Enhertu Demonstrates Significant Progression-Free Survival Benefit in First-Line HER2 Mutant Metastatic NSCLC
Daiichi Sankyo and AstraZeneca have announced positive topline results from the Phase 3 DESTINY-Lung04 trial, demonstrating that Enhertu® (trastuzumab deruxtecan) significantly improved progression-free survival (PFS) compared with the current global standard of care in patients with previously untreated, unresectable, locally advanced or metastatic HER2-mutant non-squamous non-small cell lung cancer (NSCLC).
The findings represent an important development in the treatment of patients whose tumors harbor HER2 mutations, a molecular alteration associated with a distinct subset of NSCLC. DESTINY-Lung04 is evaluating Enhertu as a first-line treatment in the metastatic setting, where the current standard approach generally combines platinum-based chemotherapy with pemetrexed and the immune checkpoint inhibitor pembrolizumab.
According to the topline results, Enhertu achieved a statistically significant and clinically meaningful improvement in PFS compared with the global standard-of-care regimen. The trial will continue according to plan so that investigators can assess additional secondary endpoints, including overall survival (OS). Further details of the efficacy results are expected to be presented at a future medical meeting and submitted to regulatory authorities worldwide.
Enhertu is a HER2-directed antibody-drug conjugate (ADC) specifically engineered using Daiichi Sankyo’s DXd technology. The medicine is being jointly developed and commercialized globally by Daiichi Sankyo and AstraZeneca.
Addressing an Unmet Need in HER2-Mutant Lung Cancer
NSCLC represents the most common form of lung cancer and includes multiple molecularly defined subtypes. Among these, tumors carrying HER2 mutations account for approximately 2% to 4% of NSCLC cases. Although the proportion is relatively small, the number of patients affected globally is substantial because of the overall incidence of lung cancer.
HER2, also known as ERBB2, is a protein involved in signaling pathways that regulate cell growth and survival. Mutations in the HER2 gene can drive abnormal tumor growth and contribute to disease progression. Identifying these mutations through comprehensive molecular testing has therefore become increasingly important as targeted treatment options continue to expand.
For patients with HER2-mutant NSCLC who present with metastatic disease, treatment in the first-line setting has traditionally relied on a combination of immunotherapy and platinum-based chemotherapy. While this approach can provide meaningful clinical benefit for some patients, a considerable proportion eventually experience disease progression.
The persistence of progression following first-line treatment highlights the need for therapies capable of targeting specific molecular drivers of disease earlier in the treatment journey. The DESTINY-Lung04 findings suggest that Enhertu could potentially become an important targeted treatment option in the first-line setting for patients with HER2-mutant metastatic NSCLC.
DESTINY-Lung04 Evaluates Enhertu as an Initial Treatment
The DESTINY-Lung04 study is designed to assess whether using Enhertu earlier in the treatment sequence can improve outcomes compared with established first-line therapy.
The Phase 3 trial enrolled patients with unresectable, locally advanced or metastatic non-squamous NSCLC whose tumors contain HER2 mutations. Participants were evaluated in the first-line setting, meaning they had not previously received systemic treatment for their advanced or metastatic disease.
The primary endpoint of the study is progression-free survival, which measures the length of time patients live without their disease worsening or progressing. In DESTINY-Lung04, Enhertu demonstrated a statistically significant and clinically meaningful improvement in PFS compared with the combination of platinum-pemetrexed chemotherapy and pembrolizumab.
The trial will continue to assess overall survival and other secondary endpoints. Because overall survival data are not yet mature, the companies indicated that the study will proceed as planned to allow for continued follow-up of patients.
The positive PFS result provides an important indication that Enhertu may be able to delay disease progression when used at the beginning of treatment for this genetically defined population.
Potential to Move Targeted Therapy Earlier
John Tsai, MD, Global Head of R&D at Daiichi Sankyo, highlighted the significance of the findings, noting that Enhertu is already established as an antibody-drug conjugate option for patients with HER2-mutant metastatic NSCLC following previous treatment.
The DESTINY-Lung04 results build on that experience by investigating whether the medicine can deliver benefits earlier in the course of metastatic disease. According to Daiichi Sankyo, the results show that Enhertu delayed disease progression compared with the global standard of care, supporting the potential for the therapy to move into the first-line treatment setting.
The ability to use a targeted therapy earlier could be particularly important for patients whose tumors contain actionable genomic alterations. Rather than waiting until after progression on chemotherapy and immunotherapy, patients could potentially receive a therapy designed specifically to target their tumor biology at the time metastatic disease is initially diagnosed.
Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology Hematology R&D at AstraZeneca, described DESTINY-Lung04 as the first Phase 3 trial to demonstrate a PFS benefit against the global standard of care in this particular first-line treatment setting.
