Positive results from the DESTINY-Lung04 Phase III trial showed AstraZeneca and Daiichi Sankyo's 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 a 1st-line treatment of patients with unresectable, locally advanced or metastatic HER2-mutant non-squamous non-small cell lung cancer (NSCLC).
Results were presented today during the Presidential Symposium at the IASLC 2026 World Conference on Lung Cancer (#WCLC26) hosted by the International Association for the Study of Lung Cancer in Seoul, South Korea (abstract #PL03.08).
In the primary endpoint of PFS, Enhertu monotherapy significantly reduced the risk of disease progression or death by 37.0% versus pembrolizumab plus chemotherapy (hazard ratio [HR] 0.63; 95% confidence interval [CI] 0.50-0.79; p<0.0001). Median PFS was 14.3 months with Enhertu compared to 8.3 months for pembrolizumab plus chemotherapy as assessed by blinded independent central review (BICR). A favourable PFS trend was seen for Enhertu across key subgroups, including the prespecified stratification factors of brain metastases, liver metastases, smoking status, HER2 mutation status (exon 19 or exon 20), and de novo or recurrent disease.
Objective response rate (ORR) with Enhertu was 70.0% versus 44.5% with pembrolizumab plus chemotherapy. Median duration of response (DoR) for Enhertu was 13.4 months and 9.7 months with pembrolizumab plus chemotherapy.
Julia Rotow, MD, Assistant Professor of Medicine, Dana-Farber Cancer Institute and lead investigator of the trial, said: "HER2-mutant non-small cell lung cancer is an aggressive disease with limited responses to current first-line standard of care, and many patients experience disease progression within a year of starting treatment. With seventy per cent of patients responding and a median progression-free survival of 14.3 months, trastuzumab deruxtecan has the potential to become an important new first-line treatment option for these patients."
Susan Galbraith, Executive Vice President, Oncology Haematology R&D, AstraZeneca, said: "DESTINY-Lung04 is the first Phase III trial to demonstrate superior progression-free survival versus the global first-line standard of care in patients with HER2-mutant advanced non-small cell lung cancer. These results add to the growing body of evidence supporting Enhertu as an important treatment for patients with HER2 alterations and underscore its potential role at the time of metastatic diagnosis, when treatment has the greatest opportunity to improve outcomes."
John Tsai, Global Head, R&D, Daiichi Sankyo, said: "Enhertu was the first HER2-directed medicine and antibody drug conjugate approved for patients with HER2-mutant non-small cell lung cancer and has become a second-line standard-of-care treatment. The progression-free survival benefit of six months and strong response rates seen in DESTINY-Lung04 reinforce the importance of targeting HER2 directly in these patients and support the potential of Enhertu in the first-line setting where delaying disease progression for as long as possible is a critical goal."
(n=227)
(12.4-16.5)
(7.0-9.9)
(95% CI)iv
(63.6-75.9)
(37.9-51.2)
(10.4-17.2)
(7.0-11.1)
(20.3-26.3)
(15.6-21.8)
(26.2-33.4)
(27.7-40.7)
At the time of analysis, the overall survival (OS) data were 46.9% mature and no formal hypothesis testing was performed. While there was no observed benefit in OS, varied and imbalanced subsequent therapy patterns between arms may limit the interpretation of this result. Imbalances include greater use of HER2-directed therapies in the pembrolizumab plus chemotherapy arm versus the Enhertu arm (48.0% vs 23.3%) and limited use of subsequent immunotherapy plus chemotherapy in the Enhertu arm (23.8%).
The safety profile of Enhertu observed in DESTINY-Lung04 was generally consistent with its known profile with no new safety concerns identified.
Despite longer treatment exposure in the Enhertu arm (median 12.3 months versus 7.1 months), Grade 3 or higher treatment related adverse events (AEs) were comparable between Enhertu and pembrolizumab plus chemotherapy (34.1% in the Enhertu arm and 33.6% in the pembrolizumab plus chemotherapy arm). The most common Grade 3 or higher AE occurring in 5% or more of patients treated in both arms was neutropenia (occurring in 11.1% of patients in the Enhertu arm and 14.1% in the pembrolizumab plus chemotherapy arm). Interstitial lung disease (ILD) or pneumonitis events occurred in 20.8% of patients treated with Enhertu as determined by an independent adjudication committee. The majority of ILD or pneumonitis events were low Grade (Grade 1 [n=7; 3.1%] or Grade 2 [n=30; 13.3%]). There were five Grade 3 (2.2%), one Grade 4 (0.4%) and four Grade 5 (1.8%) ILD events in the Enhertu arm.
Enhertu is 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 (TSE: 4568) 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.1 In 2024, approximately 2.6 million new lung cancer cases were reported worldwide, with an estimated 1.8 million deaths.1 NSCLC is the most common type of lung cancer, accounting for approximately 85% of cases.2 Prognosis is particularly poor for patients with metastatic NSCLC as only approximately 10% will live beyond five years after diagnosis.3-5
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.6-9 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.6, 10-14
The global standard of care in the 1st-line metastatic setting of patients with HER2-mutant NSCLC is a combination of immunotherapy and doublet platinum-based chemotherapy.15-17 However, many patients do not respond to 1st-line treatment and experience disease progression, underscoring the need for additional treatment options.18
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 BICR. Secondary endpoints include ORR and DOR assessed by BICR and investigator, PFS2 by investigator, OS, pharmacokinetics and safety.
