A first patient has been dosed in a phase I study evaluating the safety and tolerability of U3-1402, in patients with metastatic or unresectable epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) whose disease has progressed while taking an EGFR tyrosine kinase inhibitor (TKI).

U3-1402 is an investigational and potential first-in-class HER3-targeting antibody-drug conjugate or ADC being developed by Daiichi Sankyo. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapeutic 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.


New treatments are needed that work to overcome resistance associated with current EGFR TKIs…

EGFR tyrosine kinase inhibitor
Today, treatment with EGFR TKIs such as erlotinib, gefitinib, or afatinib is used as first-line therapy for metastatic EGFR-mutated NSCLC. [1][2][3][4] However, patients eventually develop resistance to these treatments, typically experiencing disease progression within a year.  [1][2][3][4]  More than half of these patients develop resistance with a secondary EGFR mutation called T790M, which may be treated with EGFR TKI osimertinib.[1][2][3][4] Patients who experience disease progression following EGFR TKI treatment and who have tumors that lack the T790M mutation may be treated with chemotherapy, immunotherapy, or with investigational treatments.[3][4]

Expression of HER3, a member of the HER family of receptor tyrosine kinases, is believed to play a role in tumor growth and proliferation in many different types of cancer including NSCLC.[5] Studies have shown that HER3 overexpression in lung cancer can also be associated with acquired resistance to other EGFR family targeted interventions such as TKIs and anti-EGFR antibody therapies.[5] Patients with NSCLC with high levels of HER3 may face a significantly worse prognosis and decreased survival.[5][6][7] Currently, there are no approved HER3-targeted therapies.

“While the treatment of metastatic EGFR-mutated NSCLC has significantly improved over the past decade, new treatments are needed that work to overcome resistance associated with current EGFR TKIs,” said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.

“In this study, we are exploring whether the smart delivery of chemotherapy with U3-1402 to cancer cells that express HER3 – a known feature of resistance in pre-treated EGFR-mutated NSCLC – could become a new treatment strategy for these patients.”

Phase I study
U3-1402 is currently being evaluated in two phase I clinical studies including a phase I/II study for HER3-expressing metastatic or unresectable breast cancer and a phase 1 study for metastatic or unresectable EGFR-mutated NSCLC.

The global, phase I, open label, two-part study will enroll patients with metastatic or unresectable EGFR-mutated NSCLC whose disease has progressed while taking an EGFR TKI. This includes patients who experienced disease progression during treatment with erlotinib, gefitinib, or afatinib and whose tumors have tested negative for the T790M mutation and patients who experienced disease progression during treatment with osimertinib regardless of T790M status. The primary objectives of the study are to assess the safety and tolerability of U3-1402 and determine the recommended dose for the dose expansion part of the study. The secondary objectives are to characterize the pharmacokinetics of U3-1402 and to evaluate preliminary efficacy by measuring antitumor activity of U3-1402.

The study is expected to enroll more than 60 patients at approximately 17 sites globally.