First HER2-directed therapy to show a strong tumor response in this population

Data from HER2-mutant cohort of pivotal DESTINY-Lung01 Phase II trial presented at ESMO and published in The New England Journal of Medicine

WILMINGTON, DE, USA I September 18, 2021 I Detailed primary results from the positive Phase II DESTINY-Lung01 trial of ENHERTU® (fam-trastuzumab deruxtecan-nxki), the AstraZeneca and Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) HER2-directed antibody drug conjugate (ADC), showed a robust and durable tumor response in previously treated patients with HER2-mutant (HER2m) unresectable and/or metastatic non-squamous non-small cell lung cancer (NSCLC). Results presented during a late-breaking Proffered Paper session at the European Society for Medical Oncology (ESMO) Congress 2021 and simultaneously published in The New England Journal of Medicine confirm ENHERTU as the first HER2-directed therapy to show a strong tumor response in this patient population.

Lung cancer is the leading cause of cancer death among both men and women, and accounts for about one-fifth of all cancer deaths globally, with 80-85% classified as NSCLC.1-3 There are currently no medicines approved specifically for the treatment of HER2m NSCLC, which affects approximately 2-4% of patients with NSCLC.4,5

Primary results from the HER2m cohort (cohort 2) of DESTINY-Lung01 in previously treated HER2m NSCLC demonstrated a confirmed objective response rate (ORR) of 54.9% in patients treated with ENHERTU (6.4 mg/kg) as assessed by independent central review (ICR). One (1.1%) complete response (CR) and 49 (53.8%) partial responses (PR) were observed. A confirmed disease control rate (DCR) of 92.3% was seen with a reduction in tumor size observed in most patients. After a median follow-up of 13.1 months, the median duration of response (DoR) for ENHERTU was 9.3 months. The median progression-free survival (PFS) was 8.2 months and the median overall survival (OS) was 17.8 months.

Bob Li, MD, PhD, MPH, Memorial Sloan Kettering Cancer Center, said: “Despite more than 20 years of research into HER2-mutations in non-small cell lung cancer, there are currently no approved HER2-targeted therapies for non-small cell lung cancer. Patients with HER2-mutant non-small cell lung cancer are associated with younger age, female sex, never smoking history and a poor prognosis with increased incidence of brain metastases, representing unmet clinical need. The impressive results from DESTINY-Lung01 showed most patients experienced a reduction in tumor size with ENHERTU treatment, suggesting this medicine has the potential to become the new standard of care for these patients.”

Susan Galbraith, Executive Vice President, Oncology R&D, said: “Lung cancer is a devastating diagnosis, and for patients with HER2-mutant lung cancer, a targeted treatment for their specific disease has not been an option. These data reinforce the potential of ENHERTU to become the first HER2-directed therapy for these patients and reaffirm how this treatment is truly delivering on its transformative potential.”

Ken Takeshita, Global Head, Research and Development, Daiichi Sankyo, said: “ENHERTU is the first HER2-directed therapy to demonstrate a robust and durable tumor response in patients with HER2-mutant non-small cell lung cancer. This is potentially great news for patients, and so we are continuing to conduct research, with the goal of bringing ENHERTU to those with this specific form of lung cancer.”

Responses were observed across HER2m subtypes, as well as in patients with no detectable HER2 expression or HER2 gene amplification. Efficacy was observed in subgroups including prior treatment with platinum-based therapy, or platinum-based and anti–PD-(L)1 therapy, as well as asymptomatic brain metastases at baseline.

Summary of results

Efficacy Measure HER2m Total Evaluable (n=91)i
Confirmed ORR (%) (95% CI)ii,iii 54.9% (44.2 – 65.4)
Complete response (%) 1.1%
Partial response (%) 53.8%
Stable disease (%) 37.4%
DCR (95% CI)iv 92.3% (84.8–96.9)
Median DoR (months) (95% CI) 9.3 months (5.7 – 14.7)
Median PFS (months) (95% CI) 8.2 months (6.0 – 11.9)
Median OS (months) (95% CI) 17.8 months (13.8 – 22.1)

i ENHERTU 6.4mg/kg; median duration of follow-up was 13.1 months

ii As assessed by independent central review

iii ORR is (CR + PR)

iv DCR is (CR + PR +SD)

The overall safety profile of ENHERTU was consistent with previous ENHERTU NSCLC trials, with no new safety signals identified. The most common Grade 3 or higher drug-related treatment-emergent adverse events were neutropenia (18.7%) and anemia (9.9%). Rates of treatment-related interstitial lung disease (ILD) or pneumonitis were consistent with previous trials in lung cancer. There were 24 cases of ILD or pneumonitis, as determined by an independent adjudication committee with the majority (75%) low Grade (Grade 1 or 2), with four Grade 3 and two Grade 5 (ILD or pneumonitis-related death).

