Enhertu Demonstrates Superior Efficacy Over Kadcyla in Phase 3 Head-to-Head Trial for HER2-Positive Metastatic Breast Cancer, Setting New Standard of Care

September 21, 2021 /BioonBIOON/ --AstraZeneca(AstraZeneca) and Daiichi Sankyo (Daiichi Sankyo) recently at the 2021 European medicalTumorDetailed positive results from the head-to-head Phase 3 DESTINY-Breast03 trial were presented at the European Society for Medical Oncology (ESMO) Virtual Congress, with data showing that:previously treated with trastuzumab and a taxane for HER2-positive unresectable and/or metastaticBreast CancerAmong patients, the HER2-targeted antibody-drug conjugate (ADC) Enhertu (trastuzumab deruxtecan) demonstrated significantly superior efficacy compared to Roche's HER2-targeted ADC product Kadcyla (trastuzumab emtansine, T-DM1), with highly consistent and significant benefits observed across multiple efficacy endpoints and key subgroups.

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. Data from this trialThe data support the potential of Enhertu as a new standard of care for these patients with HER2-positive breast cancer.

Data presented at the meeting showed that in a 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 in the Enhertu group and 13.9 months in the Kadcyla group, respectively, the median PFS in the Enhertu group had not been reached (95% CI: 18.5–NE), whereas the median PFS in the Kadcyla group was 6.8 months (95% CI: 5.6–8.2).

Regarding the key secondary endpoint of investigator-assessed PFS,The median PFS for patients in the Enhertu group was 3 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). A consistent PFS benefit was observed in key subgroups of patients treated with Enhertu, including those with a history of stable brain metastases.

Furthermore, for the key secondary endpoint of overall survival (OS): compared with the Kadcyla group, the Enhertu group demonstrated a strong trend toward improved OS (HR=0.56; 95% CI: 0.36–0.86; nominal p=0.007172), but the analysis was immature and not statistically significant.At one year, nearly all patients in the Enhertu group were alive (94.1%), compared with a survival rate of 85.9% in the Kadcyla group.

Compared with the Kadcyla group,Confirmed objective response rate (ORR) more than doubled in the Enhertu arm (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%), while 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 profile of Enhertu was consistent with previousClinical Trialconsistent, with no new safety issues identified. The most common grade ≥3 treatment-emergent adverse events in the Enhertu group were neutropenia (19.1%), thrombocytopenia (7.0%), leukopenia (6.6%), and nausea (6.6%).

As determined by the Independent Review Committee, 27 cases (10.5%) of treatment-related interstitial lung disease (ILD) or pneumonitis were reported. Most (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.

Javier Cortes, MD, Director of the International Breast Cancer Center (IBCC) in Barcelona, said: “Patients with previously treated HER2-positive metastatic breast cancer typically experience disease progression in less than one year with currently available HER2-targeted therapies. 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 the new standard of care for this patient population with HER2-positive metastatic breast cancer.”

AstraZenecaTumorExecutive Vice President of Research and Development Susan Galbraith said: “Today's results are groundbreaking.According to the researchers' assessment, treatment with Enhertu extended progression-free survival threefold, with a disease control rate exceeding 95%, compared to 77% for Kadcyla. Additionally, no grade 4 or 5 interstitial lung disease events were observed in the trial, and the safety profile was encouraging.These unprecedented findings demonstrate that Enhertu has the potential to bring a paradigm shift in the treatment of HER2-positive metastatic breast cancer, highlighting its potential to transform the lives of more patients in earlier treatment settings.”

In March 2019, AstraZeneca and Daiichi Sankyo reached a deal with a total value of $6.9 billion for immune...TumorCollaborate to 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 a HER2-targeting humanized monoclonal antibody, trastuzumab, to a novel topoisomerase I inhibitor exatecan derivative (DX-8951 derivative, DXd) via a tetrapeptide linker, enabling targeted delivery of the cytotoxic payload into cancer cells and reducing systemic exposure to the cytotoxic agent compared to conventional chemotherapy.

As of now,Enhertu (5.4 mg/kg) has been approved in multiple countries: as a 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 cancer in women and one of the leading causes of cancer-related mortality among females. Approximately 20% of breast cancer cases are HER2-positive. Despite recent therapeutic advances and the approval of multiple novel agents, a significant unmet clinical need persists among 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 protein expressed in variousTumorCell surface expression in gastric, breast, lung, and colorectal cancers is associated with aggressive disease and a poorer prognosis. (Bioon.com)

Original Source:Enhertu reduced the risk of disease progression or death by 72% vs. trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer