On September 15, 2023 AstraZeneca and Daiichi Sankyo reported that Enhertu (trastuzumab deruxtecan) has been recommended for approval in the European Union (EU) as monotherapy for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) whose tumours have an activating HER2 (ERBB2) mutation and who require systemic therapy following platinum-based chemotherapy with or without immunotherapy (Press release, AstraZeneca, SEP 15, 2023, View Source [SID1234635178]).

Enhertu is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency based its positive opinion on the primary results from the DESTINY-Lung02 Phase II trial, which were presented at the IASLC 2023 World Conference on Lung Cancer and simultaneously published in the Journal of Clinical Oncology.

In the trial, Enhertu (5.4mg/kg) demonstrated a confirmed objective response rate (ORR) of 49.0% (95% confidence interval [CI] 39.0-59.1) and a disease control rate (DCR) of 93.1% (95% CI 86.4-97.2), as assessed by blinded independent central review (BICR), in patients with previously treated advanced or metastatic HER2-mutant (HER2m) NSCLC. One (1.0%) complete response (CR) and 49 (48.0%) partial responses (PR) were observed. The median duration of response (DoR) was 16.8 months (95% CI 6.4-not estimated [NE]). Median follow-up was 11.5 months at time of data cut-off of 23 December 2022.

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "HER2-mutant non-small cell lung cancer is an aggressive form of lung cancer that often affects younger patients and has a poor prognosis, with limited approved therapies. This milestone recognises the unmet need in the European Union and if approved, Enhertu will provide the first targeted treatment option for these patients."

Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: "Enhertu is the first therapy to demonstrate a strong and durable tumour response in patients with previously treated HER2-mutant advanced non-small cell lung cancer, validating HER2 as an actionable target in lung cancer and supporting the potential to provide a much-needed option for these patients. This CHMP opinion is a positive step forward in advancing this HER2-directed antibody drug conjugate for these patients and we look forward to the European Commission decision."

The safety profile of Enhertu in the DESTINY-Lung02 trial was consistent with previous clinical trials with no new safety signals identified.

Notes

HER2m NSCLC
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 9% will live beyond five years after diagnosis.3

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours, 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 2-4% 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.6 HER2 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 utilised in the identification of HER2 (ERBB2) mutations.8,9

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 approvals of Enhertu by the Israel Ministry of Health (MOH) Pharmaceutical Division, the Japan Ministry of Health, Labour and Welfare and the accelerated US Food and Drug Administration (FDA) approval of Enhertu in unresectable or metastatic HER2m NSCLC.10,11

DESTINY-Lung02
DESTINY-Lung02 is a global, randomised Phase II trial evaluating the safety and efficacy of Enhertu in patients with HER2m advanced or 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 randomised 2:1 to receive Enhertu 5.4mg/kg (n=102) or Enhertu 6.4mg/kg (n=50).

The primary endpoint of the trial is confirmed ORR as assessed by BICR. Secondary endpoints include confirmed DCR, DoR and PFS assessed by investigator and BICR, OS and safety.

DESTINY-Lung02 enrolled 152 patients at multiple sites, including Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

Enhertu
Enhertu 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 programme 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 more than 50 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 (5.4mg/kg) is approved in more than 40 countries 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 (5.4mg/kg) is approved in Israel, Japan and under accelerated approval in the US for the treatment of adult patients with unresectable or metastatic NSCLC whose tumours 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 trial. Continued approval for this indication in the US may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4mg/kg) is approved in more than 30 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 trials.

Enhertu development programme
A comprehensive clinical development programme is underway globally, evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

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