Trastuzumab Deruxtecan Boosts PFS in First-Line HER2-Mutant NSCLC

First-line fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) showed a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs standard of care in patients with unresectable, locally advanced or metastatic HER2-mutated nonsquamous non–small cell lung cancer (NSCLC), according to a news release from AstraZeneca on the phase 3 DESTINY-Lung04 trial (NCT05048797).¹

What did DESTINY-Lung04 show?

Topline results from DESTINY-Lung04 showed that T-DXd produced a statistically significant and clinically meaningful improvement in PFS vs the global standard of care as first-line treatment. According to the developers, this makes T-DXd the first and only HER2-directed medicine to improve PFS over the global standard of care in a phase 3 trial in this setting.

The safety profile of trastuzumab deruxtecan was generally consistent with its known profile. No new safety concerns were identified.

Investigators will continue to evaluate secondary end points such as overall survival (OS). Additionally, the data will be presented at a future medical meeting and shared with global regulatory authorities.

“DESTINY-Lung04 [is] the first phase 3 trial to demonstrate a [PFS] benefit vs the global standard of care in this first-line setting, supporting the potential for [T-DXd] to move earlier in the treatment of HER2-mutant [NSCLC],” said Susan Galbraith, executive vice president of oncology hematology research and development at AstraZeneca, in the press release.¹ “This aggressive lung cancer often affects younger patients and has historically had limited first-line targeted treatment options, making these positive results an important step forward in bringing additional effective therapies to patients at metastatic diagnosis when there is the greatest opportunity to improve outcomes.”

What is the DESTINY-Lung04 trial design?

DESTINY-Lung04 is a global, randomized, open-label, phase 3 trial evaluating the efficacy and safety of T-DXd at 5.4 mg/kg compared with standard of care, which consisted of platinum and pemetrexed doublet chemotherapy in combination with pembrolizumab (Keytruda), in patients with unresectable, locally advanced or metastatic nonsquamous NSCLC harboring a HER2 exon 19 or 20 mutation. The trial enrolled 454 patients across multiple sites in Asia, Europe, and North America, who were randomly assigned 1:1 to receive T-DXd or standard of care. Randomization was stratified by smoking history and presence or history of brain metastasis.

The primary end point is PFS as assessed by blinded independent central review (BICR). Secondary end points include OS, investigator-assessed PFS, overall response rate, duration of response by BICR and investigator evaluation, pharmacokinetics, and safety.

Patients 18 years and older with a left ventricular ejection fraction of at least 50%, measurable disease per RECIST v1.1 guidelines, and an ECOG performance status of 0 or 1 were eligible for enrollment on the study.² Having adequate cardiac, renal, and hepatic function was another requirement for enrollment.

What is T-DXd?

Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate (ADC) designed using the DXd ADC technology of Daiichi Sankyo. The agent consists of a HER2 monoclonal antibody attached to topoisomerase I inhibitor payloads via tetrapeptide-based cleavable linkers. It is being jointly developed and commercialized by AstraZeneca and Daiichi Sankyo.

What is the role of T-DXd in HER2-mutant NSCLC?

T-DXd is currently approved for the treatment of patients with unresectable or metastatic NSCLC whose tumors have activating HER2 mutations and who have received a prior systemic therapy. HER2 mutations have been reported in approximately 2% to 4% of patients with nonsquamous NSCLC, occurring predominantly in younger women and people with no smoking history, and have been associated with poor prognosis and an increased incidence of brain metastases.

References

1. Enhertu demonstrated statistically significant and clinically meaningful improvement in progression-free survival as 1st-line treatment of patients with HER2-mutant advanced non-small cell lung cancer in DESTINY-Lung04 phase III trial. News release. AstraZeneca. August 17, 2026. Accessed August 18, 2026. https://tinyurl.com/mrj2kwe9
2. A study to investigate the efficacy and safety of trastuzumab deruxtecan as the first treatment option for unresectable, locally advanced/​metastatic non-small cell lung cancer with HER2 mutations. ClinicalTrials.gov. Updated July 10, 2026. Accessed August 18, 2026. https://tinyurl.com/mw625vpv