Axplora

Following initiation of pivotal phase II studies in HER2-positive breast cancer and gastric cancer, the initiation of a third phase II study in colorectal cancer demonstrates commitment of Daiichi Sankyo to accelerating the development of DS-8201, an investigational HER2-targeting antibody drug conjugate or ADC, across multiple HER2-expressing tumors.

As part of this commitment, a first patient was dosed in a global phase II study evaluating the safety and efficacy of DS-8201 in patients with HER2-expressing advanced colorectal cancer who have received at least two prior lines of standard treatment.

Antibody drug conjugate are targeted cancer medicines that deliver cytotoxic chemotherapy “payload” to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.


Given the existing unmet medical need for advanced colorectal cancer, we are exploring the smart delivery of chemotherapy with DS-8201 as a potential new type of targeted treatment for patients with HER2-expressing disease who have progressed on or become resistant to standard therapies


Designed using Daiichi Sankyo’s proprietary technology, DS-8201 is a smart chemotherapy comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

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Increase in approved treatments
An increase in the number of approved targeted therapies for advanced colorectal cancer over the past decade has helped improve outcomes for some patients, however efficacy and tolerability of second and third-line treatments remain limited.[1][2][3][4][5]

Approximately 3% of colorectal cancers overexpress the HER2 protein, which is a well-established therapeutic target in breast and gastric cancer.1 In addition, research indicates that HER2 amplification may be associated with resistance to anti-epidermal growth factor receptor (EGFR)-targeted therapy and shorter survival.[6][7]

Colorectal cancer is the third most common cancer worldwide. In 2012, there were approximately 1.36 million new cases diagnosed and 690,000 deaths worldwide.[8] Approximately 25 percent of patients have metastatic disease at diagnosis, meaning the disease has spread to distant organs, and about 50 percent of patients with colorectal cancer will eventually develop metastases.[9] Prognosis for these patients remains poor.[10]

Currently, no approved HER2-targeting therapies exist for patients with colorectal cancer.

“Given the existing unmet medical need for advanced colorectal cancer, we are exploring the smart delivery of chemotherapy with DS-8201 as a potential new type of targeted treatment for patients with HER2-expressing disease who have progressed on or become resistant to standard therapies,” noted Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.

“Similar to our breast and gastric cancer programs, we are pursuing a development path focused first on patients with HER2-overexpressing tumors followed by potential expansion to include patients with advanced colorectal cancer with lower levels of HER2 expression,” Yver added.

Colorectal Cancer Trial
The global, multi-center, phase 2, open-label, three-cohort study will investigate the safety and efficacy of DS-8201 in patients with HER2-expressing advanced colorectal cancer. The first part of the study will enroll patients with HER2-positive (defined as IHC3+ or IHC2+/ISH+) advanced colorectal cancer. The primary endpoint of the study is overall response rate. Secondary endpoints include progression-free survival, overall survival, duration of response, disease control rate, pharmacokinetics and safety. Exploratory endpoints include time to response and biomarker analysis. This part of the study is expected to enroll approximately 50 patients in North America, Europe and Japan.

Following the outcome of the first part of the study, two additional exploratory cohorts may proceed to enroll patients whose tumors have lower levels of HER2-expression.

Ongoing research
Daiichi Sankyo’s DS-8201 is the lead product in the investigational ADC Franchise of the company.

In addition to the phase II study in HER2-expressing advanced colorectal cancer, DS-8201 is currently in pivotal phase 2 clinical development for HER2-positive unresectable and/or metastatic breast cancer resistant or refractory to T-DM1 (DESTINY-Breast01) in North America, Europe and Asia, and pivotal phase 2 development for HER2-positive advanced gastric cancer resistant or refractory to trastuzumab (DESTINY-Gastric01) in Japan and South Korea.

DS-8201 is also in phase I development for other HER2-expressing advanced/unresectable or metastatic solid tumors.

Breakthrough Therapy designation
DS-8201 has been granted Breakthrough Therapy designation for the treatment of patients with HER2-positive, locally advanced or metastatic breast cancer who have been treated with trastuzumab and pertuzumab and have disease progression after ado-trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche), and Fast Track designation for the treatment of HER2-positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2-targeted therapies including T-DM1 by the U.S. Food and Drug Administration (FDA). DS-8201 is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

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