Daiichi Sankyo announced that the European Medicines Agency (EMA) has validated the Type II Variation application for ENHERTU® (trastuzumab deruxtecan) as a monotherapy for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations and who have received a prior systemic therapy. ENHERTU is a specifically engineered HER2 directed antibody drug conjugate (ADC) being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca. Validation confirms that the application is complete and commences the scientific review process by the EMA's Committee for Medicinal Products for Human Use.

This application is based on data from the DESTINY-Lung02 phase 2 trial presented at the European Society for Medical Oncology (ESMO) 2022 Congress and the DESTINY-Lung01 phase 2 trial published in the New England Journal of Medicinewith updated data also presented at ESMO 2022. DESTINY-Lung02 is a global, randomized phase 2 trial evaluating the safety and efficacy of ENHERTU in patients with HER2 mutant metastatic NSCLC with disease recurrence or progression during or after at least one regimen of prior anticancer therapy that must have contained a platinum-based chemotherapy. Patients were randomized 2:1 to receive ENHERTU 5.4 mg/kg (Cohort 1; n=102) or ENHERTU 6.4 mg/kg (Cohort 2; n=50).

The primary endpoint of the trial is confirmed objective response rate (ORR) as assessed by blinded independent central review (BICR). Secondary endpoints include confirmed disease control rate (DCR), duration of response (DoR) and progression free survival (PFS) assessed by investigator and BICR, investigator-assessed overall survival (OS) and safety. DESTINY-Lung02 enrolled 152 patients at multiple sites, including Asia, Europe, Oceania and North America.

DESTINY-Lung01 is a global phase 2, open-label, two-cohort trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg or 6.4 mg/kg) in patients with HER2 mutant (cohort 2, n=91) or HER2 overexpressing (cohort 1 and 1a, n=90) (defined as immunohistochemistry (IHC) 3+ or IHC 2+) unresectable or metastatic non-squamous NSCLC relapsed from or refractory to standard treatment or for which no standard treatment is available. The primary endpoint of the trial is confirmed ORR by independent central review (ICR). Key secondary endpoints include DoR, DCR, PFS, OS and safety.

DESTINY-Lung01 enrolled 181 patients at multiple sites, including Asia, Europe and North America. Lung cancer is the second most common form of cancer globally, with more than two million cases diagnosed in 2020.1 In Europe, lung cancer is the third most commonly diagnosed cancer with more than 477,000 cases diagnosed in 2020.2 Lung cancer is also the leading cause of cancer-related deaths in Europe, with nearly 400,000 deaths reported in 2020.2 Prognosis is particularly poor for patients with metastatic NSCLC as only approximately 8% will live beyond five years after diagnosis. 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.

Certain HER2 (ERBB2) gene alterations (called HER2 mutations) have been identified in patients with non-squamous NSCLC as a distinct molecular target, and occur in approximately 2% to 4% of patients with this type of lung cancer.4,5 While HER2 gene mutations can occur in a range of patients, they are more commonly found in patients with NSCLC who are younger, female and have never smoked.6HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis, with an increased incidence of brain metastases.7 Next-generation sequencing has been utilized in the identification of HER2 (ERBB2) mutations. Although the role of anti-HER2 treatment is well established in breast and gastric cancers, there were no approved HER2 directed therapies in NSCLC prior to the accelerated U.S. Food and Drug Administration (FDA) approval of ENHERTU in unresectable or metastatic HER2 mutant NSCLC. ENHERTU® (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directed antibody drug conjugate (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 (5.4 mg/kg) is approved in more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received a (or one or more) 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 also is approved in several countries 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 based on the results from the DESTINY-Breast01 trial. ENHERTU (5.4 mg/kg) is approved in Brazil and the U.S. for the treatment of adult patients with unresectable or metastatic HER2 low (immunohistochemistry (IHC) 1+ or IHC 2+/in-situ hybridization (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 under accelerated approval in the U.S. for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by a FDA-approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial.

Continued approval 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 several countries for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 and/or DESTINY-Gastric02 trial. A comprehensive global development program is underway evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2targetable cancers including breast, gastric, lung and colorectal cancers.

Trials in combination with other anticancer treatments, such as immunotherapy, also are underway.