Daiichi Sankyo Submits New Drug Application for Trastuzumab Deruxtecan to Japanese Regulators

Earlier this week Daiichi Sankyo confirmed this week that it has submitted a New Drug Application (NDA) to Japan’s Ministry of Health, Labour and Welfare (MHLW) for the use of [fam-] trastuzumab deruxtecan, aslo known as DS-8201, an investigational HER2 targeting antibody-drug conjugate or ADC, for the treatment of patients with HER2 positive metastatic breast cancer.

ADCs 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.

Mode of Action of DS-8201
Mode of Action of [Fam-] trastuzumab deruxtecan or DS-8201

The NDA submitted in Japan is primarily based on the positive results from the pivotal Phase II DESTINY-Breast01 trial of [fam-] trastuzumab deruxtecan, an open-label, global, multicenter trial, which evaluated dosing, efficacy and safety in patients with HER2 positive metastatic breast cancer.

[Fam-] trastuzumab deruxtecan* is the lead product in the investigational ADC Franchise of the Daiichi Sankyo Cancer Enterprise and the most advanced program in AstraZeneca’s ADC Scientific platform. The collaboration between the companies started earlier this year when they entered into a global collaboration to jointly develop and commercialize [fam-] trastuzumab deruxtecan worldwide, except in Japan where Daiichi Sankyo will maintain exclusive rights.

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Designed using Daiichi Sankyo’s proprietary DXd ADC technology, [fam-] trastuzumab deruxtecan is 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.

A broad and comprehensive development program with [fam-] trastuzumab deruxtecan is underway in North America, Europe and Asia, including five pivotal trials in HER2 expressing breast and gastric cancers, including in breast cancer patients with HER2 low expression. [Fam-] trastuzumab deruxtecan is also in phase 2 development for HER2 expressing advanced colorectal cancer and metastatic non-squamous HER2 overexpressing or HER2 mutated NSCLC, and phase 1 development in combination with nivolumab for HER2 expressing metastatic breast and bladder cancers.

[Fam-] trastuzumab deruxtecan was granted Breakthrough Therapy Designation in 2017 by the U.S. 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 T-DM1. Fast Track Designation was also granted in the U.S. for the treatment of HER2 positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2 targeted medicines, including T-DM1.

In addition to receiving Fast Track Designation in the United states, the investigational drug received SAKIGAKE designation for the treatment of advanced HER2 positive advanced gastric or gastroesophageal junction cancer by the Japan Ministry of Health, Labour and Welfare.

Unmet Need
Approximately one in five breast cancers are HER2 positive. [1][2] Despite recent improvements and approvals of new therapies, there remains significant unmet clinical needs for patients with advanced HER2 positive metastatic breast cancer. [3][4] This disease remains incurable with these patients eventually progressing after available therapies.[3][4]

The submission also includes data from the phase I trial published in The Lancet Oncology.[1] The response rate observed in DESTINY-Breast01, as assessed by an independent review committee, confirmed the clinical activity observed in the phase I trial.

DESTINY-Breast01 is a pivotal phase II, open-label, global, multicenter, two-part trial evaluating the safety and efficacy of [fam-] trastuzumab deruxtecan in patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche). The primary endpoint of the trial 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 trial 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 trial. The second part enrolled patients into one of two cohorts: patients resistant or refractory to T-DM1 (part 2a) and patients who discontinued treatment with T-DM1 for reasons other than resistant or refractory disease (part 2b). Enrollment into DESTINY-Breast01 was completed in September 2018 with 253 patients at more than 100 sites across North America, Europe, Japan and other countries in Asia.

Data from DESTINY-Breast01 will be presented at an upcoming medical meeting.

“We are proud to initiate this critical next step in the regulatory process in Japan and look forward to the presentation of the phase II DESTINY-Breast01 study of [fam-] trastuzumab deruxtecan to the scientific community,” noted Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.

“We look forward to working closely with the Japan Health Authority on our application for [fam-] trastuzumab deruxtecan in order to bring this important potential new treatment to patients in Japan,” Yver added.

Ongoing development
[Fam-] trastuzumab deruxtecan is currently in development for the treatment of patients with a variety of HER2 expressing or HER2 mutant cancers, including gastric, colorectal and lung cancer, as well as in breast cancer with HER2 low expression.  

The safety and tolerability profile of [fam-] trastuzumab deruxtecan in DESTINY-Breast01 was consistent with the phase I trial data published in The Lancet Oncology, in which the most common adverse events (≥30 percent, any grade) included nausea, decreased appetite, vomiting, alopecia, fatigue, anemia, diarrhea and constipation. Cases of drug-related pneumonitis, including grade 5 events, have also been reported in the clinical development program.

Role of HER2
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 in breast cancer patients.[2]

For a patient to be considered HER2 positive, tumor cancer cells are usually tested by one of two methods: immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH). IHC test results are reported as: 0, IHC 1+, IHC 2+, or IHC 3+.[2] A finding of IHC 3+ and/or FISH amplification is considered positive.[2] There are currently no approved HER2 targeted therapies for HER2 FISH negative, IHC 2+ or IHC 1+ tumors.

Clinical trials
DS-8201a in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer [DESTINY-Breast01] – NCT03248492

* [Fam-] trastuzumab deruxtecan is known as fam-trastuzumab deruxtecan in U.S. only; and as trastuzumab deruxtecan in other regions of world.

[1] Tandon A, et al. HER-2/neu Oncogene Protein and Prognosis in Breast Cancer. J Clin Oncol. 1989;7(8):1120-8.
[2] Sledge G, et al. Past, Present, and Future Challenges in Breast Cancer Treatment. J Clin Oncol. 2014;32(19):1979-1986.
[3] de Melo Gagliato D, et al. Mechanisms of Resistance and Sensitivity to Anti-HER2 Therapies in HER2+ Breast Cancer. Oncotarget. 2016;7(39):64431-46.
[4] National Comprehensive Cancer Network (NCCN). NCCN Guidelines. Breast Cancer. Online. Last accessed August 2019.
[5] Tamura, K, et al. Trastuzuamb deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Lancet Oncol. 2019;20(6):816-826.
[6] American Cancer Society. Breast Cancer HER2 Status. Online. Last accessed August 2019.

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