AstraZeneca and Daiichi Sankyo announced positive topline results from the Phase III DESTINY-Lung04 trial, in which Enhertu (trastuzumab deruxtecan) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) as first-line treatment for patients with unresectable, locally advanced or metastatic HER2-mutant non-squamous non-small cell lung cancer (NSCLC).
Enhertu was compared with the global standard of care of platinum-pemetrexed doublet chemotherapy plus pembrolizumab. According to AstraZeneca and Daiichi Sankyo, Enhertu is the first and only HER2-directed medicine to demonstrate a PFS improvement over the global standard of care in a Phase III trial in this setting.
The companies have not yet reported the magnitude of the PFS benefit or other detailed efficacy results. The trial will continue as planned to evaluate secondary endpoints, including overall survival, and the findings will be presented at an upcoming medical meeting and shared with global regulatory authorities.
John Tsai, MD, Global Head of R&D at Daiichi Sankyo, said the findings show that first-line Enhertu “delays disease progression compared to the global standard of care,” highlighting its potential to move the treatment earlier in metastatic disease.
Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology Hematology R&D at AstraZeneca, said DESTINY-Lung04 is the first Phase III trial to demonstrate a PFS benefit over the global standard of care in this first-line setting. She described the results as “an important step forward” for patients diagnosed with metastatic HER2-mutant NSCLC.
The safety profile of Enhertu in DESTINY-Lung04 was generally consistent with its known profile, with no new safety concerns identified.
HER2 mutations are reported in approximately 2% to 4% of patients with non-squamous NSCLC. The current global standard of care in the first-line metastatic setting for patients with HER2-mutant NSCLC has generally consisted of immunotherapy combined with platinum-based chemotherapy.
About DESTINY-Lung04
DESTINY-Lung04 (NCT05048797) is a global, randomized, open-label Phase III trial evaluating the efficacy and safety of Enhertu at 5.4 mg/kg compared with platinum-pemetrexed doublet chemotherapy plus pembrolizumab in patients with unresectable, locally advanced or metastatic non-squamous NSCLC harboring a HER2 exon 19 or exon 20 mutation.
A total of 454 patients were enrolled across sites in Asia, Europe, and North America and randomized 1:1 to Enhertu or standard of care. Randomization was stratified by smoking history and the presence or history of brain metastases.
The primary endpoint is PFS assessed by blinded independent central review. Secondary endpoints include overall survival, investigator-assessed PFS, overall response rate, duration of response, pharmacokinetics, and safety.
About Enhertu
Enhertu (trastuzumab deruxtecan) is a HER2-directed antibody-drug conjugate discovered by Daiichi Sankyo and jointly developed and commercialized by Daiichi Sankyo and AstraZeneca. It consists of a HER2 monoclonal antibody linked to a topoisomerase I inhibitor payload using Daiichi Sankyo’s DXd ADC technology.
Enhertu is currently approved in more than 80 countries and regions for patients with previously treated metastatic NSCLC whose tumors harbor activating HER2 (ERBB2) mutations. It is also approved across several other HER2-directed indications.
The DESTINY-Lung04 results evaluate whether Enhertu can move into the first-line treatment setting for patients with HER2-mutant advanced NSCLC.
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