T-DXd improved PFS in the phase 3 DESTINY-Lung04 trial for first-line HER2-mutant NSCLC.
Improved efficacy and consistent safety was shown for the antibody-drug conjugate (ADC), fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) vs standard of care treatment in unresectable, locally advanced, or metastatic HER2-mutant non-squamous, non-small cell lung cancer (NSCLC) in the frontline setting, according to topline results from the phase 3 DESTINY-Lung04 trial (NCT05048797).
Data from the trial reported that T-DXd produced a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs global standard of care as first-line treatment (n = 454). A consistent safety profile with T-DXd was also reported, with no new safety concerns being raised.
“DESTINY-Lung04 [has] become the first phase 3 trial to demonstrate a PFS benefit versus the global standard of care in this first-line setting, supporting the potential for T-DXd to move earlier in the treatment of HER2-mutated NSCLC,” Susan Galbraith, MD, PhD, executive vice president of Oncology Hematology Research and Development at AstraZeneca said in a news release. “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.”
The global, randomized, open-label trial enrolled patients who were 18 years of age with unresectable, locally advanced, or metastatic, non-squamous NSCLC harboring a HER2 exon 19 or exon 20 mutations.2 Patients also needed to have an ECOG performance status of 1 or less, adequate organ function, measurable disease per RECIST 1.1 criteria, left ventricular ejection fraction of at least 50%, and be treatment naive for palliative intent systemic therapy for locally advanced or metastatic disease.
If patients had targetable alterations to EGFR or other targetable mutations, untreated brain metastases, autoimmune disorders, or myocardial infarction within 6 months, they were not included in the trial.
Patients were randomly assigned to receive T-DXd or standard of care, stratified by smoking history and presence or history of brain metastases.1 Patients in the standard of care arm received a combination of cisplatin, carboplatin, pembrolizumab (Keytruda), and pemetrexed.
The primary end point of DESTINY-Lung04 is PFS by blinded independent central review (BICR), alongside secondary end points like overall survival (OS), overall response rate, duration of response per BICR, pharmacokinetics and safety.
T-DXd is currently approved in multiple breast cancer settings based on data from several trials like the phase 3 DESTINY-Breast11 trial (NCT05113251) which supported the
“T-DXd is already established as the first and only ADC 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, MD, executive vice president and global head of Research and Development at Daiichi Sankyo in a news release.
DESTINY-Lung04 will continue as planned to evaluate secondary end points like OS and data are expected to be presented at an upcoming meeting.
