Daiichi Sankyo Company, Limited announced that the first patient has been dosed in a global phase 2 study evaluating the efficacy and safety of DS-8201, an investigational HER2-targeting antibody drug conjugate (ADC), in patients with unresectable and/or metastatic non-squamous HER2-overexpressing or HER2-mutated non-small cell lung cancer (NSCLC) that has progressed after one or more prior therapies.

The introduction of targeted therapies and checkpoint inhibitors in recent years has improved the treatment landscape for metastatic NSCLC patients, who previously had limited options beyond systemic chemotherapy. However, for those who are not eligible for available treatments, or whose cancer continues to progress, new approaches are needed to help manage the disease. HER2 overexpression has been reported in rates ranging from 4 to 35 per cent of NSCLC, depending on the published series and methods, and is associated with poor disease prognosis and shortened overall survival. HER2 mutations have more recently been identified as distinct molecular targets for NSCLC and have been reported in up to 5 per cent of NSCLC. Currently no therapy is specifically approved for HER2-overexpressing or HER2-mutated non-small cell lung cancer.

“There is renewed interest in exploring alterations in the HER2 pathway as treatment targets for NSCLC and clinical research suggests a potential role for a HER2-targeting ADC agent,” said Gilles Gallant, BPharm, PhD, Vice President, Global Team Leader DS-8201, Oncology Research and Development, Daiichi Sankyo. “DS-8201 is specifically designed to target and deliver chemotherapy inside HER2-expressing cancer cells, and we are advancing it to phase 2 in non-small cell lung cancer as part of our broad program in multiple types of HER2-expressing tumours.”

The global, multicenter, phase 2, open-label, two-cohort study is investigating the safety and efficacy of DS-8201 in patients with HER2-overexpressing and/or HER2-mutated unresectable and/or metastatic non-squamous NSCLC that has progressed after one or more systemic therapies. Cohort 1 will enroll approximately 40 patients with HER2-overexpressing (defined as IHC 3+ or IHC 2+), unresectable and/or metastatic non-squamous NSCLC, and Cohort 2 will enroll approximately 40 patients with HER2-mutated, unresectable and/or metastatic non-squamous NSCLC.

The primary endpoint is objective response rate. Key secondary endpoints include efficacy (duration of response, disease control rate, progression free survival, overall survival and investigator-assessed objective response rate), safety, and pharmacokinetic endpoints. Exploratory efficacy endpoints include time to response as well as biomarker endpoints for mechanisms of response and resistance.

Lung cancer is the most common cancer in the world and the leading cause of cancer deaths. There were approximately 1.8 million new cases of lung cancer reported globally in 2012 and approximately 1.69 million deaths globally from lung cancer in 2015.Lung cancer is the most common cancer in men, and incidence among women is increasing in many parts of the world.

DS-8201 is the lead product in the investigational ADC Franchise of the Daiichi Sankyo Cancer Enterprise. 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, 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.

In addition to the phase 2 NSCLC study, 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; pivotal phase 2 development for HER2-positive advanced gastric cancer resistant or refractory to trastuzumab (DESTINY-Gastric01) in Japan and South Korea; phase 2 development in advanced colorectal cancer in North America, Europe and Japan; and phase 1 development for other HER2-expressing advanced/unresectable or metastatic solid tumors in the US and Japan.

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), 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 US Food and Drug Administration (FDA). DS-8201 has received SAKIGAKE Designation for the treatment of HER2-positive advanced gastric or gastroesophageal junction cancer by the Japan Ministry of Health, Labour and Welfare (MHLW). DS-8201 is an investigational agent and is not approved by the FDA or any other regulatory agency worldwide as a treatment for any indication.  Safety and efficacy have not been established.