, South Korea. Abstract PL03.08