Daiichi Sankyo Company, Limited announced that long-term phase 1 safety and efficacy data for DS-8201, an investigational HER2-targeting antibody drug conjugate (ADC), in 241 heavily pretreated patients with HER2-expressing breast, gastric and other solid cancers who received recommended expansion doses of 5.4 mg/kg or 6.4 mg/kg, presents during an Oral Abstract Session at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.
Updated preliminary results in a subgroup analysis of 34 patients with heavily pretreated HER2-low-expressing metastatic breast cancer showed that DS-8201 demonstrated a confirmed overall response rate of 50.0 per cent (17/34 patients) and a disease control rate of 85.3 per cent. Preliminary estimates of median duration of response have reached 11 months and median progression-free survival has reached 12.9 months. A total of 14 patients (41.2 per cent) were continuing to receive treatment at the time of data cutoff, which was April 18, 2018.
“HER2-targeted treatments historically have not been effective in treating metastatic breast cancer with low levels of HER2 expression,” said Hiroji Iwata, MD, PhD, Vice Director and Chief of Breast Oncology at Aichi Cancer Center Hospital, Nagoya, Japan. “While these results of DS-8201 in the HER2-low-expressing subgroup need to be further confirmed in a larger clinical setting, the preliminary data are intriguing in that we may need to begin rethinking how we approach HER2 as a cell surface target for precision medicine treatment in metastatic breast cancer.”
In an updated preliminary subgroup analysis in 99 efficacy evaluable patients with HER2-positive metastatic breast cancer pretreated with ado-trastuzumab emtansine (T-DM1) (as well as trastuzumab and pertuzumab in the majority of cases), DS-8201 demonstrated a confirmed overall response rate of 54.5 per cent (54/99 patients) and a disease control rate of 93.9 per cent (93/99 patients). Median duration of response and median progression-free survival have not yet been reached. Out of 111 patients with HER2-positive metastatic breast cancer who received at least one dose of DS-8201, 65 (55.1 per cent) were continuing to receive treatment at the time of data cut off.
Updated overall safety data across all subgroups of the phase 1 study were reported. The most common adverse events (>30 per cent, any Grade), included nausea (68.9 per cent), decreased appetite (55.6 per cent), alopecia (36.1 per cent), vomiting (34.9 per cent) and anemia (32.0 per cent). Grade 3 adverse events occurring in =10 per cent of patients included decreased neutrophil count (15.4 per cent), anemia (14.9 per cent), decreased white blood cell count (12.4 per cent) and decreased platelet count (10.4 per cent). Twenty-three patients (9.5 per cent) discontinued treatment due to adverse events, which included ten (10) Grade 5 adverse events: pneumonitis ), disease progression interstitial lung disease (ILD) , ileus pneumonia aspiration and pneumonia . All reported or suspected cases of ILD or pneumonitis currently are under review by an independent ILD adjudication committee.
“These updated results further support our broad and comprehensive development program underway exploring the potential of DS-8201 in HER2-low-expressing breast cancer, which represents about half of all breast cancers, as well as in HER2-positive metastatic breast cancer, where unmet treatment needs remain,” said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. “Our pivotal phase 2 trial in HER2-positive metastatic breast cancer is underway, and we are planning phase 3 trials in HER2-low-expressing and HER2-positive metastatic breast cancer in order to determine whether the smart delivery of chemotherapy with DS-8201 may be an effective treatment option against breast tumors that express varying levels of HER2 as a cell surface antigen. A similar biological paradigm is being tested in our other ongoing phase 2 studies of DS-8201 in gastric and colorectal cancer.”
Updated preliminary results of two additional subgroup analyses were reported in addition to the two breast cancer subgroups. In the subgroup of 44 patients with HER2-expressing (defined as IHC 3+ or IHC 2+/ISH-) gastric cancer or gastroesophageal junction adenocarcinoma previously treated with trastuzumab and chemotherapy, DS-8201 demonstrated a confirmed overall response rate of 43.2 per cent (19/44 patients) and a disease control rate of 79.5 per cent (35/44 patients). Preliminary estimates of median duration of response has reached 7.0 months (95 per cent CI: NA) and median progression-free survival has reached 5.6 months (95 per cent CI: 3.0, 8.3).
In an updated preliminaryanalysis in 31 evaluable patients with other HER2-expressing solid tumors such as colorectal and non-small cell lung cancer, DS-8201 demonstrated a confirmed overall response rate of 38.7 per cent (12/31 patients) and a disease control rate of 83.9 per cent (26/31 patients). Preliminary estimates of median duration of response has reached 12.9 months (95 per cent CI: 2.8, 12.9) and median progression-free survival has reached 12.1 months (95% CI: 2.7, 14.1).
Several unmet needs remain today in HER2-expressing metastatic breast cancer. Many HER2-positive tumors advance to the point where no currently approved HER2-targeting treatment continues to control the disease, and there is no current standard of care for HER2-positive tumors after treatment with trastuzumab, pertuzumab and T-DM1. Additionally, there are no anti-HER2 therapies indicated for HER2 low-expressing tumors (IHC 2+/FISH- or IHC 1+).
HER2-expressing gastric cancer also 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.5 Currently, there are no approved HER2-targeting therapy options for patients with HER2-positive advanced gastric cancer after treatment with trastuzumab.
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.6
DS-8201 is the lead product in the investigational ADC Franchise of the Daiichi Sankyo Cancer Enterprise. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy (“payload”) 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 ADC technology, DS-8201 is a smart chemotherapy 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 compared to the way chemotherapy is commonly delivered.
DS-8201 is currently in pivotal phase 2 clinical development for HER2-positive unresectable and/or metastatic breast cancer resistant or refractory to T-DM1 in North America, Europe and Asia; pivotal phase 2 development for HER2-positive advanced gastric cancer resistant or refractory to trastuzumab in Japan and South Korea; phase 2 development for HER2-expressing advanced colorectal cancer in North America, Europe and Japan; phase 2 development for unresectable and/or metastatic non-squamous HER2-overexpressing or HER2-mutated non-small cell lung cancer (NSCLC) in North America, Europe and Japan; and phase 1 development for other HER2-expressing advanced/unresectable or metastatic solid tumors in the US and Japan.