Updated analysis from ongoing phase I study of DS-8201 (trastuzumab deruxtecan), an investigational HER2-targeting antibody-drug conjugate or ADC being developed by Daiichi Sankyo, demonstrated a confirmed overall response rate of 45.5% and a disease control rate of 81.8% in 44 evaluable patients with HER2-expressing gastric cancer previously treated with trastuzumab (Herceptin®; Genentech/Roche) and chemotherapy.

Antibody-drug Conjugates or ADCs are targeted cancer medicines that deliver a cytotoxic (chemotherapeutic) payload directly to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. This targeted approach reduces systemic exposure to the cytotoxic payload compared to the way chemotherapy is commonly delivered.

Designed using Daiichi Sankyo’s proprietary ADC technology, DS-8201 is comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker.

Gastrointestinal Cancers Symposium
Daiichi Sankyo presented the updated trial data for DS-8201 in patients with HER2-expressing gastric cancer during a poster session at 2018 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium being held January 18 – 20, 2018 in San Francisco, California.

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Unmet medical need
Gastric cancer is the fifth most common cancer worldwide, with nearly one million new cases reported in 2012.[1] Approximately one in five gastric cancers overexpress HER2, a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells.[2] HER2-expressing gastric cancer is an area of unmet medical need as advances in the treatment of the disease have been limited, largely due to its genetic complexity and heterogeneity.[3]

Currently, there are no approved HER2-targeting therapy options for patients with HER2-positive advanced gastric cancer after treatment with trastuzumab.


A comprehensive translational research effort is planned and underway to further understand the biological basis for the observed activity…


Trial design
The open-label, two-part phase 1 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 DS-8201 and determine the maximum tolerated dose. Data from this part of the study were published in the Lancet Oncology.[4]

In the dose expansion part of the phase I study, DS-8201 is given to patients with HER2-positive advanced or metastatic breast cancer or gastric cancer, HER2 low-expressing breast cancer or other HER2-expressing or mutant solid tumors. Patient enrollment in the two breast cancer cohorts and the HER2-expressing solid tumors cohort is ongoing in the U.S. and Japan.

Updated Trial results
Updated preliminary subgroup analysis results in 44 of 45 efficacy evaluable patients with HER2-expressing gastric cancer or gastroesophageal junction adenocarcinoma previously treated with trastuzumab and chemotherapy showed that DS-8201 demonstrated a confirmed overall response rate of 45.5% (20 of 44 patients) and a disease control rate of 81.8% (36 of 44 patients). Median duration of response was 7.0 months (95% CI: NR).

The Kaplan-Meier estimate of median progression-free survival was 5.8 months (95 percent CI: 3.0, 8.3). A total of 17 out of 44 patients were continuing to receive treatment at the time of data cut-off.

Schematic 1.0: The primary purpose of the DESTINY-Gastric01 study (NCT03329690) is to compare the efficacy and safety of DS-8201a (trastuzumab deruxtecan) and physician’s choice treatment in HER2-overexpressing advanced gastric or gastroesophageal junction adenocarcinoma patients who have progressed on two prior treatment regimens including fluoropyrimidine agent, platinum agent, and trastuzumab.[5]
“Gastric cancer can be difficult to treat due to its molecular complexity, and currently there are no HER2- targeted therapies or antibody drug conjugates approved for HER2-positive advanced gastric cancer that progresses following treatment with trastuzumab,” explained Toshihiko Doi, MD, PhD, Department of Experimental Therapeutics, National Cancer Center Hospital East.

“These phase I results are encouraging and demonstrate the importance of continuing to study the potential of DS-8201 in treating HER2-positive gastric cancer. The pivotal phase II study is currently underway,” Doi added.

Additional analysis
A preliminary subgroup analysis of patients previously treated with CPT-11 (irinotecan; Camptosar®) showed similar response rates to the overall study population, which may suggest an absence of relevant cross-resistance to smart chemotherapy delivery to tumor cells by the ADC construct of DS-8201.

The preliminary subgroup analysis of 23 patients treated with DS-8201 demonstrated a confirmed overall response rate of 43.5% (10 of 23 patients) and a disease control rate of 82.6% (19 of 23 patients). Median duration of response was 6.9 months (95% CI: NR).

The Kaplan-Meier estimate of median progression-free survival for this subgroup of patients was 4.1 months (95 percent CI: 2.5, 8.3).

“These data from patients with HER2-positive gastric cancer who have failed HER2-targeted therapy combined with chemotherapy, and for many who also failed irinotecan as a systemic chemotherapy suggest that the ADC technology of DS-8201 appears able to deliver on what it was specifically researched and innovated for: a smart chemotherapy approach to tumors expressing some degree of HER2 receptors, regardless of prior treatment with a topoisomerase I inhibitor,” said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.

“A comprehensive translational research effort is planned and underway to further understand the biological basis for the observed activity, including the role of tumor heterogeneity and HER2 expression, the mechanisms of resistance that may have contributed to failing prior lines of treatment, and factors more directly related to the unique pharmacological profile of DS-8201,” Yver concluded.

Safety data and adverse events
Updated preliminary safety data for this subgroup of trastuzumab-treated HER2-expressing gastric cancer patients were also reported.

The most common adverse events (>30%, any grade) included nausea (71.1%), decreased appetite (64.4%), platelet count decreased (33.3%), white blood cell count decreased (33.3%) and constipation (31.1%).

Grade 3 adverse events occurring in >10 percent of patients included anemia (24.4%), neutrophil count decreased (15.6%), platelet count decreased (13.3%) and white blood cell count decreased (11.1%).

Grade 4 adverse events included platelet count decreased (4.4 %), white blood cell count decreased (4.4%) and neutrophil count decreased (4.4%). Three patients discontinued treatment due to treatment-emergent adverse events (pneumonia, decreased appetite, and pneumonitis). Two potential cases of interstitial lung disease (ILD) were reported by the investigators (one grade 1 and one grade 3) in gastric cancer subjects and together with all reported or suspected ILD cases are being assessed by an independent ILD adjudication committee. These include two cases of potential Grade 5 pneumonitis previously reported in the breast cancer cohorts.

Based on these phase I data, patients are currently being enrolled in the pivotal, phase II open-label DESTINY-Gastric01 study investigating the safety and efficacy of DS-8201 in patients with HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma (defined as IHC3+ or IHC2+/ISH+) who have progressed on two prior regimens including fluoropyrimidine agent, platinum agent and trastuzumab.

Breakthrough Therapy designation
In 2017 DS-8201 was been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration (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 ado-trastuzumab emtansine (T-DM1, Kadcyla®; Genentech/Roche), 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 ado-trastuzumab emtansine.