On December 19, 2022 AstraZeneca and Daiichi Sankyo reported that Enhertu (trastuzumab deruxtecan) has been approved in the European Union (EU) as monotherapy for the treatment of adult patients with advanced HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen (Press release, AstraZeneca, DEC 19, 2022, View Source [SID1234625380]).
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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 in November 2022 and is based on results from the DESTINY-Gastric02 and DESTINY-Gastric01 Phase II trials.
In DESTINY-Gastric02, which enrolled patients from North America and Europe, treatment with Enhertu resulted in a confirmed objective response rate (ORR) of 41.8% as assessed by independent central review (ICR). Median duration of response (DoR) was 8.1 months.
In DESTINY-Gastric01, which enrolled patients from Japan and South Korea, treatment with Enhertu resulted in a confirmed ORR of 40.5% versus 11.3% with chemotherapy (irinotecan or paclitaxel) as assessed by ICR. The median DoR was 11.3 months with Enhertu versus 3.9 months with chemotherapy. Patients treated with Enhertu had a 41% reduction in the risk of death versus patients treated with chemotherapy (based on a hazard ratio of 0.59; 95% confidence interval: 0.39-0.88; p=0.0097) with a median overall survival (OS) of 12.5 months versus 8.4 months.
Approximately 136,000 cases of gastric cancer are diagnosed annually in Europe, where it represents the sixth leading cause of cancer death.1,2 Gastric cancer is typically diagnosed in the advanced stage. Even when the disease is diagnosed at earlier stages, the survival rate remains modest.3,4 Approximately one in five gastric cancers are HER2-positive.5,6
Eric Van Cutsem, MD, PhD, Head of Department of Oncology at the University of Leuven, Belgium and Founding Chair of the ESMO (Free ESMO Whitepaper)-GI/World Congress of Gastrointestinal Cancers, said: "Today’s news is a welcome advance for patients with HER2-positive advanced gastric cancer. Patients with this disease face poor outcomes following progression on initial treatment with a HER2-directed medicine as many do not respond to further treatment, and even those that do respond often do not have durable responses. Data from the DESTINY-Gastric02 and DESTINY-Gastric01 trials support Enhertu becoming a new standard of care for patients in this setting."
Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: "Today’s important approval makes Enhertu the first HER2-directed medicine to be approved for gastric cancer in the European Union in more than a decade. Patients across the EU with advanced HER2-positive disease who have progressed following treatment in the first-line setting, may now have the opportunity to benefit from treatment with Enhertu."
Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi Sankyo, Inc., said: "Enhertu is the first antibody drug conjugate to be approved in Europe for advanced gastric cancer, representing a major advance in treating this difficult-to-treat cancer. With this approval, we can now offer patients with previously treated HER2-positive gastric cancer a treatment with clinically meaningful efficacy."
In both trials, the safety profiles observed in patients treated with Enhertu were consistent with those seen in other trials of Enhertu with no new safety signals identified.
Enhertu is also approved in the US and several other countries for locally advanced or metastatic HER2-positive gastric cancer.
Notes
Financial considerations
Following EU approval, an amount of $35m is due from AstraZeneca to Daiichi Sankyo as a milestone payment for the previously treated HER2-positive gastric 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 collaboration 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.
HER2-positive gastric cancer
Gastric (stomach) cancer is the fifth most common cancer worldwide and the fourth highest leading cause of cancer mortality, with a five-year global survival rate of 5% to 10% for advanced or metastatic disease.3,7,8 Approximately one million new patients were diagnosed with gastric cancer in 2020, with 768,000 deaths reported globally.2 In Europe, approximately 136,000 cases of gastric cancer are diagnosed annually, and Eastern Europe has the second highest incidence of gastric cancer worldwide after Eastern Asia.2,8 Gastric cancer is the sixth leading cause of cancer death in Europe and is typically diagnosed in the advanced stage. Even when diagnosed in earlier stages of the disease, the survival rate remains modest.1,3,4
Approximately one in five gastric cancers are HER2-positive.5,6 HER2 is a tyrosine kinase receptor growth promoting protein expressed on the surface of many types of tumours including breast, gastric, lung and colorectal cancers.5 HER2 overexpression may be associated with a specific HER2 gene alteration known as HER2 amplification.6
Recommended first-line treatment in the EU for HER2-positive advanced or metastatic gastric cancer is combination chemotherapy plus trastuzumab, an anti-HER2 medicine, which has been shown to improve survival outcomes when added to chemotherapy.9,10 For patients with metastatic gastric cancer that progresses following initial treatment with a trastuzumab-based regimen, there were previously no other approved HER2-directed medicines in the EU prior to the approval of Enhertu.7,11,12
DESTINY-Gastric02
DESTINY-Gastric02 is an open-label, single-arm Phase II trial in patients evaluating the efficacy and safety of Enhertu (6.4mg/kg) in patients with HER2-positive metastatic and/or unresectable gastric or GEJ adenocarcinoma with disease progression on or after a trastuzumab-containing regimen.
The primary endpoint of DESTINY-Gastric02 is confirmed ORR based on ICR. Secondary endpoints include progression-free survival (PFS), OS, DoR and safety.
DESTINY-Gastric02 enrolled 79 patients at multiple sites in North America and Europe. For more information about the trial, visit ClinicalTrials.gov.
DESTINY-Gastric01
DESTINY-Gastric01 is a randomised, open-label Phase II trial evaluating the efficacy and safety of Enhertu (6.4mg/kg) in patients with primarily HER2-positive (defined as immunohistochemistry [IHC] 3+ or IHC 2+/in-situ hybridisation [ISH]+) advanced gastric cancer or GEJ adenocarcinoma with disease progression following two or more prior treatment regimens including fluoropyrimidine (5-FU), platinum chemotherapy and trastuzumab. Patients were randomised 2:1 to receive Enhertu or physician’s choice of chemotherapy (paclitaxel or irinotecan monotherapy).
The primary endpoint of DESTINY-Gastric01 is ORR. Secondary endpoints include OS, PFS, DoR, disease control rate and time to treatment failure, as well as pharmacokinetic and safety endpoints.
DESTINY-Gastric01 enrolled 187 patients at multiple sites in Japan and South Korea. 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 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 (5.4mg/kg) 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 (5.4mg/kg) is approved in Brazil and the US 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 chemotherapy 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 under accelerated approval in the US for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer whose tumours have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy, based on the results of the DESTINY-Lung02 trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Enhertu (6.4mg/kg) is approved in several countries for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or GEJ who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 and/or DESTINY-Gastric02 trial.
Enhertu development programme
A comprehensive development programme 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.
Regulatory applications for Enhertu in breast, non-small cell lung and gastric cancer are currently under review in several countries.