First-line trastuzumab deruxtecan (T-DXd; ENHERTU) improves progression-free survival compared with standard chemoimmunotherapy in patients with advanced or metastatic HER2-mutant non-small cell lung cancer (NSCLC), according to new phase 3 data.

Among over 400 patients in the DESTINY-Lung04 trial, T-DXd achieved an “unprecedented” median progression-free survival of 14.3 months vs 8.3 months with pembrolizumab plus platinum-based chemotherapy.

This is the first phase 3 trial to show benefit from HER2-directed therapy over standard-of-care therapy as upfront treatment for patients with HER2-mutant NSCLC, according to researcher Julia Rotow, MD, of Dana-Farber Cancer Institute in Boston.

It “establishes T-DXd as a new first-line treatment option,” she said during a presentation at the World Conference on Lung Cancer (WCLC) 2026 in Seoul, Korea.

At the same time, the trial showed no improvement in overall survival with T-DXd, at a median of 29 months vs 33 months with chemoimmunotherapy. Whether that partly reflects imbalances in subsequent therapies remains an open question, Rotow said.

HER2-mutant NSCLC is a rare but aggressive malignancy, and patients often don’t respond to first-line immunotherapy plus chemotherapy.

Earlier this year, zongertinib tablets became the first targeted treatment to be recommended as initial therapy for this patient group by the National Comprehensive Cancer Network.

On the basis of the new results, T-DXd might be added to the list, according to James Chih-Hsin Yang, MD, PhD, of National Taiwan University in Taipei, Taiwan, who served as the study discussant at the conference.

Whether chemoimmunotherapy should be moved to the second-line setting is up for discussion, Yang added.

The open-label DESTINY-Lung04 enrolled treatment-naive patients with unresectable locally advanced or metastatic NSCLC harboring HER2 exon 19 or exon 20 mutations.

A total of 454 patients were randomly assigned to receive either T-DXd 5.4 mg/kg intravenously (IV) every 3 weeks or pembrolizumab 200 mg IV every 3 weeks, plus platinum chemotherapy (cisplatin 75 mg/m² or carboplatin area under the curve of 5 IV) and pemetrexed 500 mg/m² IV. The primary endpoint was progression-free survival by blinded independent central review.

Over a median follow-up of about 21 months, median progression-free survival was 14.3 months vs 8.3 months with T-DXd vs standard therapy, representing a 6-month hazard ratio of 0.63 (P < .0001).

Rotow said the benefit was consistent across prespecified subgroups, including patients with brain or liver metastases, patients older than 65 years, and those with a history of tobacco use.

The objective response rate was 70% vs 44.5% with T-DXd vs the control arm (odds ratio, 2.93; 95% CI, 2.00-4.34). Median duration of response was 13.4 months and 9.7 months, respectively.

There was no evidence of benefit for overall survival, with 115 deaths (50.7%) in the T-DXd arm and 98 (43.2%) in the chemoimmunotherapy arm, and a hazard ratio of 1.15 (95% CI, 0.88-1.52). Rotow said formal hypothesis-testing was still pending, but subsequent treatments may have affected those outcomes.

“There was overlap of the survival curves until approximately 24 months, at which point there was late divergence,” she said during her presentation. “Changes in available HER2-directed standard-of-care in the subsequent line occurred during the course of the study and may have impacted overall survival findings.”

Among patients discontinuing all study treatments, more than twice as many in the control arm subsequently received HER2-directed therapy (48% vs 23% in the T-DXd arm).

As for safety, investigator-assessed drug-related adverse events occurred in 90.3% vs 89.5% of patients in the T-DXd arm vs the control arm, with 15.5% and 10% judged as serious, respectively.

Nearly 21% of patients receiving T-DXd developed drug-related interstitial lung disease (ILD)/pneumonitis compared with only 2.3% of those receiving chemoimmunotherapy. Most cases in the T-DXd arm (79%) were grade 1 or 2, and 66% resolved; among patients who developed grade 3 or less ILD and discontinued T-DXd, 64% received subsequent therapy.

Responding to a question from the audience, Rotow said that while ILD requires appropriate monitoring and management to prevent worsening, “reassuringly…we saw that patients who did experience ILD still went on to next-line therapies at similar rates to other arms in the study and to patients without ILD.”

Yang, who was a co-investigator on the trial, acknowledged that the lack of overall survival benefit was “disturbing.”

But like Rotow, he said the finding may be related to use of effective subsequent therapies, including zongertinib and sevabertinib, which was approved earlier this month in the US for first-line treatment of locally advanced or metastatic non-squamous NSCLC.

This study was sponsored by AstraZeneca. Both Rotow and Yang reported financial ties to the company.