Enhertu® Demonstrated a Median Progression-Free Survival of 14.3 Months as First-Line Therapy in Patients with HER2 Mutant Advanced Non-Small Cell Lung Cancer in DESTINY-Lung04 Phase 3 Trial

• Represents a six-month improvement in median progression-free survival versus pembrolizumab plus chemotherapy
• Daiichi Sankyo and AstraZeneca’s Enhertu is the first HER2 directed medicine to delay disease progression over standard of care in a phase 3 trial in this setting

TOKYO--(BUSINESS WIRE)--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).

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

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.

About the Daiichi Sankyo and AstraZeneca Collaboration
Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize Enhertu in March 2019 and Datroway^® in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of Enhertu and Datroway.

Enhertu U.S. Indications and Important Safety Information
Indications
ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for:

• HER2-Positive Early Breast Cancer
  • As neoadjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) Stage II or III breast cancer, as determined by an FDA-authorized test followed by a taxane, trastuzumab, and pertuzumab (THP)
  • As monotherapy in adult patients with HER2-positive (IHC 3+ or ISH+) breast cancer who have residual invasive disease after neoadjuvant HER2-targeted treatment
    
    
• HER2-Positive Metastatic Breast Cancer
  • In combination with pertuzumab as first-line treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer, as determined by an FDA-authorized test
  • As monotherapy 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
    
    
• HER2-Low and HER2-Ultralow Metastatic Breast Cancer
  • As monotherapy 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 an FDA-authorized test, that has progressed on one or more endocrine therapies in the metastatic setting
  • As monotherapy for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-authorized test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy
    
    
• HER2-Mutant Unresectable or Metastatic Non-Small Cell Lung Cancer (NSCLC)
  • As monotherapy for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-authorized test, and who have received a prior systemic therapy
  • This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
    
    
• HER2-Positive Locally Advanced or Metastatic Gastric Cancer
  • As monotherapy for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen
    
    
• HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors
  • As monotherapy 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
    
    This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
    

 Important Safety Information

Contraindications
None.

Warnings and Precautions
Interstitial Lung Disease / Pneumonitis
Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose 1 level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

HER2-Positive, HER2-Low, and HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
ENHERTU as Monotherapy
In patients treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Median time to first onset was 5.5 months (range: 0.9 to 31.5). Fatal outcomes due to ILD and/or pneumonitis occurred in 0.9% of patients treated with ENHERTU.

ENHERTU in Combination with Pertuzumab
In patients treated with ENHERTU 5.4 mg/kg in combination with pertuzumab (N=431), ILD occurred in 12% of patients. Median time to first onset was 8.0 months (range: 0.6 to 33.8). Fatal outcomes due to ILD and/or pneumonitis occurred in 0.5% of patients treated with ENHERTU in combination with pertuzumab.

ENHERTU followed by THP
In patients treated with ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11, ILD occurred in 4.4% of patients. Median time to first onset was 2.7 months (range: 1.1 to 6.0). Fatal outcomes due to ILD and/or pneumonitis occurred in 1 patient (0.3%) treated with ENHERTU followed by THP.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21).

Neutropenia
Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 10⁹/L), interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 10⁹/L), interrupt ENHERTU until resolved to Grade 2 or less, then reduce dose by 1 level. For febrile neutropenia (ANC <1.0 x 10⁹/L and temperature >38.3º C or a sustained temperature of ≥38º C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by 1 level.

HER2-Positive, HER2-Low, and HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
ENHERTU as Monotherapy
In patients treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients. Nineteen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 939). Febrile neutropenia was reported in 1% of patients.

ENHERTU in Combination with Pertuzumab
In patients treated with ENHERTU 5.4 mg/kg in combination with pertuzumab (N=431), decreased neutrophil count occurred in 79% of patients. Median time to first onset was 22 days (range: 5 to 994). Twenty-nine percent had Grade 3 or 4 decreased neutrophil count. Febrile neutropenia was reported in 2.6% of patients.

ENHERTU followed by THP
In patients treated with ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11, a decrease in neutrophil count was reported in 58% of patients. Seventeen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 42 days (range: 11 to 165). Febrile neutropenia was reported in 0.9% of patients.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187).

MEDIA CONTACTS:
Global:
Jennifer Brennan
jennifer.brennan@daiichisankyo.com
+1 908 900 3183 (mobile)

Japan:
DS-PR_jp@daiichisankyo.com

INVESTOR RELATIONS CONTACT:
DaiichiSankyoIR_jp@daiichisankyo.com