Positive high-level results from the DESTINY-Lung04 Phase III trial showed Enhertu (trastuzumab deruxtecan) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) versus global standard of care (platinum-pemetrexed doublet chemotherapy plus pembrolizumab) as 1st-line treatment of patients with unresectable, locally advanced or metastatic HER2-mutant non-squamous non-small cell lung cancer (NSCLC). The trial will continue as planned to evaluate secondary endpoints including overall survival.
The global standard of care for patients with HER2-mutant NSCLC in the 1st-line metastatic setting is a combination of immunotherapy and platinum-based chemotherapy.1-3 However, many patients do not respond to 1st-line treatment and experience disease progression, underscoring the need for additional treatment options.3-7 Approximately 2-4% of patients with NSCLC have tumours with a HER2 mutation.8-10
Susan Galbraith, Executive Vice President, Oncology Haematology R&D, AstraZeneca, said: “Our oncology pipeline continues to advance with DESTINY-Lung04 becoming the first Phase III trial to demonstrate a progression-free survival benefit versus the global standard of care in this first-line setting, supporting the potential for Enhertu to move earlier in the treatment of HER2-mutant non-small cell lung cancer. 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.”
John Tsai, Global Head, R&D, Daiichi Sankyo, said: “Enhertu is already established as the first and only antibody drug conjugate for the second-line treatment of HER2-mutant metastatic non-small cell lung cancer. The positive results seen in DESTINY-Lung04 show that treatment with Enhertu 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.”
The safety profile of Enhertu observed in DESTINY-Lung04 was generally consistent with its known profile, with no new safety concerns identified.
The DESTINY-Lung04 data will be presented at a forthcoming medical meeting and shared with global regulatory authorities.
Enhertu is currently approved to treat patients with previously treated metastatic NSCLC whose tumours have activating HER2 (ERBB2) mutations, and to treat patients with HER2-positive solid tumours, including HER2-overexpressing metastatic NSCLC, who have received prior treatment and who have no satisfactory treatment options.
Enhertu is a specifically engineered HER2-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.
Notes
HER2-mutant NSCLC
Lung cancer is the most commonly diagnosed cancer globally and remains the leading cause of cancer-related death in both men and women.11 In 2024, approximately 2.6 million new lung cancer cases were reported worldwide, with an estimated 1.8 million deaths.11 NSCLC is the most common type of lung cancer, accounting for approximately 85% of cases.12 Prognosis is particularly poor for patients with metastatic NSCLC as only approximately 10% will live beyond five years after diagnosis.13-15
HER2 is a tyrosine kinase receptor protein involved in cell growth and differentiation and expressed on the surface of multiple tumour types. HER2 mutations have been identified in NSCLC as distinct molecular targets and have been reported in approximately 2-4% of patients with non-squamous NSCLC.8-10 These HER2 mutations are predominantly seen in younger women and people with no smoking history and have been independently associated with cancer cell growth and poor prognosis, with an increased incidence of brain metastases.8,16-20
The global standard of care in the 1st-line metastatic setting for patients with HER2-mutant NSCLC is a combination of immunotherapy and platinum-based chemotherapy.1-3 While these treatment regimens have been shown to improve survival in NSCLC, many patients do not respond to 1st-line treatment and experience disease progression, underscoring the need for additional treatment options.3-7
DESTINY-Lung04
DESTINY-Lung04 is a global, randomised, open-label, Phase III trial evaluating the efficacy and safety of Enhertu (5.4mg/kg) compared to standard of care (platinum-pemetrexed doublet chemotherapy in combination with pembrolizumab) in patients with unresectable, locally advanced or metastatic, non-squamous NSCLC harbouring a HER2 exon 19 or 20 mutation.
Patients were randomised 1:1 to receive either Enhertu or standard of care. Randomisation was stratified by smoking history and presence or history of brain metastasis. The primary endpoint of DESTINY-Lung04 is PFS as assessed by blinded independent central review (BICR). Secondary endpoints include OS, investigator-assessed PFS, overall response rate and duration of response as assessed by BICR and investigator, pharmacokinetics and safety.
