On June 1, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that preliminary data from the dose escalation part of an ongoing phase 1/2 study with investigational U3-1402 in heavily pretreated patients with HER3-positive metastatic breast cancer will be presented during a Poster Discussion Session on Monday, June 4 at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL (Abstract 2512; 3:00 – 4:15 PM CDT) (Press release, Daiichi Sankyo, MAY 31, 2018, View Source [SID1234527019]).
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Safety results were reported for 34 patients receiving U3-1402 in dose levels between 1.6 mg/kg to 8.0 mg/kg given every three weeks. A maximum tolerated dose has not yet been reached. The most common adverse events (>30 percent, any Grade) included nausea (82 percent), platelet count decreased/thrombocytopenia (68 percent), decreased appetite (62 percent), neutrophil count decreased/neutropenia (59 percent), white blood cell count decreased (53 percent), vomiting (50 percent), ALT increased (38 percent), AST increased (38 percent), anemia (38 percent), stomatitis (32 percent) and diarrhea (32 percent). The most common adverse events Grade ≥3 (>10 percent of patients) were thrombocytopenia (29 percent), neutrophil count decreased/neutropenia (27 percent), white blood cell count decreased (18 percent) and anemia (12 percent). The following dose-limiting toxicities were observed: Grade 4 platelet count decreased (3 patients), Grade 3 ALT increased (2 patients), and Grade 2 AST increased (1 patient).
Preliminary results in 32 efficacy evaluable patients showed that U3-1402 demonstrated a confirmed overall response rate of 47 percent (15/32 patients) and a disease control rate of 94 percent (30/32 patients).
"There is a clinical need for additional treatments for metastatic breast cancer, especially for those tumors that express HER3, which is associated with poor prognosis and for which no targeted therapies are currently available," said Takahiro Kogawa, MD, PhD, National Cancer Center Hospital East in Japan, and an investigator for the study. "These preliminary results suggest that U3-1402 could be a potential new treatment approach for metastatic breast tumors that express HER3, and the study will move forward to determine the most suitable dosing regimen for further clinical evaluation."
"These findings with U3-1402, which are the first reported clinical data evaluating an ADC in HER3-expressing cancer, build upon our historical understanding of exploring the role of HER3 as a potential target," said Kouichi Akahane, PhD, MBA, Executive Officer, Head of Oncology Function, R&D Division, Daiichi Sankyo. "Furthermore, these results seen with U3-1402 offer proof-of-concept of the portability of our proprietary DXd and linker ADC technology, which has been specifically designed to smartly deliver chemotherapy with the precision of a targeted therapy."
About the Phase 1 Study
In this three-part open-label global phase 1/2 study, U3-1402 is given as an intravenous infusion every three weeks. The first part of the study (dose escalation) is assessing the safety, tolerability and maximum tolerated dose of U3-1402 in HER3-positive (defined as IHC 2+/3+) metastatic breast cancer patients who are refractory or intolerant to standard treatment, or for whom no standard treatment is available. The second part of the study (dose-finding) will assess the safety and efficacy of U3-1402 and determine the recommended phase 2 dose in HER3-positive metastatic breast cancer patients who have received six or fewer prior chemotherapy regimens. The third part of the study (phase 2) will assess the safety and efficacy of the recommended dose of U3-1402 in HER3-positive metastatic breast cancer patients who have received six or fewer prior chemotherapy regimens. The study is currently enrolling patients in Japan and is preparing to expand to include patients in the U.S. For more information about this study, please visit ClinicalTrials.gov.
About HER3-Positive Metastatic Breast Cancer
Breast cancer is typically classified and treated based on one of three types of biomarker status classifications: hormone-receptor positive (HR+), where the tumor cells contain either estrogen receptors (ER) or progesterone receptors (PR); HER2-positive (HER2+), where the tumor cells overexpress HER2; and triple negative, where the tumor cells do not have estrogen or progesterone receptors and are HER2-negative.However, human epidermal growth factor receptor 3 (known as HER3 or ERBB3) is a tyrosine kinase receptor that is increasingly being recognized as important to tumor growth in certain cancers including breast cancer. Patients living with invasive breast cancer with high levels of HER3 face a significantly worse prognosis and decreased survival, and to date there is no approved HER3-directed therapy option.
Part of the investigational ADC Franchise of the Daiichi Sankyo Cancer Enterprise, U3-1402 is an investigational and potential first-in-class HER3-targeting ADC. ADCs 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. Designed using Daiichi Sankyo’s proprietary ADC technology, U3-1402 is a smart chemotherapy comprised of a human anti-HER3 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.
U3-1402 is currently being evaluated in two phase 1 clinical studies, including a phase 1/2 study for HER3-expressing metastatic or unresectable breast cancer in Japan and a phase 1 study for metastatic or unresectable EGFR-mutated non-small cell lung cancer (NSCLC) in the U.S.
U3-1402 is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.