Trastuzumab Deruxtecan | Drug Description

Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed or ADC of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. The drug is being developed by Daiichi Sankyo/AstraZeneca and available in the United States as fam-trastuzumab deruxtecan-nxki. The drug is branded as Enhertu®.

The drug was approved in late December 2019 by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting.

This indication was approved under the FDA’s Accelerated Approval based on tumor response rate and duration of response. However, continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Approved indication
The approval of trastuzumab deruxtecan was based on the results of the registrational Phase II trial DESTINY-Breast01 in which the drug was dosed at 5.4mg/kg monotherapy in patients with HER2-positive metastatic breast cancer.

All patients received prior trastuzumab, trastuzumab emtansine and 66% had prior pertuzumab.

The Phase II trial results showed a confirmed objective response rate of 60.3% (n=111, 95% CI 52.9-67.4) including a 4.3% complete response rate (n=8) and a 56.0% partial response rate (n=103). The median duration of response of 14.8 months (95% CI 13.8-16.9) was demonstrated as of 1 August 2019. [1]

In addition, a median progression-free survival of 16.4 months (95% CI 12.7-not estimable), based upon a median duration of follow up of 11.1 months, was recently presented at the San Antonio Breast Cancer Symposium and published online in The New England Journal of Medicine. [2]

Prevalence of HER2status across cancer types
There is a high unmet medical need in HER2+, HER2 low and HER2 mutant tumors across multiple cancer types. Shown here is the prevalence of HER2status across cancer types. Source: Daiichi Sankyo/AstraZeneca.

HER2-positive breast cancer
Approximately one in five breast cancers are HER2-positive. [3][4] Despite recent improvements and approvals of new medicines, there remains significant unmet needs for patients with HER2-positive metastatic breast cancer. [5][6] This disease remains incurable with patients eventually progressing after available treatments. [5][6]

HER2 is a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells that are associated with aggressive disease and poor prognosis in patients with breast cancer.[7] 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+. [3] A finding of IHC 3+ and/or FISH amplification is considered positive. [3]

Clinical trial: DESTINY-Breast01
DESTINY-Breast01 (NCT03523585) is a registrational Phase II, a single-arm, open-label, global, multicentre, two-part trial evaluating the safety and efficacy of Enhertu in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine.

The primary endpoint of the trial is the objective response rate, as determined by independent central review.

Secondary objectives include duration of response, disease control rate, clinical benefit rate, progression-free survival, and overall survival. Enrolment into DESTINY-Breast01 was completed in September 2018 with 184 patients at more than 100 sites globally.

Ongoing clinical development
A comprehensive development program is underway globally with various registrational trials in HER2-expressing metastatic breast and gastric cancers including a trial in patients with metastatic breast cancer and low levels of HER2 expression.

Trastuzumab deruxtecan is in phase III development versus (ado-) trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche) in the DESTINY-Breast03 trial (NCT03529110) and versus investigator’s choice post-T-DM1 in the DESTINY-Breast02 trial (NCT03523585) for HER2 positive metastatic breast cancer; pivotal phase II development for HER2 positive advanced gastric cancer resistant or refractory to trastuzumab (DESTINY-Gastric01); phase II development for HER2 expressing advanced colorectal cancer; phase II development for metastatic non-squamous HER2 overexpressing or HER2 mutated NSCLC; and, phase I development in combination with nivolumab (Opdivo®; Bristol-Myers Squibb) for HER2 expressing metastatic breast and bladder cancer. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Trastuzumab Deruxtecan
Trastuzumab deruxtecan (DS-8201a) is a HER2-targeting antibody-drug conjugate or ADC), structurally composed of a humanized anti-human HER2 (anti-hHER2) antibody, an enzymatically cleavable peptide-linker, and a proprietary topoisomerase I inhibitor payload (exatecan derivative or DX-8951 / DXd).

Mode of action
ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy, known as the “payload,” to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.

The drug is designed using Daiichi Sankyo’s proprietary ADC technology.

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.

Information for patient
See Medication Guide

[1] ENHERTU® [fam-trastuzumab deruxtecan-nxki] US prescribing information; 2019.
[2] Modi, S., et. al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. NEJM. December 11, 2019. DOI:10.1056/NEJMoa1914510.
[3] Tandon AK, Clark GM, Chamness GC, Ullrich A, McGuire WL. HER-2/neu oncogene protein and prognosis in breast cancer. J Clin Oncol. 1989;7(8):1120–1128. doi:10.1200/JCO.1989.7.8.1120
[4] Sledge GW, Mamounas EP, Hortobagyi GN, Burstein HJ, Goodwin PJ, Wolff AC. Past, present, and future challenges in breast cancer treatment. J Clin Oncol. 2014;32(19):1979–1986. doi:10.1200/JCO.2014.55.4139
[5] de Melo Gagliato D, Jardim DL, Marchesi MS, Hortobagyi GN. Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER2+ breast cancer. Oncotarget. 2016;7(39):64431–64446. doi:10.18632/oncotarget.7043
[6] National Comprehensive Cancer Network (NCCN). NCCN Guidelines. Breast Cancer. Online. Last accessed March 31, 2020.
[7] American Cancer Society. Breast Cancer HER2 Status. Online. Last accessed March 31, 2020.