FDA Grants Breakthrough Therapy Designation to Enhertu in HER2-Positive Metastatic Breast Cancer Based on Phase 3 Trial Outperforming Kadcyla

October 13, 2021 /BioonBIOON/ --AstraZeneca(AstraZeneca) and Daiichi Sankyo (Daiichi Sankyo) recently jointly announced that the U.S. Food and Drug Administration (FDA) GrantedHER2-targeted antibody-drug conjugate (ADC) Enhertu (trastuzumab deruxtecan)Breakthrough Therapy Designation (BTD):For the treatment of unresectable or metastatic HER2-positive disease in patients who have previously received one or more anti-HER2 regimensBreast CancerAdult patients.

BTD is an FDA new drug review pathway designed to expedite the development and review of new drugs intended to treat serious or life-threatening conditions, where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies on clinically significant endpoints.To date, Enhertu has received USFDAFour BTDs were granted, two of which are for the treatment of breast cancer.

This latest BTD is based on the results of the groundbreaking head-to-head Phase 3 DESTINY-Breast03 trial:Compared with Roche's HER2-targeted ADC product Kadcyla (trastuzumab emtansine, T-DM1), Enhertu reduced the risk of disease progression or death by 72%.. This unprecedented result indicates that Enhertu has the potential to drive a paradigm shift in the treatment of HER2-positive metastatic breast cancer and demonstrates Enhertu's potential to improve patient outcomes in earlier treatment settings.

Breast cancer remains the most common cancer worldwide, in 2020DiagnosisWith over 2 million cases reported, resulting in nearly 685,000 deaths globally. Approximately one-fifth of breast cancer cases are considered HER2-positive. Despite initial treatment with trastuzumab and taxanes, patients with HER2-positive metastatic breast cancer typically experience disease progression, necessitating more effective treatment options to further delay disease progression and prolong survival.

Kadcyla is a targeted therapy approved for the treatment of the aforementioned patients with HER2-positive breast cancer. DESTINY-Breast03 is the first global Phase 3 head-to-head trial comparing Enhertu with a positive control drug. Patients with previously treated HER2-positive metastatic breast cancer receiving currently available HER2-targeted therapies typically experience disease progression in less than one year.In the DESTINY-Breast03 trial, patients treated with Enhertu demonstrated highly consistent and significant benefits across various efficacy endpoints and key subgroups, supporting the potential of Enhertu as a new standard of care for patients with HER2-positive metastatic breast cancer.

The detailed positive results of the DESTINY-Breast03 trial were presented in September this year at the 2021 European MedicalTumorPresented at the virtual conference of the European Society for Medical Oncology (ESMO), data showed that: in patients with HER2-positive unresectable and/or metastatic breast cancer who had previously received trastuzumab and taxane therapy, Enhertu demonstrated significantly superior efficacy compared to Kadcyla, with highly consistent and significant benefits observed across multiple efficacy endpoints and key subgroups.

Data presented at the meeting showed that, in the prespecified interim analysis, the DESTINY-Breast03 trial met the primary endpoint of progression-free survival (PFS):Compared with Kadcyla, Enhertu significantly reduced the risk of disease progression or death by 72%.(HR = 0.28; 95% CI: 0.22–0.37; p = 7.8 × 10⁻²²). After a follow-up of 15.5 months for the Enhertu group and 13.9 months for the Kadcyla group, respectively, the median PFS for patients in the Enhertu group had not been reached (95% CI: 18.5–NE), while the median PFS for patients in the Kadcyla group was 6.8 months (95% CI: 5.6–8.2).

For the key secondary endpoint of investigator-assessed PFS,EThe median PFS for patients in the Enhertu group was three times that of the Kadcyla group.(25.1 months vs. 7.2 months; HR = 0.26; 95% CI: 0.20-0.35; p = 6.5x10E-24). Consistent PFS benefits were observed in key subgroups of patients receiving Enhertu, including those with stable brain metastases.

Additionally, for the key secondary endpoint of overall survival (OS):Compared with the Kadcyla arm, the Enhertu arm showed a strong trend toward improved OS (HR = 0.56; 95% CI: 0.36–0.86; nominal p = 0.007172)., but this analysis remains immature and is not statistically significant. Nearly all patients in the Enhertu group survived at one year (94.1%), compared with a survival rate of 85.9% in the Kadcyla group.

Compared with the Kadcyla group, the confirmed objective response rate (ORR) in the Enhertu group more than doubled (79.7% vs 34.2%).。In the Enhertu group, complete response (CR) was observed in 42 patients (16.1%) and partial response (PR) in 166 patients (63.6%), whereas in the Kadcyla group, complete response (CR) was observed in 23 patients (8.7%) and partial response (PR) in 67 patients (25.5%).

In this trial, the safety of Enhertu was consistent with previousClinical TrialConsistent, no new safety issues were identified. The most common Grade ≥3 treatment-emergent adverse events in the Enhertu arm were neutropenia (19.1%), thrombocytopenia (7.0%), leukopenia (6.6%), and nausea (6.6%). As determined by an Independent Review Committee, 27 cases (10.5%) of treatment-related interstitial lung disease (ILD) or pneumonitis were reported. The majority (9.7%) were low-grade (Grade 1 or 2), with 2 Grade 3 (0.8%) events reported. No Grade 4 or 5 ILD or pneumonitis events occurred.

DESTINY-Breast03 Trial Results

In March 2019, AstraZeneca and Daiichi Sankyo reached a $6.9 billion immuno-TumorThrough collaboration, jointly develop Enhertu for the treatment of cancer patients with various HER2 expression levels or HER2 mutations, including gastric cancer, colorectal cancer, lung cancer, and HER2-low breast cancer.

Enhertu is a next-generation antibody-drug conjugate (ADC) that links trastuzumab, a humanized monoclonal antibody targeting HER2, to a novel topoisomerase I inhibitor, an exatecan derivative (DX-8951 derivative, DXd), via a tetrapeptide linker. It enables targeted delivery of the cytotoxic agent into cancer cells, thereby reducing systemic exposure to the cytotoxic payload compared with conventional chemotherapy.

To date, Enhertu (5.4 mg/kg) has been approved in multiple countries: as monotherapy 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 in the metastatic setting. Additionally, Enhertu (6.4 mg/kg) has also been approved in multiple countries: for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have previously received a trastuzumab-containing regimen.

Breast cancer is the most common type of cancer among women and one of the leading causes of cancer-related mortality in women. Approximately 20% of breast cancer cases are HER2-positive. Despite recent therapeutic advances and the approval of several new agents, a significant unmet clinical need remains in patients with HER2-positive metastatic breast cancer. The disease remains incurable, and patients ultimately experience disease progression following currently available therapies. HER2 is a growth-promoting receptor tyrosine kinase expressed in various...TumorCell surface expression in cancers including gastric, breast, lung, and colorectal cancer is associated with aggressive disease and poor prognosis. (Bioon.com)

Original Source:Enhertu granted Breakthrough Therapy Designation in US for patients with HER2-positive metastatic breast cancer treated with one or more prior anti-HER2-based regimens