Daiichi Sankyo, Gustave Roussy Research Partnership Holds Promise for NSCLC, Breast Cancer Paradigms

Article

A multi-year, multi-study research collaboration between Daiichi Sankyo and Gustave Roussy Cancer Center will support the clinical, translational, and preclinical evaluation of 2 of the company’s lead antibody-drug conjugates: DS-1062 in advanced non–small cell lung cancer, and patritumab deruxtecan in metastatic breast cancer.

Fabrice André, MD, PhD

Fabrice André, MD, PhD

A multi-year, multi-study research collaboration between Daiichi Sankyo and Gustave Roussy Cancer Center will support the clinical, translational, and preclinical evaluation of 2 of the company’s lead antibody-drug conjugates (ADCs): DS-1062 in advanced non–small cell lung cancer (NSCLC), and patritumab deruxtecan in metastatic breast cancer.

The partnership will commence with 2 Gustave Roussy-led, 2 Daiichi-funded adaptive phase 2 trials to evaluate the safety and efficacy of the investigational agents, as well as potential markers of response and resistance to the respective therapies.1

The adaptive study designs are expected to expedite the identification of individuals who benefit from treatment with the ADCs. Furthermore, in their incorporation of repeated clinical and biomarker assessments, the studies will also aid efforts to recognize factors associated with individual patient response and subsequently refine development.

Characterizing markers of response and resistance will be a crux of the collaboration, according to Fabrice André, MD, PhD, director of research at Gustave Roussy Cancer Center, Villejuif, France, who explained that investigators will use 3 different approaches to identify these distinguishers. The first method involves performing a biopsy before and after treatment to derive biomarkers from patients’ cellular content.

“The second strategy will be to predefine a hypothesis about the biomarkers based on what we observe on the basic science side,” André told OncLive®. “For example, we would investigate the journey of the ADC in lysosome and the role of the DNA repair protein for resistance. Our third strategy will be to use screening of the cancer cell to identify mechanisms of resistance, thanks to a system of screening to knockout gene or induce gene expression.”

Both studies will be open label and will enroll up to 100 patients each across various sites in France. The first trial will evaluate DS-1062 in patients with advanced NSCLC who progressed on prior anti–PD-1/PD-L1 therapy and platinum-doublet chemotherapy. The second trial will examine patritumab deruxtecan in patients with HER3-expressing metastatic breast cancer. The primary end point, shared by the 2 trials, is objective response rate assessed by independent central review. Key secondary end points, which will also remain consistent across the 2 studies, include clinical benefit rate, progression-free survival, duration of response, overall survival, and safety measures.

Although the safety and efficacy of DS-1062 and patritumab deruxtecan have yet to be established, mechanistically, the agents are known to deliver cytotoxic chemotherapy to cancer cells via a linker attached to a monoclonal antibody (mAb) that binds to a specific target expressed on the malignant cells. Specifically, DS-1062 uses a humanized anti-TROP2 mAb affixed to a topoisomerase I inhibitor payload by a tetrapeptide-based linker. Patritumab deruxtecan has the same payload and linker as DS-1062 but comprises a human anti-HER3 antibody.

Immunotherapies, administered to patients who express PD-L1, and targeted therapies, given to those with a genomic alteration that predicts sensitivity to precision interventions, dominate the NSCLC landscape, André said, adding that cytotoxic agents have also been shown to have activity in NSCLC, albeit modest.

The development of DS-1062 represents the potential for a new class of agents, ADCs, in the treatment of this tumor type. “What we expect to have is a third innovative [set of] drugs in this disease; that will be ADCs,” André said, adding that Gustave Roussy investigators similarly “expect to develop a drug that will synergize with immunotherapeutics, and perhaps a targeted therapy, to prolong survival.”

By contrast, ADCs are less new to the breast cancer landscape, but approvals have typically favored HER2-positive or triple-negative disease. At present, no therapies are specifically indicated for the treatment of patients with HER3-expressing breast cancer, thus providing a rationale for pursing a HER3-targeted treatment.2

Beyond the phase 2 studies to be led by Gustave Roussy, DS-1062 and patritumab deruxtecan are under investigation in other clinical trials, including a phase 1 (NCT03401385) evaluation of the former agent in patients with advanced solid tumors that are relapsed on or refractory to standard treatment or for whom no standard treatment is available.1 This study is currently enrolling 350 patients with unresectable/advanced NSCLC or metastatic triple-negative breast cancer.

Meanwhile, patritumab deruxtecan is being studied in the phase 1 setting in patients with previously treated metastatic or unresectable NSCLC; this trial continues to enroll patients with this disease (NCT03260491). The ADC is also the subject of study in an ongoing phase 1/2 trial (NCT02980341) in patients with HER3-expressing breast cancer.

These established research initiatives will later be joined by additional studies under Daiichi and Gustave Roussy’s collaboration, which will explore DS-1062 and patritumab deruxtecan in combination with other agents.

References

  1. Daiichi Sankyo and Gustave Roussy enter innovative research collaboration for Dxd ADCs DS-1062 and patritumab deruxtecan. News release. Gustave Roussy. July 22, 2020. Accessed September 8, 2020. https://bit.ly/2GJ0ppJ.
  2. Liu X, Liu S, Lyu H, Riker AI, Zhang Y, Liu B. Development of effective therapeutics targeting HER3 for cancer treatment. Biol Proced Online. 2019;21:5. doi:10.1186/s12575-019-0093-1
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