In clinical trials, trastuzumab deruxtecan or DS-8201, an investigational HER2-targeting antibody-drug conjugate or ADC being developed by Daiichi Sankyo, demonstrated preliminary antitumor activity in patients with HER2-expressing solid tumors such as colon cancer, non-small cell lung cancer and other tumor types. These data were presented during a poster session at the European Society for Medical Oncology (ESMO) 2017 Congress in Madrid, Spain.

Trastuzumab deruxtecan (DS-8201) is the lead product in the ADC Franchise of the Daiichi Sankyo Cancer Enterprise. Antibody-drug Conjugates are a type of targeted cancer medicine that deliver cytotoxic chemotherapeutic anticancer payload to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.

Using Daiichi Sankyo’s proprietary ADC technology, DS-8201 is a smart chemotherapy comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor (DXd) payload by a tetrapeptide linker. It is designed to deliver enhanced cancer cell destruction upon release inside the cell and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

Listen to The Onco’Zine Brief on PRX | Public Radio Exchange: Developing Novel Therapies for HER2-positive Advanced or Metastatic Breast Cancer: An Interview with Daichi Sankyo’s Antoine Yver, M.D., MSc.

Trastuzumab deruxtecan is currently in phase II clinical development for HER2-positive unresectable and/or metastatic breast cancer resistant or refractory to T-DM1 (DESTINY-Breast01), and in phase I development for HER2 low-expressing breast cancer, HER2-positive gastric cancer and other HER2-expressing solid tumors.

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Breakthrough Therapy
The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to trastuzumab deruxtecan 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 ado-trastuzumab emtansine (T-DM1), and Fast Track designation for the treatment of HER2-positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2-targeted therapies including T-DM1.

Phase I trial
The open-label two-part phase 1 dosing study is currently evaluating DS-8201 in patients with advanced/unresectable or metastatic solid tumors that are refractory or intolerant to standard treatment, or for whom no standard treatment is available. The primary objective of the dose escalation phase of the study was to assess the safety and tolerability of trastuzumab deruxtecan and determine the maximum tolerated dose. In the dose expansion part of the phase 1 study, trastuzumab deruxtecan is given in one of two doses (5.4 mg/kg and 6.4 mg/kg) to patients with HER2-positive advanced or metastatic breast cancer and gastric cancer, HER2 low-expressing breast cancer and other HER2-expressing solid tumors. Patient enrollment in the two breast cancer cohorts is ongoing in the U.S. and Japan.

Trial results
Preliminary results from the ongoing trastuzumab deruxtecan phase I study showed that DS-8201 demonstrated an overall confirmed response rate of 32% and a disease control rate of 82% in a subgroup analysis of 22 of 25 evaluable patients with HER2-expressing solid tumors, which included colon cancer (11 patients), non-small cell lung cancer (6 patients), salivary gland cancer (4 patients), Paget’s disease (2 patients), cholangiocarcinoma (1 patient) and esophageal cancer (1 patient).

Two of 10 evaluable patients with colon cancer, one out of five evaluable patients with non-small cell lung cancer and three of four evaluable patients with salivary gland cancer achieved partial responses. Two additional patients with colon cancer and non-small cell lung cancer with one post baseline scan showed a partial response yet to be confirmed at subsequent scans. A total of 168 patients have been treated in both the dose escalation (24 patients) and dose expansion (144 patients) parts of the study as of August 1, 2017.

Safety data for 168 patients who received at least one dose of DS-8201 in study parts 1 and 2 and across different cohorts of the study also were reported. The most common adverse events (any grade) seen in all patients to date included nausea (67%), decreased appetite (56%), vomiting (33%), anemia (30%) and decreased platelet count (29%). Grade 3 adverse events occurring in >10% of patients included anemia (13%), decreased neutrophil count (14%) and decreased white blood cell count (11%). Grade 4 adverse events occurred in ≤ 3% of patients and included decreased platelet count (3.0%), decreased neutrophil count (2.4%), decreased white blood cell count (1.8%) and anemia (1.2%).

“These preliminary results are consistent with other data previously reported in the HER2-positive metastatic breast and gastric cancer cohorts of this study, demonstrating that further study is warranted for DS-8201 across other HER2-expressing solid tumors,” said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.

“These data add to the growing body of clinical evidence suggesting that trastuzumab deruxtecan could potentially become an important new treatment option for many different types of solid tumors that overexpress HER2. In addition to initiating our pivotal phase II study of DS-8201 in HER2-positive metastatic breast cancer, we are exploring next steps for the development of DS-8201 across multiple HER2-expressing tumor types,” Yver added.

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