Daiichi Sankyo and Gustave Roussy have signed a multi-year, multi-study research collaboration for the ongoing development of DS-1062 and patritumab deruxtecan (previously known as U3-1402), two antibody-drug conjugates being developed for the treatment of patients with lung and breast cancer.

DS-1062 and patritumab deruxtecan are two of three lead DXd ADCs in the oncology pipeline of Daiichi Sankyo. These agents 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.

Latebreaking news for the two investigational agents was presented during the 2019 during IASLC World Conference on Lung Cancer, held September 7-10, 2019 in Barcelona, Spain.[1]

Investigational agents
The investigational agents are designed using Daiichi Sankyo’s proprietary DXd ADC technology. DS-1062 is comprised of a humanized anti-TROP2 monoclonal antibody attached to a topoisomerase I inhibitor payload by a tetrapeptide-based linker and patritumab deruxtecan is comprised of a human anti-HER3 antibody patritumab* and with the same payload and linker.

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DS-1062 is currently being evaluated in a phase I trial in patients with advanced solid tumors that are refractory to or relapsed from standard treatment or for whom no standard treatment is available. The study is currently enrolling patients with unresectable advanced NSCLC and unresectable/advanced or metastatic triple negative breast cancer.

Patritumab deruxtecan is currently being evaluated in a phase I study in previously treated patients with metastatic or unresectable NSCLC. Patritumab deruxtecan is also being evaluated in a phase I/II study in patients with HER3 expressing metastatic breast cancer.

The collaboration will focus on clinical and translational research, including potential combination strategies for DS-1062, a TROP2 directed DXd ADC, in patients with advanced non-small cell lung cancer (NSCLC), and for patritumab deruxtecan, a HER3 directed DXd ADC, in patients with metastatic breast cancer.

“We look forward to engaging and collaborating with the deep expertise and cutting-edge oncology research capabilities of Gustave Roussy, the premier European Cancer Center, to further advance clinical development of DS-1062 and patritumab deruxtecan,” said Antoine Yver, MD, MSc, AIHP, ACCA Paris, Global Head, Oncology R&D, Daiichi Sankyo.

“This innovative research program includes two precision-medicine rich phase 2 trials designed with an adaptive approach to help determine which patients are most likely to benefit from our ADCs with optimal speed and efficiency. Combination therapy strategies will also be explored in other studies.”

Photo:Jean-Charles Soria, Ph.D, is a Medical Oncologist and Professor of Medicine at Paris-Saclay University. He holds a doctorate in molecular biology. He completed his training during a two year appointment at the MD Anderson Cancer Center in Houston, Texas, where in addition he was an associate professor from 2013 to 2017. Soria was an elected member of the Oncology Section of the National University Council for 3 years and was the Director of the Gustave-Roussy SIRIC Socrate (Integrated Cancer Research Site) over 5 years (2012-2017). He studied health management at the Harvard Business School in 2017-2018. Over the last three years, Soria has appeared in the list of the most influential research scientists in the world. Since September 2017, Soria has been Senior Vice-President, Research & Development in Oncology, with AstraZeneca in Gaithersburg, Maryland, where he leads research teams responsible for strategy and for development of new agents in immuno-oncology, cell therapy and conjugated antibodies. In March 2019 AstraZeneca signed a global development and commercialisation collaboration agreement with Daiichi Sankyo Company for trastuzumab deruxtecan (DS-8201), a proprietary antibody-drug conjugate (ADC) being developed by Daiichi Sankyo. Photo courtesy: © 2020 Gustave-Roussy. Used with permission.

“This is a strategic partnership for Gustave Roussy and it brings together all the skills which are essential for top quality research in oncology,” said Professor Jean-Charles Soria, Ph.D, General Director of Gustave Roussy.

“Launching clinical trials to test two promising molecules in advanced non-small cell lung cancer and metastatic breast cancer is essential for diseases which unfortunately have an increasing incidence and for which there is an urgent need to make progress,” Soria added

“It is by pushing the boundaries of innovation that we will further improve the quality of care for our patients,” he concluded.

Adaptive trial
Under the agreement, Daiichi Sankyo, provides funding and support to Gustave Roussy for a comprehensive, integrative research program including clinical, translational and preclinical studies for DS-1062 and patritumab deruxtecan in lung and breast cancer, respectively.

Two adaptive** phase II trials will be conducted, including a multicenter, open-label study to evaluate efficacy, safety and markers of response and resistance to DS-1062 in patients with advanced NSCLC who have progressed on anti-PD-1/PD-L1 therapy and platinum-doublet chemotherapy.

The second multicenter, open-label phase II study will evaluate the efficacy, safety and biomarkers of response and resistance to patritumab deruxtecan in patients with HER3 expressing metastatic breast cancer.

Each study will enroll up to 100 patients and will be conducted in several sites in France.

The primary endpoint for both studies is objective response rate (ORR) as assessed by independent central review. Secondary endpoints include clinical benefit rate (CBR), progression-free survival (PFS), duration of response (DOR), overall survival (OS) and safety measures. The studies also will primarily be conducted to analyze biomarker expression and tumor sensitivity; the role of receptor biology in the pharmacological activity of the Daiichi Sankyo DXd ADC platform, as well as factors contributing to treatment resistance; immunogenicity and mechanism of action.

The adaptive trial design includes ongoing clinical and biomarker assessments to identify factors associated with individual patient response and the ability to fine-tune development accordingly.

Additional research to be conducted under the collaboration includes several studies exploring multiple therapeutic combinations for each ADC.

* Patritumab is a fully human monoclonal antibody directed against the membrane-bound receptor HER3 (ERBB3). The antibody binds to and inhibits HER3 activation, which may result in inhibition of HER3-dependent PI3K/Akt signaling and so inhibition of cellular proliferation and differentiation. HER3, a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, is frequently overexpressed in solid tumors, including breast, lung, and colorectal tumors of epithelial origin. It has no active kinase domain itself but is activated through heterodimerization with other members of the EGFR receptor family that do.

** The adaptive trial design refers to a clinical trial that evaluates an investigational therapeutic agent by observing participant outcomes on a prescribed schedule, and modifying parameters of the trial protocol in accord with those observations. Adaptive trials are often more efficient, more informative and ethical than trials with a traditional fixed design since they often make better use of resources, including time and money. They often require fewer participating patients. Adaptive designs can be applied across all phases of clinical research, from early-phase I dose escalation to confirmatory and pivotal phase III studies.

Clinical Trials
Study of DS-1062a in Advanced or Metastatic Non Small Cell Lung Cancer With Actionable Genomic Alterations – NCT04484142
First-in-human Study of DS-1062a for Advanced Solid Tumors – NCT03401385
A Study to Evaluate U3-1402 in Subjects With Advanced or Metastatic Colorectal Cancer – NCT04479436
Phase I/II Study of U3-1402 in Subjects With Human Epidermal Growth Factor Receptor 3 (HER3) Positive Metastatic Breast Cancer – NCT02980341
U3-1402 in Metastatic or Unresectable Non-Small Cell Lung Cancer – NCT03260491

[1] Hofland P. WCLC 2019: Daiichi Sankyo to Present Late-breaking Results from U3-1402 and DS-1062 Studies. JADC August 26, 2019 [Article]

Featured Image: Women and the power to fight breast cancer Courtesy: © 2017 – 2020. Fotolia/Adobe. Used with permission.

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