In May 2020, ENHERTU was granted Breakthrough Therapy Designation in the US for the treatment of HER2m metastatic NSCLC.

ENHERTU is being further assessed in a comprehensive clinical development program evaluating efficacy and safety across multiple HER2-targetable cancers, including breast, gastric, lung and colorectal cancers.

Several presentations featured during the ESMO Congress 2021 will showcase the strength and depth of ENHERTU data across multiple tumor types, including gastric, lung and breast cancers, reinforcing the transformational potential of this medicine in the treatment of HER2-targetable cancers.

Important Safety Information


ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:

  • Unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

    This indication is approved under accelerated approval based on tumor 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.

  • Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.

Please see accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

HER2-mutant NSCLC

Lung cancer is the leading cause of cancer death among both men and women and accounts for about one-fifth of all cancer deaths globally, with 80-85% classified as NSCLC.1-3 For patients with metastatic disease, prognosis is particularly poor, as only approximately 6% will live beyond five years after diagnosis.2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including lung, breast, gastric and colorectal cancers. HER2 gene alterations (called HER2 mutations) have been identified in NSCLC, specifically adenocarcinomas, as distinct molecular targets and have been reported in approximately 2-4% of patients with NSCLC.4,5 These HER2 gene mutations are predominantly seen in younger women, with no smoking history and have been independently associated with cancer cell growth and poor prognosis with an increased incidence of brain metastases.4,6-10 Although the role of anti-HER2 treatment is well established in breast and gastric cancer, HER2 is still an emerging biomarker in NSCLC with no approved HER2-directed therapies.4,11


DESTINY-Lung01 is a global, Phase II, open-label, multi-center, two-cohort trial testing the safety and efficacy of ENHERTU in patients with HER2-mutant (6.4 mg/kg) or HER2 overexpressing (defined as IHC3+ or IHC2+) unresectable and/or metastatic non-squamous NSCLC. Patients had progressed after one or more systemic therapies including chemotherapy, molecular targeted therapy or immunotherapy. The primary endpoint is confirmed ORR by independent central review. ORR, or tumor response rate, represents the percentage of patients whose disease decreased and/or disappears. Key secondary endpoints include DoR, DCR, PFS and OS.

DESTINY-Lung01 enrolled approximately 180 patients at multiple sites including the US, Europe and Japan. For more information about the trial, visit


ENHERTU (fam-trastuzumab deruxtecan-nxki) is a HER2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, 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 topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

ENHERTU (5.4mg/kg) is approved in Canada, the EU, Israel, Japan, the UK and the US for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting based on the results from the DESTINY-Breast01 trial.

ENHERTU (6.4mg/kg) is also approved in Israel, Japan and the US for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

ENHERTU development program

A comprehensive development program is underway globally, evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2-targetable cancers, including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

ENHERTU was highlighted in the Clinical Cancer Advances 2021 report as one of two significant advancements in the “ASCO Clinical Advance of the Year: Molecular Profiling Driving Progress in GI Cancers,” based on data from both the DESTINY-CRC01 and DESTINY-Gastric01 trials, as well as one of the targeted therapy advances of the year in non-small cell lung cancer (NSCLC), based on the interim results of the HER2-mutated cohort of the DESTINY-Lung01 trial.

In May 2020, ENHERTU also received Breakthrough Therapy Designation for the treatment of patients with metastatic NSCLC whose tumors have a HER2-mutation and with disease progression on or after platinum-based therapy.

Daiichi Sankyo collaboration

Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU (a HER2-directed ADC) in March 2019, and datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for manufacturing and supply of ENHERTU and datopotamab deruxtecan.

AstraZeneca in lung cancer

AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most.

The Company’s comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, including osimertinib and gefitinib; durvalumab and tremelimumab; ENHERTU and datopotamab deruxtecan in collaboration with Daiichi Sankyo; savolitinib in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action.

AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment.

AstraZeneca in oncology

AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit and follow us on Twitter @AstraZenecaUS.


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SOURCE: AstraZeneca