About one in five breast cancers overexpress HER2, a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells, which is associated with aggressive disease.
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, IHC1+, IHC2+ or IHC3+.  A finding of IHC3+ is considered HER2-positive. A finding of IHC2+ is borderline and typically is confirmed by a positive FISH test.
Unmet Medical Need
In the treatment of cancer, several unmet medical needs remain today in HER2-expressing metastatic breast cancer (also called stage IV or advanced breast cancer).
Metastatic breast cancer is breast cancer that has spread beyond the breast to other organs in the body, including bones, lungs, liver or brain. In many cases, these 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 ado-trastuzumab emtansine (T-DM1).  Additionally, there are no anti-HER2 therapies indicated for HER2 low-expressing tumors (IHC2+/FISH- or IHC1+).
The results seen in patients with HER2 low-expressing breast cancer are compelling and could challenge how we define HER2-positive breast cancer with regards to ADC therapy. Clearly, further study of DS-8201 is warranted in both these types of HER2-expressing breast cancer
Updated study results
Updated safety and efficacy data from two subgroups of evaluable patients with metastatic breast cancer from an ongoing Phase I study of DS-8201, an investigational HER2-targeting antibody-drug conjugate (ADC) being developed by Daiichi Sankyo, presented during a Spotlight Poster Discussion session at the San Antonio Breast Cancer Symposium (SABCS) held December 5 – 9, 2017 in San Antonio, Texas (USA), shows significant benefit in patients with advanced HER2-positive breast cancer.
DS-8201 is the lead product in the ADC Franchise of the Daiichi Sankyo Cancer Enterprise. Antibody-drug Conjugates or 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.
Among 57 evaluable patients the data showed an overall response rate of 61.4% (35 of 57 patients) and disease control rate of 94.7% (54 of 57 patients) in patients with HER2-positive metastatic breast cancer pretreated with ado-trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche).
In addition, among 50 of these patients who were also pretreated with pertuzumab (Perjeta®; Genentech/Roche), DS-8201 demonstrated a confirmed overall response rate of 62% (31 of 50 patients) and a disease control rate of 94% (47 of 50 patients). In 39 efficacy evaluable HER2-positive patients with hormone-receptor positive disease, DS-8201 demonstrated an overall response rate of 56.4% (22 of 39 patients) and disease control rate of 92.3% (36 of 39 patients).
The majority of patients with HER2-positive metastatic breast cancer were continuing to receive treatment at the time of data cut-off. Preliminary estimates of median progression free survival have reached 10.4 months.
Additionally, preliminary results in another subgroup showed that DS-8201 demonstrated a confirmed overall response rate of 31.6% (6 of 19 patients) and a disease control rate of 84.2% (16 of 19 patients) in 19 efficacy evaluable patients with heavily pretreated HER2 low-expressing breast cancer (defined as IHC2+/ISH- or IHC 1+). In 16 of these patients also classified with hormone-receptor positive disease, DS-8201 demonstrated an overall response rate of 31.3% (5 of 16 patients) and a disease control rate of 87.5% (14 of 16 patients).
Most patients with HER2 low-expressing breast cancer were continuing to receive treatment at the time of data cut-off.
Median progression free survival has not yet been reached.
“These updated data in HER2-positive metastatic breast cancer are exciting in that DS-8201 is showing potential in treating patients who have progressed on several other HER2-targeting agents,” noted Shanu Modi, MD, Breast Medical Oncologist, Memorial Sloan Kettering Cancer Center and study investigator.
“The results seen in patients with HER2 low-expressing breast cancer are compelling and could challenge how we define HER2-positive breast cancer with regards to ADC therapy. Clearly, further study of DS-8201 is warranted in both these types of HER2-expressing breast cancer,” Modi added.
“These data add to the growing evidence that underscore the potential of our smart chemotherapy DS-8201 to treat HER2-expressing breast cancer,” said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.
“While we already have advanced DS-8201 into a pivotal Phase II trial for HER2-positive metastatic breast cancer, we are exploring next steps for the development of DS-8201 in HER2 low-expressing breast cancer.”
During this year’s SABCS combined preliminary safety data for both HER2 low-expressing and HER2-positive breast cancer subgroups were reported. The most common adverse events (>30% any grade) included nausea (73.0%), decreased appetite (55.7%), alopecia (40.0%), vomiting (39.1%), anemia (34.8%), diarrhea (33.9%) and constipation (30.4%).
Grade 3 adverse events occurring in >10% of patients included decreased neutrophil count (10.4%) and decreased white blood cell count (10.4%).
Grade 4 adverse events included decreased neutrophil count (4.3%, decreased platelet count (2.6%) and anemia (0.9%). Two cases of potential Grade 5 pneumonitis have been reported and will be assessed by an interstitial lung disease (ILD) adjudication committee.
The open-label, two-part Phase I 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.
In the dose expansion part of the Phase I study, DS-8201 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 and the HER2-expressing solid tumors cohort is ongoing in the U.S. and Japan.
DS-8201 is currently in Phase II clinical development for HER2-positive unresectable and/or metastatic breast cancer resistant or refractory to T-DM1 (DESTINY-Breast01), Phase II development for HER2-positive advanced gastric cancer resistant or refractory to trastuzumab (DESTINY-Gastric01), and Phase I development for other HER2-expressing advanced/unresectable or metastatic solid tumors. 
The investigational drug has 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), 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.