On September 13, 2026 Daiichi Sankyo reported positive results from the DESTINY-Lung04 phase 3 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 a first-line treatment of patients with unresectable, locally advanced or metastatic HER2 mutant non-squamous non-small cell lung cancer (NSCLC). Results were presented today (#PL03.08) in Presidential Symposium 2 at the IASLC 2026 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer (#WCLC26).
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Enhertu is a specifically engineered HER2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca (LSE/STO/NYSE: AZN).
In the primary endpoint analysis, 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 (95% CI: 12.4-16.5) with Enhertu compared to 8.3 months (95% CI: 7.0-9.9) for pembrolizumab plus chemotherapy as assessed by blinded independent central review (BICR). A favorable PFS trend was seen for Enhertu across key subgroups, including the prespecified stratification factors of presence or history of brain metastases, smoking status, HER2 mutation status (exon 19 or exon 20), de novo or recurrent disease and presence of liver metastases.
Objective response rate (ORR) with Enhertu was 70.0% (95% CI: 63.6-75.9) versus 44.5% (95% CI: 37.9-51.2) with pembrolizumab plus chemotherapy. Median duration of response (DOR) for Enhertu was 13.4 months (95% CI: 10.4-17.2) and 9.7 months (95% CI: 7.0-11.1) with pembrolizumab plus chemotherapy. Median PFS2 (time from treatment start to second tumor progression or death from any cause) with Enhertu was 22.7 months (95% CI: 20.3-26.3) compared to 17.3 months (95% CI: 15.6-21.8) with pembrolizumab plus chemotherapy.
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% versus 23.3%), and limited use of subsequent immunotherapy plus chemotherapy in the Enhertu arm (23.8%).
"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," said Julia Rotow, MD, Assistant Professor of Medicine, Dana-Farber Cancer Institute and Lead Investigator of the DESTINY-Lung04 Trial. "With 70 percent 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."
The safety profile of Enhertu observed in DESTINY-Lung04 was generally consistent with its known profile with no new safety signals identified. Grade 3 or higher treatment related adverse events (TRAE) occurred in 34.1% of patients treated with Enhertu. The most common grade 3 or higher TRAE occurring in 5% or more of patients treated with Enhertu was neutropenia (11.1%). 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 (2.2%) grade 3, one (0.4%) grade 4 and four (1.8%) grade 5 ILD events in the Enhertu arm.
"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," said John Tsai, MD, Global Head of R&D, Daiichi Sankyo. "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."
"DESTINY-Lung04 is the first phase 3 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," said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology Hematology R&D, AstraZeneca. "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."
Patients in the DESTINY-Lung04 trial received prior radiotherapy, chemotherapy, immunotherapy or targeted therapy for early-stage disease. Approximately three-quarters (75.8%) of the patients in the Enhertu arm had de novo disease, meaning the lung cancer was first diagnosed in the metastatic setting, and nearly one-quarter (22.9%) had brain metastases at baseline. Median duration of follow-up was 21.6 months with patients receiving Enhertu and 20.4 months with patients receiving pembrolizumab plus chemotherapy. As of the data cut-off date of June 9, 2026, 50 patients remained on study treatment with 40 patients still receiving Enhertu and 10 patients receiving pembrolizumab plus chemotherapy.
Summary of DESTINY-Lung04 Primary Results
Efficacy Measure
Enhertu (5.4 mg/kg)
(n=227)
Pembrolizumab plus
Chemotherapy
(n=227)
Median PFSi, (months) (95% CI)
14.3 months (12.4-16.5)
8.3 months (7.0-9.9)
HR = 0.63 (0.50-0.79); p<0.0001
ORRii (%) (95% CI)
70.0% (63.6-75.9)
44.5% (37.9-51.2)
CRi,iii, % (n)
1.8% (4)
1.8% (4)
PRi,iii, % (n)
68.3% (155)
42.7% (97)
SDi,iii, % (n)
26.9% (61)
43.2% (98)
Median DORi, (months) (95% CI)
13.4 months (10.4-17.2)
9.7 months (7.0-11.1)
Median PFS2iv, (months) (95% CI)
22.7 months (20.3-26.3)
17.3 months (15.6-21.8)
HR = 0.80 (0.62-1.02)
Median OSv, (months) (95% CI)
29.3 months (26.2-33.4)
33.1 months (27.7-40.7)
HR = 1.15 (0.88-1.52)
CI, confidence interval; CR, complete response; DOR, duration of response; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease
i Assessed by BICR
ii ORR is (CR + PR)
iii Includes unconfirmed responses
iv Assessed by investigator
v At DCO, overall data maturity for OS was 46.9%. No formal hypothesis testing was performed at this interim analysis; formal hypothesis testing will be performed at the second interim analysis and final analysis
About DESTINY-Lung04
DESTINY-Lung04 is a global, randomized, open-label, phase 3 trial evaluating the efficacy and safety of Enhertu (5.4 mg/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 harboring a HER2 exon 19 or 20 mutation.
