Trastuzumab Deruxtecan Achieves 60.9% Objective Response Rate in Heavily Pretreated HER2-Positive Metastatic Breast Cancer, Highlighting Potential as New Standard of Care

December 13, 2019 /BioValleyBIOON/ -- San AntonioBreast CancerThe San Antonio Breast Cancer Symposium (SABCS) is the largest and most influential breast cancerMeeting, with over 7,000 researchers and physician representatives from more than 90 countries worldwide attending each year. The 42nd SABCS meeting was recently held in San Antonio, USA, in 2019. At this conference,AstraZeneca(AstraZeneca) and its partner Daiichi Sankyo announced positive detailed data from the global, pivotal, single-arm, Phase II DESTINY-Breast01 trial of trastuzumab deruxtecan (DS-8201), a HER2-targeted antibody-drug conjugate (ADC).

This is a pivotal, single-arm, open-label, global, multicenter, two-part trial evaluating the safety and efficacy of DS-8201 as monotherapy in patients with HER2-positive, unresectable and/or metastatic breast cancer. Patient enrollment was completed in September 2018, comprising 184 patients from more than 100 clinical sites worldwide. These patients had previously received two or more HER2-targeted regimens; the median number of prior therapies for metastatic disease was 6 (range: 2–27). Prior therapies included trastuzumab emtansine (T-DM1, 100%), trastuzumab (100%), pertuzumab (65.8%), other anti-HER2 therapies (54.3%), hormonal therapy (48.9%), and other systemic treatments (99.5%). The primary endpoint of the study was the overall response rate (ORR), as assessed by an independent central review committee (IRC).

In the study, the median treatment duration with DS-8201 was 10 months (range: 0.7–20.5), and the median follow-up time was 11.1 months (range: 0.7–19.9). As of the data cutoff date of August 1, 2019, 42.9% of patients were still receiving treatment.

Data showed that the objective response rate (ORR) for DS-8201 monotherapy (5.4 mg/kg) was 60.9%, the disease control rate (DCR) was 97.3%, the median duration of response (DoR) was 14.8 months, and the median progression-free survival (PFS) was 16.4 months. The median overall survival (OS) was not reached, with an estimated one-year survival rate of 86%. Results were consistent across all subgroups. The safety and tolerability profile of DS-8201 in this study was consistent with that observed in Phase I trials.

AstraZenecaTumorJosé Baselga, Executive Vice President of Research and Development, stated: “The clinically meaningful and durable responses observed in these patients demonstrate the potential of DS-8201 to establish a new standard of care. These results are impressive, as the women with advanced breast cancer had previously received multiple therapies for HER2-positive metastatic breast cancer.”

Ian E. Krop, Deputy Director of the Breast Oncology Program at the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute and principal investigator of the DESTINY-Breast01 trial, stated, “These results are particularly striking because DS-8201 induced high levels of durableTumorreduction, as most of them had exhausted most or even all standard therapies for HER2-positive metastatic breast cancer. We are excited about these results and their potential to help patients with advanced breast cancer.”

Approximately 20% of breast cancer cases are HER2-positive. Despite therapeutic advances and the approval of multiple novel agents in recent years, there remains a significant unmet clinical need among patients with advanced HER2-positive metastatic breast cancer. This disease remains incurable, and patients ultimately experience disease progression after receiving currently available therapies.

HER2 is a tyrosine kinase receptor growth-promoting protein present on the surface of certain cancer cells and is associated with aggressive disease and poor prognosis in breast cancer patients. Tumor cells are typically tested for HER2 expression using either immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH). IHC results are reported as IHC 0, IHC 1+, IHC 2+, or IHC 3+. The presence of IHC 3+ and/or FISH amplification is considered HER2-positive. Currently, there are no targeted therapies for HER2 FISH-negative, IHC 2+, or IHC 1+TumorHER2-targeted drugs.

Trastuzumab deruxtecan (DS-8201) is a next-generation antibody-drug conjugate (ADC) that links trastuzumab, a humanized monoclonal antibody targeting HER2, to an exatecan derivative (DXd, a derivative of DX-8951), a novel topoisomerase I inhibitor, via a tetrapeptide linker. This formulation enables targeted delivery of the cytotoxic agent into cancer cells, thereby reducing systemic exposure to the cytotoxic payload compared with conventional chemotherapy.

In March this year, AstraZeneca and Daiichi Sankyo reached an agreement worth up to $6.9 billion for immuneTumorCollaborate to jointly develop trastuzumab deruxtecan for the treatment of patients with various cancers characterized by different levels of HER2 expression or HER2 mutations, including gastric cancer, colorectal cancer, lung cancer, and HER2-low breast cancer. Under the agreement, both parties will jointly develop and commercialize trastuzumab deruxtecan on a global scale, with Daiichi Sankyo retaining exclusive rights for the Japanese market and assuming full responsibility for manufacturing and supply.

In terms of regulatory affairs, in October this year, the Biologics License Application (BLA) for DS-8201 in the treatment of HER2-positive metastatic breast cancer was accepted by the U.S. FDA and granted priority review, with approval expected in the second quarter of 2020. Previously,FDADS-8201 has been granted Breakthrough Therapy Designation and Fast Track Designation. In addition, regulatory applications for DS-8201 have been submitted in Japan. According to forecasts by the pharmaceutical market research firm EvaluatePharma, if successfully launched, DS-8201 is expected to achieve sales of $2 billion in 2024. (Bioon.com)

Original Source:Trastuzumab deruxtecan achieved a tumour response rate of 60.9% in pivotal Phase II HER2-positive metastatic breast cancer trial