A first patient has been enrolled in DESTINY-Gastric01 (NCT03329690), a pivotal phase II study in Japan and South Korea evaluating the safety and efficacy of DS-8201, an investigational HER2-targeting antibody-drug conjugate or ADC being developed by Daiichi Sankyo, in patients with HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma, also known s GEJ, which is resistant or refractory to trastuzumab.
Gastroesophageal junction adenocarcinoma remains a significant clinical problem and reprents a major unmet medical need. Although incidence rates for esophageal squamous cell carcinoma and distal gastric carcinoma have been declining, the trends for adenocarcinoma of the esophagus and proximal stomach have been rising rapidly. This increase, particularly among white males, is generally associated with a poor prognosis. A review of the disease shows an average, 5-year, survival rate of these patients to be 12.5%, with a median survival of 36.5 days (0 days- 68.1 months). This increases to 18.9% with best supportive care .
The majority of patients present with advanced disease and less than 50% undergo curative treatment. However, a substantial percentage of patients eligible for major surgery achieve long-term survival.
“Japan and South Korea have some of the highest rates of gastric cancer worldwide and there have been limited advances in targeted treatments over the past decade,” said Koichi Akahane, Ph.D, MBA, Executive Officer, Head of Oncology Function, R&D Division, Daiichi Sankyo.
“The initiation of this pivotal study will allow us to evaluate whether the smart delivery of chemotherapy with DS-8201 may be a potential new treatment option to help address the high unmet medical need of gastric cancer,” Akahane added.
Approximately one in five gastric cancers overexpress HER2, a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells. HER2-expressing gastric cancer is an area of unmet medical need as advances in the treatment of the disease have been limited, largely due to its genetic complexity and heterogeneity. Currently, no approved HER2-targeting therapy options exist for patients with HER2-positive advanced gastric cancer after trastuzumab.
Gastric cancer is the fifth most common cancer worldwide, with nearly one million new cases reported in 2012. Approximately half of all gastric cancer cases occur in eastern Asia, with South Korea and Japan having the first and third highest incidence rate worldwide, respectively.. Gastric cancer is the third leading cause of cancer-related death worldwide, and the second and third leading cause of cancer-related death in Japan and South Korea, respectively.
DS-8201 is the lead product in the ADC Franchise of the Daiichi Sankyo Cancer Enterprise. ADCs are targeted cancer medicines that deliver a cytotoxic chemotherapy payload to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.
Designed using Daiichi Sankyo’s proprietary ADC technology, DS-8201 is a smart chemotherapy comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor (DXd) 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 compared to the way chemotherapy is commonly delivered.
“We are excited to initiate this second pivotal study of DS-8201 as it represents an important next step to accelerate the development of DS-8201,” said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. “With limited treatment options available for advanced gastric cancer, including no approved antibody drug conjugate, we are exploring the potential of DS-8201 as a new treatment option for this type of HER2-expressing cancer.”
DESTINY-Gastric01 is a pivotal phase II, open-label study investigating the safety and efficacy of DS-8201 in patients with HER2-expressing advanced gastric cancer or gastroesophageal junction adenocarcinoma (defined as IHC3+ or IHC2+/ISH+) who have progressed on two prior regimens including fluoropyrimidine agent, platinum agent and trastuzumab. Patients participating in this trial will be randomized 2:1 to DS-8201 or physician’s choice of treatment (paclitaxel or irinotecan monotherapy). The primary endpoint of the study is objective response rate. Secondary endpoints include progression-free survival, overall survival, duration of response, disease control rate, time to treatment failure, pharmacokinetics and safety.
DESTINY-Gastric01 also will include two non-randomized exploratory cohorts to examine the safety and efficacy of DS-8201 in patients with HER2 low-expressing advanced gastric cancer, who have not been treated previously with a HER2-targeting therapy. The first exploratory cohort will enroll patients with HER2 low-expression defined as IHC2+/ISH-, and the second exploratory cohort will include HER2 low-expression defined as IHC1+.
The study is expected to enroll up to 180 patients in the pivotal cohort and 40 patients in the exploratory cohorts in Japan and South Korea.
In addition to the DESTINY-Gastric01 study, DS-8201 is currently in phase 2 clinical development for HER2-positive unresectable and/or metastatic breast cancer resistant or refractory to ado-trastuzumab emtansine (T-DM1) (DESTINY-Breast01) and in phase 1 development for other HER2-expressing advanced/unresectable or metastatic solid tumors.