HER2-mutated non-small cell lung cancer (NSCLC) is an aggressive molecular subtype associated with a high risk of brain metastases and poor prognosis. Mutations in the HER2-encoding ERBB2 gene are detected in 2% to 4% of non-squamous NSCLCs.

Chemo-immunotherapy has been the global frontline standard in this setting, Julia Rotow, MD, said. However, she said “chemo-immunotherapy offers limited response rates and limited durability of [treatment] effect in this patient population, highlighting the need for personalized HER2-directed treatment options.”

Dr. Rotow, Assistant Professor of Medicine at the Harvard Medical School and Clinical Director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute in Boston, presented the primary results from the global phase III DESTINY-Lung04 study during the second Presidential Symposium at the 2026 World Conference on Lung Cancer on September 14. The study compared the HER2-directed antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) to standard-of-care (SoC) pembrolizumab combined with platinum doublet-based chemotherapy and pemetrexed as first-line treatment for patients with metastatic NSCLC whose tumors harbored HER2 exon 19 or exon 20 mutations.

Presidential Symposium 2

T-DXd for HER2-mutated NSCLC

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Dr. Rotow said T-DXd significantly improved progression-free survival (PFS) by blinded independent committee review (BICR), the primary endpoint of DESTINY-Lung04, compared with pembrolizumab plus chemotherapy. She said the median PFS per BICR was 14.3 months with T-DXd versus 8.3 months with chemo-immunotherapy, resulting in a 37% reduction in risk of progression or death (HR 0.63; 95% CI, 0.50-0.79; P<0.0001).

James Chih-Hsin Yang, MD, PhD, Executive Vice President of National Taiwan University, Taiwan, who discussed the study findings, framed the 6-month improvement in median PFS with T-DXd as “unprecedented” for a monotherapy in frontline metastatic NSCLC, adding, “such data are very rare.”

Analyses of PFS outcomes stratified by prespecified factors showed PFS advantage with T-DXd across subgroups, including in patients with brain or liver metastases, with a history of tobacco use, and in those aged 65 or older.

In addition to the PFS benefit, Dr. Rotow said the secondary endpoints of overall response rate (ORR), median duration of response (mDOR), and median PFS2 favored T-DXd. ORR was 70% with T-DXd versus 40.5% with chemo-immunotherapy; mDOR was 13.4 months versus 9.7 months; and mPFS2 was 22.7 months versus 17.3 months.

These data highlight the durability of the treatment effect with T-DXd, she said.

“Interim OS analysis did not demonstrate an OS benefit with T-DXd, with more formally powered OS analyses [currently] pending,” Dr. Rotow added. The median OS was 29.3 months with T-DXd, compared with 33.1 months with chemo-immunotherapy, with a hazard ratio of 1.15.

Dr. Rotow shared data on the subsequent therapies that patients received after discontinuing all study treatments. More patients remained on treatment in the T-DXd arm than in the comparator arm, 17.7% versus 4.5%, and subsequent anti-cancer therapy use was similar between arms, 71.5% versus 72.4%.

However, subsequent HER2-directed therapy use was imbalanced: 48.0% of patients in the chemo-immunotherapy arm received subsequent HER2-targeted treatments, compared with 22.9% in the T-Dxd arm. Also, while all patients in the chemo-immunotherapy arm received immunotherapy by definition, less than a quarter (23.8%) in the T-Dxd arm received subsequent immunotherapy.

Dr. Rotow said this imbalance in access to both HER2-directed and immunotherapy may impact interpretation of the OS findings.

Summarizing the safety findings, Dr. Rotow said, “While median treatment duration was longer in the T-Dxd arm, similar rates of higher-grade adverse events (AEs) and AEs associated with dose modification or treatment discontinuation were seen in both arms.”

Consistent with the known safety profile of T-DXd, more interstitial lung disease (ILD) events were reported with T-DXd; most (78.7%) were grade 1 or 2, and a majority (66%) resolved with supportive care/appropriate management.

Notably, in most (90%) cases where ≥grade 3 ILD events were reported, steroid initiation was delayed, or suboptimal dosing of steroids was used. Dr. Rotow said ILD remains an important risk of T-DXd and should be monitored and managed appropriately.

In his discussion, Dr. Yang agreed. “There is room for improvement in managing T–DXd–associated toxicities,” he said.

Dr. Yang contextualized the DESTINY-Lung04 data in the current landscape of HER2-directed therapies in NSCLC. He noted that DESTINY-Lung04 is the first global prospective randomized study to compare a HER2-directed therapy with chemo-immunotherapy in the first-line setting in this population.

Two other HER2-directed small molecule TKIs, zongertininb and sevabertinib, gained accelerated approval in 2026 in the first-line setting based on single-arm studies.

Dr. Yang said that, overall, one-year PFS outcomes from the single-arm phase1/2 Beamion LUNG-1 and SOHO-01 trials of first-line HER2-selective TKIs zongertinib and sevabertinib, respectively, in patients with HER2-mutated metastatic NSCLC are comparable to those seen with T-DXd in DESTINY-Lung04.

T-DXd is poised to enter the first-line setting in HER2-mutated NSCLC, with likely regulatory approval based on the DESTINY-Lung04 data, Dr. Yang concluded. T-DXd, as well as zongertinib and sevabertinib, are likely to be included as first-line options when clinical practice guidelines undergo revision, he said. Nevertheless, he noted that first-line chemo-immunotherapy still has a role in a subset of patients with HER2-altered NSCLC.