T-DXd Improves PFS vs Standard of Care in First-Line HER2-Mutant NSCLC

The antibody-drug conjugate (ADC) rastuzumab deruxtecan (T-DXd; Enhertu) produced a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with global standard of care as first-line treatment for patients with unresectable, locally advanced, or metastatic, nonsquamous HER2-mutant non–small cell lung cancer (NSCLC), according to topline results from the phase 3 DESTINY-Lung04 trial (NCT05048797).¹

DESTINY-Lung04 is the first phase 3 trial in which a HER2-directed medicine has improved PFS over global standard of care in this first-line setting. Standard of care in this population is a platinum-pemetrexed doublet chemotherapy plus pembrolizumab (Keytruda). The trial will continue as planned to evaluate secondary end points, including overall survival (OS); specific PFS data were not disclosed, and the sponsors said full results will be presented at a forthcoming medical meeting and shared with global regulatory authorities.

"[T-DXd] is already established as the first and only antibody drug conjugate for the second-line treatment of HER2-mutant metastatic [NSCLC]. The positive results seen in DESTINY-Lung04 show that treatment with [T-DXd] in the first-line setting delays disease progression compared to the global standard of care, highlighting its potential to improve outcomes for patients earlier in the treatment of metastatic disease,” said John Tsai, global head, Research and Development, Daiichi Sankyo, in a news release.¹

Study Design

DESTINY-Lung04 is a global, randomized, open-label, phase 3 trial evaluating T-DXd (5.4 mg/kg) vs standard of care (platinum-pemetrexed doublet chemotherapy plus pembrolizumab) in patients with unresectable, locally advanced, or metastatic, nonsquamous NSCLC harboring a HER2 exon 19 or 20 mutation.^1,2 Patients were randomized 1:1, with stratification by smoking history and presence or history of brain metastasis.² The primary end point is PFS by blinded independent central review (BICR); secondary end points include OS, investigator-assessed PFS, overall response rate, and duration of response by BICR and investigator assessment, as well as pharmacokinetics and safety. The trial enrolled 454 patients across sites in Asia, Europe, and North America.

Clinical Context and Limitations

HER2 mutations occur in approximately 2% to 4% of patients with nonsquamous NSCLC and are more common among younger patients, women, and those with no smoking history; they have been independently associated with tumor growth, poorer prognosis, and a higher incidence of brain metastases.¹ Standard first-line treatment for HER2-mutant NSCLC combines immunotherapy with platinum-based chemotherapy, but many patients do not respond or eventually progress, reflecting a need for additional options.

T-DXd is not currently approved for first-line use. It is approved to treat previously treated, metastatic NSCLC with activating HER2 (ERBB2) mutations, based on the DESTINY-Lung02 (NCT04644237) and DESTINY-Lung05 (NCT05246514) trials, and to treat previously treated HER2-positive solid tumors, including HER2-overexpressing metastatic NSCLC, in patients with no satisfactory alternative options.

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/2kvrxyrh

2. An Open-label, Randomized, Multicenter, Phase 3 Study to Assess the Efficacy and Safety of Trastuzumab Deruxtecan as First-line Treatment of Unresectable, Locally Advanced, or Metastatic NSCLC Harboring HER2 Exon 19 or 20 Mutations (DESTINY-Lung04). ClinicalTrials.gov. Updated July 1, 2026. Accessed August 18, 2026. https://clinicaltrials.gov/study/NCT05048797