In the first-line treatment of patients with advanced HER2-mutant non-small cell lung cancer (NSCLC), trastuzumab deruxtecan (T-DXd) monotherapy confers a 6-month improvement in progression-free survival (PFS) compared with pembrolizumab plus chemotherapy, as shown in the phase III DESTINY-Lung04 trial.
Median PFS was 14.3 months with T-DXd vs 8.3 months with pembrolizumab plus chemotherapy, for a 37-percent reduction in the risk of disease progression or death (hazard ratio [HR], 0.63, 95 percent confidence interval [CI], 0.50–0.79; p<0.0001). [WCLC 2026, abstract 1052]
“The PFS benefit with T-Dxd was consistently observed across prespecified subgroups, including patients with brain or liver metastases, patients over age 65 years, and patients with history of tobacco use,” reported first study author Dr Julia Rotow from Dana–Farber Cancer Institute in Boston, Massachusetts, US.
The objective response rate (ORR) was 70 percent with T-DXd vs 44.5 percent with pembrolizumab plus chemotherapy (odds ratio, 2.93, 95 percent CI, 2.00–4.34). Median duration of response was longer with T-DXd (13.4 vs 9.7 months), as was median PFS2 (22.7 vs 17.3 months; HR, 0.80, 95 percent CI, 0.62–1.02).
No OS advantage
However, interim overall survival (OS) analysis showed an unfavourable trend for T-DXd, with a median of 29.3 months as compared with 33.1 months with pembrolizumab plus chemotherapy (HR, 1.15, 95 percent CI, 0.88–1.52). Data maturity for OS was 46.9 percent at cutoff, with a median follow-up of 21.6 months in the T-DXd group and 20.4 months in the pembrolizumab plus chemotherapy group.
Nevertheless, Rotow pointed out that the median OS of 29–33 months was strikingly better than that historically reported for this patient population, “reflecting advances in the overall treatment of options available for patients with HER2-mutant lung cancer and overall progress in the field.”
She also noted that the changes in available HER2-directed standard of care in the subsequent line of therapy occurring during the study may have impacted the OS findings.
Subsequent treatment imbalance
While a similar proportion of patients in the T-DXd and pembrolizumab plus chemotherapy groups received subsequent treatment (71.5 percent and 72.4 percent, respectively), more patients in the pembrolizumab plus chemotherapy group subsequently received HER2-directed therapies (48 percent vs 23.3 percent), including antibody-drug conjugates (ADCs; 33 percent vs 5.3 percent) and tyrosine kinase inhibitors (TKIs; 27.8 percent vs 18.1 percent).
In contrast, more patients in the T-DXd group received immunotherapy in subsequent line of treatment (28.6 percent vs 5.3 percent).
Dr Julia Rotow, Dana–Farber Cancer Institute, Boston, Massachusetts, USILD safety concerns
The rates of drug-related adverse events (AEs) were similar between the two treatment groups, despite a longer median treatment duration with T-DXd group vs pembrolizumab plus chemotherapy (12.3 vs 7.1 months), according to Rotow.
Drug-related grade ≥3 AEs occurred in 34.1 percent and 33.6 percent of patients in the T-DXd and pembrolizumab plus chemotherapy groups, respectively, and drug-related AEs led to treatment discontinuation in 15.9 percent in both groups. The most common drug-related grade ≥3 AE was neutropenia in both groups.
As for AEs of special interest, interstitial lung disease (ILD) was more common in the T-DXD group, occurring in 20.8 percent of patients vs 2.3 percent in the pembrolizumab plus chemotherapy group. Most ILD events in the T-DXd group were grade 1 or 2 (78.7 percent) and resolved in 66 percent. Nine of the 10 grade ≥3 ILD events were found to have had delayed or suboptimal dosing of steroids, including all four grade five cases.
“ILD remains an important risk of T-DXd and should be monitored and managed properly,” Rotow said.
Moving up to first-line setting
T-DXd is an HER2-directed ADC approved in multiple countries worldwide for previously treated unresectable or metastatic NSCLC with activating HER2 mutations. DESTINY-Lung04 establishes T-DXd as a new first-line option in the treatment of advanced HER2-mutant NSCLC, said study discussant Dr James Yang from the National Taiwan University Hospital in Taipei, Taiwan.
Yang noted that the 70-percent ORR, 14.4-month duration of response, and 14.3-month PFS seen with T-DXd are “unprecedented” for a first-line monotherapy in advanced NSCLC. The PFS outcome, he added, is similar to that observed with two HER2-directed TKIs, zongertinib and sevabertinib, both of which gained accelerated approval based on the single-arm phase I/II Beamion LUNG-1 and SOHO-01 trials, respectively. [N Engl J Med 2025;392:2321-2333; N Engl J Med 2025;393:1819-1832]
Yang also pointed out that some of the drug-related AEs reported for T-DXd in the second-line setting decreased in frequency when the drug was administered as a first-line therapy, although ILD remained a major safety consideration. However, despite the elevated incidence of ILD, most patients were still able to receive second-line treatment, he said.
“I’m sure that T-DXd will be listed in guidelines as a frontline option for treating metastatic or unresectable HER2-mutated NSCLC. Whether it will be preferred, I have doubts,” Yang said. “We must allow patients to receive all active treatments in order to achieve the highest overall survival at the end of the day.”
DESTINY-Lung04
The global, open-label phase III trial included 454 patients (median age 62 years, 58.1 percent female, 49.6 percent enrolled in Asia, 62.1 percent nonsmokers) with unresectable locally advanced or metastatic non-squamous NSCLC. To be included in the trial, the patients were required to be naïve to treatment, have HER2 exon 19 or 20 mutation, have ECOG PS of 0 or 1, and have at least one measurable lesion. Those with asymptomatic, stable, or treated brain metastases were allowed.
The patients were randomly assigned to receive treatment with T-DXd at 5.4 mg/kg every 3 weeks (n=227) or pembrolizumab combined with platinum chemotherapy (cisplatin or carboplatin) and pemetrexed (n=227). The primary endpoint was PFS, as assessed by blinded independent central review. Secondary endpoints included OS, ORR, duration of response, investigator-assessed PFS, and safety.
Rotow shared that formal hypothesis testing for OS will be performed at second interim and final analyses.