Bristol-Myers Squibb and Daiichi Sankyo have agreed to collaborate in a clinical trial to evaluate the combination of Bristol-Myers Squibb’s immunotherapy nivolumab (Opdivo®) and Daiichi Sankyo’s investigational antibody drug conjugate DS-8201 in HER2-expressing metastatic breast and urothelial (bladder) cancers.

Immune checkpoint inhibitor
Nivolumab is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, nivolumab has become an important treatment option across multiple cancers.

Nivolumab’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology (IO)  and includes a broad range of clinical trials across all phases, including Phase III, in a variety of tumor types. To date, the nivolumab clinical development program has enrolled more than 25,000 patients. The nivolumab trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, nivolumab was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 60 countries, including the United States, the European Union, and Japan. In October 2015, the company’s nivolumab and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

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Antibody-drug conjugate
The clinical collaboration includes DS-8201, the lead investigational product in the antibody-drug conjugate or ADC Franchise of the Daiichi Sankyo Cancer Enterprise. ADCs are a type of targeted cancer medicine that deliver cytotoxic chemotherapy (“payload”) directly to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. 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 linker designed to deliver enhanced cancer cell destruction upon release inside the cell and reduce systemic exposure to the cytotoxic payload (or chemotherapy).

DS-8201 is currently in Phase 1 clinical development for HER2-positive advanced or metastatic breast cancer and gastric cancer, HER2 low-expressing breast cancer and other HER2-expressing solid cancers. The U.S. Food and Drug Administration (FDA) granted Fast Track designation to DS-8201 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 ado-trastuzumab emtansine (T-DM1).

Immune system
“We are excited to evaluate if the combination of these two mechanisms of action – the ability of an anti-PD-1 to harness the immune system and the potential of DS-8201 to deliver chemotherapy directly to target cancer cells – may be able to improve the outcomes of patients with HER2-expressing advanced breast and bladder cancer,” said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.

“Pursuing combination studies like this is at the core of the Daiichi Sankyo Cancer Enterprise strategy, as we are looking to maximize the potential of our proprietary antibody drug conjugate technology to help address the unmet needs of patients living with cancer,” Yver further noted.

“Combination therapy with agents that target different and complementary pathways—in this case, the combination of a checkpoint inhibitor and innovative chemotherapy delivery—is a potential new approach for patients with difficult to treat cancers,” said Fouad Namouni, M.D., head of Development, Oncology, Bristol-Myers Squibb.

“We are looking forward to working with Daiichi Sankyo to investigate the synergies of these treatment methods,” Namouni added.

Clinical trial
The Phase Ib multicenter, open-label study will include two parts. The dose escalation part will determine a possible recommended dose of DS-8201 in combination with nivolumab in patients with HER2-expressing breast cancer who are refractory to standard therapies or for which no standard therapy is available. The dose expansion part of the study will evaluate the efficacy, safety and tolerability of combining nivolumab with DS-8201 at the established dose level in patients with HER2-expressing advanced/metastatic breast cancer as well as HER2-expressing urothelial (bladder) cancer in patients previously treated with chemotherapy.

The study is expected to begin enrollment in first quarter of 2018 in the US and Europe. Under the terms of the agreement, Daiichi Sankyo will be the sponsor conducting the trial.

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