Japaneses drug-maker Daiichi Sankyo announced plans to accelerate filing of their Biologics License Application (BLA) with the U.S. Food and Drug Administration (FDA) for [fam-] trastuzumab deruxtecan, also known as DS-8201, an investigational HER2 targeting antibody-drug conjugate (ADC), in patients with HER2 positive metastatic breast cancer previously treated with trastuzumab emtansine (T-DM1, Kadcyla?; Genentech/Roche) an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab covalently linked to the cytotoxic agent DM1.

Antibody-drug conjugate are a form of targeted cancer agents designed to directly deliver a payload of a cytotoxic chemotherapy 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 DXd ADC technology, trastuzumab deruxtecan is comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. The drug 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.

The submission of the application for [fam-] trastuzumab deruxtecan, which was initially planned for 2020 but is now scheduled for the first half of fiscal year 2019.

Unmet medical need
With ans estimated 2.1 million new cases of female breast cancer diagnosed in 2018, the disease is the most common cancer and the most common cause of cancer mortality in women worldwide.[1]

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HER2-positive breast cancer is a breast cancer that tests positive for a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells.

Approximately one in five breast cancers (20%) are HER2 positive (IHC3+ or IHC2+/ISH+).[2][3] HER2 is a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells that is associated with aggressive disease and poorer prognosis.[4][5]

To be considered HER2 positive, tumor cancer cells are usually tested first by immunohistochemistry (IHC) and reported as: 0, IHC 1+, IHC 2+ or IHC 3+. A finding of IHC 3+ is considered HER2 positive, and a finding of IHC 2+ is borderline and typically is confirmed by a positive fluorescent in situ hybridization (FISH) test.[3][4]

Several unmet treatment needs remain today in HER2 positive metastatic breast cancer. Many HER2 positive breast cancers eventually advance to the point where no currently approved HER2 targeting therapy continues to control the disease, and there is no established standard of care after treatment with trastuzumab (Herceptin?; Genentech/Roche) , pertuzumab (Perjeta?; Genentech/Roche) and trastuzumab emtansine.[6]

[Fam-] trastuzumab deruxtecan has been granted breakthrough therapy by the FDA 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 trastuzumab emtansine.

The initial BLA submission of [fam-] trastuzumab deruxtecan will be based on results from the pivotal phase II DESTINY-Breast01 study, which will be presented at an upcoming medical conference. Final determination of exact timing of the BLA submission of [fam-] trastuzumab deruxtecan will be based on the outcome of a pre-BLA meeting with the FDA.

?We are pleased to confirm the acceleration of the [fam-] trastuzumab deruxtecan clinical development program for this potential indication in patients with HER2 positive metastatic breast cancer pretreated with trastuzumab emtansine ahead of schedule,? noted Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.

?Simultaneously, we are committed to our aggressive development strategy evaluating the potential of [fam-] trastuzumab deruxtecan across a spectrum of HER2 expressing cancers including breast, gastric, lung and colorectal,? Yver added.

Clinical trials
[Fam-] trastuzumab deruxtecan has been investigated in a number of different clinical trials, including the DESTINY-Breast01 trial, a pivotal phase II, open-label, global, multicenter, two-part study evaluating the safety and efficacy of the investigational agent in patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with [ado-] trastuzumab emtansine.

In an interview for The Onco’Zine Brief on PRX, recorded during the 2017 annual meeting of the American Society of Clinical Oncology (ASCO), Antoine Yver, MD., MSc, Executive Vice President and Global Head, Oncology Research and Development at Daichi Sankyo talks about the development of novel, investigational agent, DS-8201.

The primary endpoint of this study is objective response rate. Secondary objectives include duration of response, disease control rate, clinical benefit rate, progression-free survival and overall survival. The first part of the study includes a pharmacokinetic stage and a dose-finding stage to identify the recommended dose of [fam-] trastuzumab deruxtecan to be evaluated in the second part of the study.

The second part of the study enrolled patients into one of two cohorts: patients resistant or refractory to [ado-] trastuzumab emtansine (part 2a) and patients who discontinued treatment with [ado-] trastuzumab emtansine for reasons other than resistant or refractory disease (part 2b).

Enrollment into DESTINY-Breast01 was completed in September 2018, with approximately 230 patients at more than 100 sites in North America, Europe, Japan and other countries in Asia.

[1] Bray F. et al. Global Cancer Statistics 2018. CA Cancer J Clin. 2018;68:394?424
[2] Sledge, et al. J Clin Oncol. 2014; 32:1-8.
[3] American Cancer Society. Tests for Stomach Cancer. 2018.
[4] American Cancer Society (ACS) Breast Cancer Overview 2018
[5] Tandon et al. J Clin Oncol. 1989; 7: 1120?8.
[6] NCCN Guidelines. Breast Cancer. Version 3.2018. October 25, 2018.

Last Editorial Review: March 29, 2019

This is an edited version of an article originally published on March 29, 2019 in the news section ADC Review | J. Antibody-drug Conjugates.

Featured Image: ASH 2019 / Daiichi Sankyo.  Courtesy:? 2010 ? 2019 Sunvalley Communication/Evan Wendt. Used with permission.

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