Patients were randomized 1:1 to receive either Enhertu or standard of care. Randomization 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 OS, investigator-assessed PFS, ORR and DOR as assessed by BICR and investigator, investigator-assessed PFS2, pharmacokinetics and safety.
DESTINY-Lung04 enrolled 454 patients across multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.
About 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.3,4,5
HER2 is a tyrosine kinase receptor protein involved in cell growth and differentiation and expressed on the surface of multiple tumor types. HER2 mutations have been identified in NSCLC as distinct molecular targets and have been reported in approximately 2% to 4% of patients with non-squamous NSCLC.6,7,8,9 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.6,10,11,12,13,14
The current global standard of care in the first-line metastatic setting of patients with HER2 mutant NSCLC has been a combination of immunotherapy and doublet platinum-based chemotherapy.15,16,17 Response rates with this treatment regimen have been limited and many patients experience disease progression, underscoring the need for additional treatment options.18
About Enhertu
Enhertu (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directed ADC. Designed using the proprietary DXd ADC Technology of Daiichi Sankyo, Enhertu is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform. Enhertu consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
Enhertu (5.4 mg/kg) followed by THP is approved in Brazil, China, India, Singapore, Taiwan and the U.S. as a neoadjuvant treatment for adult patients with HER2 positive (IHC 3+ or ISH+) stage 2 or stage 3 breast cancer based on the results from the DESTINY-Breast11 trial. Continued approval in China for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Enhertu (5.4 mg/kg) is approved in Brazil, Canada, India and the U.S. for the adjuvant treatment of adult patients with HER2 positive breast cancer who have residual invasive disease following neoadjuvant trastuzumab (with or without pertuzumab) and taxane-based treatment based on the DESTINY-Breast05 trial.
Enhertu (5.4 mg/kg) in combination with pertuzumab is approved in more than 40 countries/regions worldwide as a first-line treatment for adult patients with unresectable or metastatic HER2 positive (IHC 3+ or ISH+) breast cancer, as determined by a locally or regionally approved test, based on the results from the DESTINY-Breast09 trial.
Enhertu (5.4 mg/kg) is approved in more than 100 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+ or ISH+) breast cancer who have received a prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial.
Enhertu (5.4 mg/kg) is approved in more than 75 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic hormone receptor (HR) positive, HER2 low (IHC 1+ or IHC 2+/ ISH-) or HER2 ultralow (IHC 0 with membrane staining) breast cancer, as determined by a locally or regionally approved test, that have progressed on one or more endocrine therapies in the metastatic setting based on the results from the DESTINY-Breast06 trial.
Enhertu (5.4 mg/kg) is approved in more than 100 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.
Enhertu (5.4 mg/kg) is approved in more than 80 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 and/or DESTINY-Lung05 trials. Continued approval in China and the U.S. for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Enhertu (6.4 mg/kg) is approved in more than 90 countries/regions worldwide for the treatment of adult patients with locally advanced or metastatic HER2 positive (IHC 3+ or IHC 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01, DESTINY-Gastric02 and/or DESTINY-Gastric04 trials.
Enhertu (5.4 mg/kg) is approved in more than 45 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options based on efficacy results from the DESTINY-PanTumor02, DESTINY-Lung01, DESTINY-CRC02 and/or HERALD trials. Continued approval in the U.S. for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
About the Enhertu Clinical Development Program
A comprehensive global clinical development program is underway evaluating the efficacy and safety of Enhertu as a monotherapy or in combination or sequentially with other cancer medicines across multiple HER2 targetable cancers.
(Press release, Daiichi Sankyo, SEP 13, 2026, View Source [SID1234670784])