AstraZeneca and Daiichi Sankyo Gain EU Approval for Enhertu as Monotherapy for HER2-Mutant Lung Cancer

AstraZeneca and Daiichi Sankyo Gain EU Approval for Enhertu as Monotherapy for HER2-Mutant Lung Cancer

(IN BRIEF) AstraZeneca and Daiichi Sankyo have received European Union (EU) approval for their drug Enhertu as a monotherapy for the treatment of advanced non-small cell lung cancer (NSCLC) in adult patients with activating HER2 mutations who require systemic therapy following platinum-based chemotherapy, with or without immunotherapy. Enhertu, a HER2-directed antibody drug conjugate (ADC), demonstrated a 49.0% objective response rate in a Phase II trial, offering strong and durable results for HER2-mutant NSCLC patients. The approval marks a significant step forward in treating this specific type of lung cancer. Both companies express their commitment to HER2-targeted therapies and acknowledge Enhertu as the first ADC approved for lung cancer in the EU, now having approvals in three different tumor types. The safety profile of Enhertu remains consistent with previous trials, and a milestone payment of $75 million from AstraZeneca to Daiichi Sankyo is expected following EU approval. Lung cancer is a leading cause of cancer-related deaths in Europe, making this approval particularly impactful for patients with HER2-mutant NSCLC.

(PRESS RELEASE) CAMBRIDGE, 24-Oct-2023 — /EuropaWire/ — AstraZeneca and Daiichi Sankyo’s (trastuzumab deruxtecan) has been approved 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.

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

The approval by the European Commission follows the positive opinion of the Committee for Medicinal Products for Human Use and is based on results from the DESTINY-Lung02 Phase II trial 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), 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]).

Martin Reck, MD, PhD, Head of the Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Germany, said: “HER2-mutant non-small cell lung cancer is more commonly diagnosed in patients who are younger and female, and there are limited treatment options which often results in a poor prognosis. Enhertu is the first HER2-directed therapy to demonstrate strong and durable results for these patients, and this EU approval marks an important step forward in how the disease can be treated.”

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: “Understanding the molecular drivers behind a lung cancer diagnosis is critical, and while there are now targeted options for many patients, those with HER2-mutant non-small cell lung cancer have had few treatment options, none of which have been approved to treat their specific type of lung cancer. Enhertu is the first HER2-directed option approved for HER2-mutant disease and confirms the relevance of HER2 as a target in lung cancer.”

Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi Sankyo, Inc., said: “Since our initial approval of Enhertu for metastatic breast cancer in the EU more than two years ago, we have remained committed to bringing this innovative antibody drug conjugate to more patients with HER2-targetable tumours, especially those that have previously not been eligible for treatment with a HER2-directed therapy. With today’s news, Enhertu is the first antibody drug conjugate approved for lung cancer in the EU and is now approved in three different tumour types.”

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

Financial considerations
Following EU approval, an amount of $75m is due from AstraZeneca to Daiichi Sankyo as a milestone payment for this HER2-mutant (HER2m) NSCLC indication. The milestone payment will be capitalised as an addition to the upfront payment made by AstraZeneca to Daiichi Sankyo in 2019 and subsequent capitalised milestones.

Sales of Enhertu in most EU territories are recognised by Daiichi Sankyo. AstraZeneca reports its share of gross profit margin from Enhertu sales in those territories as alliance revenue in the Company’s financial statements. AstraZeneca will record product sales in respect of sales made in territories where AstraZeneca is the selling party.

Further details on the financial arrangements were set out in the March 2019 announcement of the collaboration.

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 multiple tumour types. 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

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 DoR, confirmed disease control rate, and progression-free survival assessed by investigator and BICR, overall survival 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 number of topoisomerase I inhibitor payloads, (an exatecan derivative, DXd), via tetrapeptide-based cleavable linkers.

Enhertu (5.4mg/kg) is approved in more than 55 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 more than 30 countries 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.

Daiichi Sankyo collaboration
Daiichi Sankyo Company, Limited (TSE: 4568) [referred to as Daiichi Sankyo] and AstraZeneca entered into a global collaboration to jointly develop and commercialise Enhertu (a HER2-directed ADC) in March 2019, and datopotamab deruxtecan (a TROP2-directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for the 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 Tagrisso (osimertinib) and Iressa (gefitinib); Imfinzi (durvalumab) and Imjudo (tremelimumab); Enhertu and datopotamab deruxtecan in collaboration with Daiichi Sankyo; Orpathys (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.

AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, 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. Please visit astrazeneca.com and follow the Company on social media @AstraZeneca.

References

1. WHO. International Agency of Cancer Research. Cancer Today. 2020. Available at: https://gco.iarc.fr/today/home. Accessed September 2023.

2. WHO. International Agency of Cancer Research. Europe. 2020. Available at: https://gco.iarc.fr/today/data/factsheets/populations/908-europe-fact-sheets.pdf. Accessed September 2023.

3. American Cancer Society. Lung Cancer Survival Rates. Available at: https://www.cancer.org/cancer/lung-cancer/detection-diagnosis-staging/survival-rates.html. Accessed September 2023.

4. Liu S, et al. Targeting HER2 Aberrations in Non–Small Cell Lung Cancer with Osimertinib. Clin Cancer Res. 2018;24(11):2594-2604.

5. Riudavets M, et al. Targeting HER2 in non-small-cell lung cancer (NSCLC): a glimpse of hope? An updated review on therapeutic strategies in NSCLC harbouring HER2 alterations. ESMO Open. 2021;6(5):100260.

6. Pillai RN, et al. HER2 mutations in lung adenocarcinomas: A report from the Lung Cancer Mutation Consortium. Cancer. 2017;123:4099-105.

7. Offin M, et al. Frequency and Outcomes of Brain Metastases in Patients With HER2-Mutant Lung Cancers. Cancer. 2019;125(24):4380-4387.

8. Hechtman, J, et al. The Past, Present, and Future of HER2 (ERBB2) in Cancer: Approaches to Molecular Testing and an Evolving Role in Targeted Therapy. Cancer Cytopathol. 2019; 127(7):428-431.

9. Gulilat, M, et al. Targeted next generation sequencing as a tool for precision medicine. BMC Med Genomics. 2019;12(1):81.

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SOURCE: AstraZeneca