Enhertu Cuts Progression Risk 37% in First-Line HER2-Mutant NSCLC, Delivering 14.3-Month Median PFS in DESTINY-Lung04
核心洞察
Enhertu achieved a median progression-free survival of 14.3 months as first-line therapy in HER2 (搜索)-mutant advanced NSCLC, a six-month improvement over pembrolizumab plus chemotherapy.
The Phase 3 DESTINY-Lung04 trial randomized 454 patients 1:1 and showed Enhertu reduced the risk of disease progression or death by 37%.
Objective response rate was 70% with Enhertu versus 44.5% with standard of care, with median duration of response of 13.4 versus 9.7 months.
AstraZeneca and Daiichi Sankyo reported that ENHERTU (fam-trastuzumab deruxtecan-nxki) achieved a median progression-free survival (PFS) of 14.3 months as first-line therapy in patients with unresectable, metastatic HER2 (搜索)-mutant non-squamous non-small cell lung cancer (搜索) (NSCLC), a six-month improvement over the current standard of care, pembrolizumab plus platinum-pemetrexed chemotherapy. The results come from the global, randomized, open-label Phase 3 DESTINY-Lung04 trial and were presented at the International Association for the Study of Lung Cancer's (IASLC) 2026 World Conference on Lung Cancer (WCLC) in Seoul, South Korea.
ENHERTU reduced the risk of disease progression or death by 37% versus pembrolizumab plus chemotherapy, according to the companies. Median PFS on second subsequent therapy was 22.7 months with ENHERTU versus 17.3 months with the comparator regimen. The companies stated that ENHERTU is the first HER2 (搜索)-directed therapy to delay disease progression over standard of care in a Phase 3 trial.
Trial Design and Endpoints
DESTINY-Lung04 evaluated ENHERTU at 5.4 mg/kg against platinum-pemetrexed doublet chemotherapy in combination with pembrolizumab in patients with unresectable, locally advanced or metastatic, non-squamous NSCLC harboring a HER2 (搜索) exon 19 or exon 20 mutation. The trial enrolled 454 patients across sites in Asia, Europe and North America, randomized 1:1, with randomization stratified by smoking history and presence or history of brain metastasis. The primary endpoint was PFS as assessed by blinded independent central review (BICR). Secondary endpoints included objective response rate (ORR) and duration of response (DOR) assessed by BICR and investigator, PFS2 by investigator, overall survival (OS), pharmacokinetics and safety.
Response Rates and Subgroup Consistency
The objective response rate was 70% with ENHERTU versus 44.5% with pembrolizumab plus chemotherapy, while median duration of response was 13.4 months compared with 9.7 months, respectively. The PFS benefit was observed across key subgroups, including patients with brain or liver metastases, different smoking histories, HER2 (搜索) exon 19 or exon 20 mutations, and de novo or recurrent disease.
Overall Survival Data Remain Immature
At the interim overall survival analysis, median OS was 29.3 months with ENHERTU versus 33.1 months with pembrolizumab plus chemotherapy. At the time of analysis, 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 (搜索)-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%).
Safety Profile Consistent With Prior Experience
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 (搜索) (occurring in 11.1% of patients in the ENHERTU arm and 14.1% in the pembrolizumab plus chemotherapy arm).
Interstitial lung disease (搜索) (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.
Positioning in the HER2-Mutant NSCLC Landscape
John Tsai, Global Head, R&D, Daiichi Sankyo, said: "ENHERTU was the first HER2 (搜索)-directed medicine and antibody drug conjugate approved for patients with HER2-mutant non-small cell lung cancer (搜索) 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 1st-line setting where delaying disease progression for as long as possible is a critical goal."
Lung cancer is the most commonly diagnosed cancer globally and remains the leading cause of cancer-related death. In 2024, approximately 2.6 million new lung cancer cases were reported worldwide, with an estimated 1.8 million deaths. NSCLC accounts for approximately 85% of lung cancer cases, and prognosis is particularly poor in the metastatic setting, with only approximately 10% of patients living beyond five years after diagnosis. HER2 (搜索) 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. These 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.
The global standard of care in the first-line metastatic setting for patients with HER2-mutant NSCLC (搜索) is a combination of immunotherapy and doublet platinum-based chemotherapy. However, many patients do not respond to first-line treatment and experience disease progression, underscoring the need for additional treatment options.
Regulatory Status and Development Program
ENHERTU is approved to treat patients with previously treated metastatic NSCLC whose tumors have activating HER2 (搜索) (ERBB2 (搜索)) mutations, and to treat patients with HER2-positive solid tumors, including HER2-overexpressing metastatic NSCLC, who have received prior treatment and who have no satisfactory treatment options. The HER2-mutant NSCLC (搜索) indication is approved under accelerated approval based on objective response rate and duration of response, with continued approval contingent upon verification and description of clinical benefit in a confirmatory trial. ENHERTU (5.4 mg/kg) is approved in more than 80 countries worldwide for unresectable or metastatic NSCLC with activating HER2 (ERBB2) mutations following prior systemic therapy, based on the DESTINY-Lung02 and/or DESTINY-Lung05 trials.
ENHERTU is a specifically engineered HER2 (搜索)-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed and commercialized by AstraZeneca and Daiichi Sankyo. It consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019, except in Japan where Daiichi Sankyo maintains exclusive rights; Daiichi Sankyo is responsible for manufacturing and supply.
Following the announcement, Daiichi Sankyo shares traded up 2.65% at JPY 2,845.50 on the Tokyo Stock Exchange, while AstraZeneca shares were trading down 1.17% at $158.30 in the overnight market after closing Friday at $160.17, up 0.33%.
Warnings and Precautions
Severe, life-threatening, or fatal interstitial lung disease (搜索) (ILD), including pneumonitis, can occur in patients treated with ENHERTU, and a higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. In patients treated with ENHERTU 5.4 mg/kg as monotherapy, ILD occurred in 12% of patients, with a median time to first onset of 5.5 months (range: 0.9 to 31.5), and fatal outcomes due to ILD and/or pneumonitis occurred in 0.9% of patients. Severe neutropenia (搜索), including febrile neutropenia, can also occur; in patients treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients, with 19% having Grade 3 or 4 decreased neutrophil count. Left ventricular dysfunction has been observed with anti-HER2 (搜索) therapies, including ENHERTU, and was reported in 4.6% of patients treated with ENHERTU 5.4 mg/kg as monotherapy, of which 0.6% were Grade 3 or 4. ENHERTU can cause fetal harm when administered to a pregnant woman.