She also emphasized that HER2-mutant lung cancer can be an aggressive disease and may affect relatively younger patients. Historically, treatment options specifically targeting HER2 mutations in the first-line setting have been limited, creating a significant unmet medical need.
Enhertu’s Role in HER2-Directed Cancer Treatment
Enhertu is an antibody-drug conjugate designed to selectively deliver a potent anticancer payload to cells expressing HER2. ADCs combine the targeting capabilities of antibodies with cytotoxic drugs, creating a treatment approach intended to deliver chemotherapy directly to cancer cells.
Enhertu consists of a HER2-directed monoclonal antibody linked to a topoisomerase I inhibitor payload through a specialized linker. After binding to HER2 on cancer cells, the ADC is internalized, allowing the payload to be released and exert its anticancer activity.
The therapy has been studied across multiple HER2-expressing and HER2-mutated cancers, helping establish its role as an important component of the companies’ oncology portfolios.
The latest DESTINY-Lung04 findings expand the clinical investigation of Enhertu in lung cancer by evaluating its use before patients receive other systemic therapies for metastatic disease.
Safety Findings Remain Consistent
The safety profile reported in DESTINY-Lung04 was generally consistent with the established safety profile of Enhertu. Importantly, the companies reported no new safety concerns emerging from the study.
Safety remains a critical consideration as therapies move into earlier lines of treatment, particularly because first-line therapy is administered when patients may have a longer expected treatment duration. Continued monitoring and longer-term follow-up from DESTINY-Lung04 will provide additional information about the safety and tolerability of Enhertu in this population.
The companies are expected to provide more detailed data at an upcoming medical conference, including additional information regarding efficacy, safety and other clinical endpoints.
Regulatory Discussions Expected Globally
Following the positive topline results, Daiichi Sankyo and AstraZeneca plan to share the DESTINY-Lung04 findings with regulatory authorities around the world. The companies are also preparing to present the detailed results at an upcoming medical meeting.
Regulatory decisions will ultimately determine whether Enhertu can be approved for first-line treatment of patients with HER2-mutant advanced or metastatic NSCLC in individual markets. The full dataset, including longer-term follow-up and overall survival results, will be important in determining the potential clinical and regulatory impact of the findings.
Enhertu is already approved in more than 80 countries and regions for previously treated patients with metastatic NSCLC whose tumors have activating HER2 mutations. The medicine is also approved in more than 45 countries and regions for certain HER2-positive solid tumors, including HER2-overexpressing metastatic NSCLC in patients who have previously received treatment and have no satisfactory alternatives.
A Potential New Treatment Option for Patients
The positive DESTINY-Lung04 results represent another milestone in the development of HER2-directed therapies for lung cancer. By demonstrating a significant PFS benefit against the current global standard of care, the trial provides evidence supporting the potential use of Enhertu as an initial therapy for patients with HER2-mutant metastatic non-squamous NSCLC.
The findings also reinforce the growing importance of biomarker testing in lung cancer. Identifying HER2 mutations can help physicians determine whether patients may be candidates for targeted therapies and allows treatment decisions to be increasingly guided by the molecular characteristics of individual tumors.
While further follow-up is required to determine the impact on overall survival and other outcomes, the Phase 3 results mark a meaningful step toward expanding targeted treatment options for HER2-mutant lung cancer. If supported by the complete clinical dataset and regulatory reviews, Enhertu could potentially provide patients with access to a HER2-directed treatment much earlier in the metastatic disease journey.
For Daiichi Sankyo and AstraZeneca, DESTINY-Lung04 further strengthens the development program for Enhertu and underscores the companies’ broader strategy of using antibody-drug conjugates to address difficult-to-treat cancers. The upcoming presentation of detailed trial results and subsequent regulatory submissions will provide greater insight into the potential role of Enhertu in first-line HER2-mutant NSCLC.
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 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.
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.12 In 2024, approximately 2.6 million new lung cancer cases were reported worldwide, with an estimated 1.8 million deaths.12 NSCLC is the most common type of lung cancer, accounting for approximately 85% of cases.13 Prognosis is particularly poor for patients with metastatic NSCLC as only approximately 10% will live beyond five years after diagnosis.14,15,16
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.8,9,10,11 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.8,17,18,19,20,21
Traditionally the global standard of care in the first-line metastatic setting of patients with HER2 mutant NSCLC has been a combination of immunotherapy and platinum-based chemotherapy.1,2,3 While these treatment regimens have been shown to improve survival in NSCLC, many patients do not respond to first-line treatment and experience disease progression, underscoring the need for additional treatment options.3,4,5,6,7
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 China, India, Singapore 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 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 Brazil, China, India, Israel, Saudi Arabia, Singapore, South Korea, Switzerland, Taiwan, the United Arab Emirates and the U.S. 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-Gastric04trials.
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.