Targeted Therapy Improves Outcomes in HER2 Lung Cancer: WCLC 2026

TRASTUZUMAB deruxtecan (T-DXd) significantly improved progression-free survival (PFS) compared with pembrolizumab plus chemotherapy in patients with previously untreated advanced or metastatic HER2-mutant non-small cell lung cancer (NSCLC), according to Phase III DESTINY-Lung04 data, presented at the WCLC 2026 Congress.

The global, open-label, randomised Phase III trial enrolled patients with unresectable locally advanced or metastatic HER2-mutant NSCLC involving exon 19 or 20. A total of 454 patients were randomised to intravenous T-DXd at 5.4 mg/kg every 3 weeks or pembrolizumab 200 mg every 3 weeks combined with platinum chemotherapy and pemetrexed.

The primary endpoint was PFS assessed by blinded independent central review. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR) and safety.

T-DXd Extends PFS And Improves Responses

At the 9 June 2026 data cut-off, median follow-up was 21.6 months with T-DXd and 20.4 months with pembrolizumab plus chemotherapy. T-DXd produced a statistically significant improvement in PFS, with median PFS of 14.3 months compared with 8.3 months (hazard ratio (HR): 0.63; 95% CI: 0.50–0.79; P<0.0001).

The objective response rate was also higher with T-DXd: 70.0% compared with 44.5% (odds ratio (OR): 2.93; 95% CI: 2.00–4.34). Median DOR was 13.4 months with T-DXd versus 9.7 months with pembrolizumab plus chemotherapy.

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). However, subsequent treatments were imbalanced between the groups, with later therapies primarily involving HER2-directed and immunotherapy-based treatments, which the investigators noted complicated interpretation of the OS findings.

Safety Profile and Clinical Implications

Adjudicated drug-related interstitial lung disease (ILD) or pneumonitis occurred in 20.8% of patients receiving T-DXd compared with 2.3% receiving pembrolizumab plus chemotherapy. Among T-DXd-treated patients who developed ILD or pneumonitis, 78.7% of events were Grade 1 or 2. All events in the pembrolizumab plus chemotherapy group were Grade 1 or 2.

The investigators reported that safety was generally consistent with the established profile of T-DXd.

DESTINY-Lung04 was described as the first global Phase III trial to demonstrate a statistically significant and clinically meaningful PFS improvement with first-line T-DXd over pembrolizumab plus chemotherapy in advanced or metastatic HER2-mutant NSCLC. The improved response rate and response durability further supported T-DXd as a new first-line treatment option for this patient population.

References

Rotow J et al. First-Line Trastuzumab Deruxtecan (T-DXd) in Patients With Metastatic HER2-Mutant NSCLC: DESTINY-Lung04 Primary Results. Abstract PL03.08. WCLC Congress; 12-15 September 2026.

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