On December 19, 2022 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 unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy (Press release, AstraZeneca, DEC 19, 2022, View Source [SID1234625381]).

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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 Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency based its positive opinion on results from the DESTINY-Breast04 Phase III trial, which were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2022 Annual Meeting and simultaneously published in The New England Journal of Medicine.1

In the trial, Enhertu reduced the risk of disease progression or death by 50% versus physician’s choice of chemotherapy (based on a hazard ratio [HR] of 0.50; 95% confidence interval [CI]: 0.40-0.63; p<0.001) in patients with HER2-low metastatic breast cancer with HR-positive or HR-negative disease. A median progression-free survival (PFS) of 9.9 months was seen with Enhertu versus 5.1 months in those treated with chemotherapy, as assessed by blinded independent central review (BICR). A 36% reduction in the risk of death (HR 0.64; 95% CI: 0.49-0.84; p=0.001) was seen with Enhertu compared to chemotherapy with a median overall survival (OS) of 23.4 months versus 16.8 months.

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "Enhertu is the first-ever HER2-directed medicine to show a survival benefit in patients with HER2-low metastatic breast cancer, confirming the importance of targeting lower levels of HER2 expression in patients previously classified as HER2-negative. The CHMP’s recommendation is encouraging and supports our ambition to evolve the way breast cancer is classified and treated to ultimately improve patient outcomes."

Ken Takeshita, Global Head, R&D Daiichi Sankyo, said: "This positive CHMP opinion recognises the unmet need in the European Union for patients with HER2-low metastatic breast cancer. Currently, once patients with HR-positive disease progress on hormone therapy there are limited effective treatments, and few targeted options are available for patients with HR-negative disease. We look forward to the European Commission decision and aim to bring Enhertu to eligible patients as soon as possible."

The safety profile observed in patients treated with Enhertu in the DESTINY-Breast04 trial was consistent with that seen in other trials of Enhertu in breast cancer with no new safety signals identified.

Notes

Breast cancer and HER2 expression
Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.2 More than two million patients with breast cancer were diagnosed in 2020 with nearly 685,000 deaths globally.2 In Europe, approximately 531,000 breast cancer patients are diagnosed annually with nearly 141,000 deaths.3

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, and is one of many biomarkers expressed in breast cancer tumours.4

HER2 expression is currently determined by an immunohistochemistry (IHC) test which estimates the amount of HER2 protein on a cancer cell, and/or an in situ hybridisation (ISH) test, which counts the copies of the HER2 gene in cancer cells.4,5 HER2 tests provide IHC and ISH scores across the full HER2 spectrum and are routinely used to determine appropriate treatment options for patients with metastatic breast cancer.

HER2-positive cancers are currently defined as HER2 expression measured as IHC 3+ or IHC 2+/ISH+, and HER2-negative cancers are defined as HER2 expression measured as IHC 0, IHC 1+ or IHC 2+/ISH-.4 However, approximately half of all breast cancers are HER2-low, defined as a HER2 score of IHC1+ or IHC 2+/ISH-.6-8 HER2-low occurs in both HR-positive and HR-negative disease.9

Currently, patients with HR-positive metastatic breast cancer and HER2-low disease have limited effective treatment options following progression on endocrine (hormone) therapy.10 Additionally, few targeted options are available for those with HR-negative disease.11

DESTINY-Breast04
DESTINY-Breast04 is a global, randomised, open-label, Phase III trial evaluating the efficacy and safety of Enhertu (5.4mg/kg) versus physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel) in patients with HR-positive or HR-negative, HER2-low unresectable and/or metastatic breast cancer previously treated with one or two prior lines of chemotherapy. Patients were randomised 2:1 to receive either Enhertu or chemotherapy.

The primary endpoint of DESTINY-Breast04 is PFS in patients with HR-positive disease based on BICR. Key secondary endpoints include PFS based on BICR in all randomised patients (HR-positive and HR-negative disease), OS in patients with HR-positive disease and OS in all randomised patients (HR-positive and HR-negative disease). Other secondary endpoints include PFS based on investigator assessment, objective response rate based on BICR and on investigator assessment, duration of response based on BICR and safety.

DESTINY-Breast04 enrolled 557 patients at multiple sites in 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 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 (5.4mg/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 systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy, based on the results of 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 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 (6.4mg/kg) is approved in several countries 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 and/or the DESTINY-Gastric02 trial.

Enhertu development programme
A comprehensive global development programme is underway 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.