Investigators are evaluating the safety and efficacy of the investigational antibody-drug conjugate vic-trastuzumab duocarmazine in patients with HER2-expressing recurrent, advanced, or metastatic endometrial cancer in the phase 2 SYD985.003 trial.
Alessandro Santin, MD
Investigators are evaluating the safety and efficacy of the investigational antibody-drug conjugate (ADC) vic-trastuzumab duocarmazine (SYD985) in patients with HER2-expressing recurrent, advanced, or metastatic endometrial cancer in the phase 2 SYD985.003 trial (NCT04205630), according to an announcement from Byondis BV, the drug developer.1
In the single-arm study, patients will receive trastuzumab duocarmazine delivered intravenously every 3 weeks. The primary end point of the trial is objective response rate, while key secondary end points include progression-free survival (PFS), overall survival (OS), and safety.
The biopharmaceutical company announced that the first patients began treatment with the ADC on July 15, 2020 at Severance Hospital, Yonsei University Health System in South Korea. Investigators hope to enroll approximately 60 patients in up to 40 clinical sites across the United States, Europe, and Asia-Pacific.
To be eligible for enrollment, patients had to have histologically confirmed recurrent, advanced, or metastatic endometrial carcinoma, have progressed on or after first-line platinum-based chemotherapy for advanced/metastatic disease, have HER2 tumor expression defined as 1+, 2+, or 3+ score on immunohistochemistry or positive by in situ hybridization, at least 1 measurable lesion per RECIST v1.1 criteria, and an ECOG performance status of 2 or less.
If patients had current or prior use if any prohibited medication listed in the study protocol, a history of infusion-related reactions and/or hypersensitivity to trastuzumab, a history of keratitis, severe, uncontrolled systemic disease at the time of screening, a history of clinically significant cardiovascular disease, symptomatic brain metastases, or a history or presence of idiopathic pulmonary fibrosis, they were not permitted to participate.
Twenty years ago, Alessandro Santin, MD, professor of Obstetrics, Gynecology, and Reproductive Sciences; disease aligned research team leader of the Gynecologic Oncology Program; and co-chief of Section of Gynecologic Oncology, at Yale Cancer Center, as well as the principal investigator on the study, and colleagues established a connection between certain forms of endometrial cancer, namely uterine serous carcinoma (USC), and HER2 expression.
Preliminary data from a phase 2 study (NCT01367002) comparing trastuzumab (Herceptin) plus carboplatin/paclitaxel versus carboplatin/paclitaxel alone showed a median PFS of 17.9 months with trastuzumab versus 9.3 months with chemotherapy alone.2 These findings led to the inclusion of the trastuzumab combination regimen for patients with HER2-positive USC in the National Comprehensive Cancer Network Guidelines.
Final data from the trial confirmed that the addition of trastuzumab to carboplatin/paclitaxel resulted in prolonged PFS and OS in patients with advanced/recurrent HER2-positive USC.3 Specifically, at a median follow-up of 25.9 months, the median PFS was 12.9 months versus 8.0 months in the investigational and control arms, respectively (HR, 0.46; 90% CI, 0.28-0.76; P = .005). In those with stage III and IV disease who were undergoing primary treatment, the improvement in median PFS with trastuzumab over chemotherapy alone was even more pronounced, at 17.7 months versus 9.3 months, respectively (HR, 0.44; 90% CI, 0.23-0.83; P = .015). The median OS for the trastuzumab combination and chemotherapy alone was 29.6 months and 24.4 months, respectively (HR, 0.58; 90% CI, 0.34-0.99; P = .046).
“My team and I are excited to participate in the phase 2 study of the investigational ADC trastuzumab duocarmazine in HER2-expressing advanced endometrial cancer,” Santin stated in a press release. “We had the opportunity to study the potential of SYD985 in our preclinical models for endometrial cancer and were impressed by its potential. This ADC combines the ‘double punch’ of anti-HER2 monoclonal antibody trastuzumab with a powerful duocarmycin-based cytotoxin – a combination that could prove beneficial for patients whose disease has progressed.”
ADC SYD985 is comprised of monoclonal antibody trastuzumab and a cleavable linker-drug known as valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA). The antibody portion of the agent adheres to HER2 on the surface of the cancer cell and the ADC is then internalized by the cell. Following proteolytic cleavage of the linker, the cytotoxin activated, inducing DNA damage, and eliciting tumor cell death. For that reason, SYD985 is considered to be a targeted chemotherapy, according to the biopharmaceutical company.
Because of the agent's unique design, there is a notable high–stability circulation and helps to the cytotoxins to release efficiently in the tumor. Uptake of the activated payload by neighboring tumor cells with lower HER2 expression could result in improved efficacy per the bystander effect.
In January 2018, the FDA granted the ADC a fast track designation for use in patients diagnosed with HER2-positive metastatic breast cancer that had progressed during or after at least 2 previous HER2-targeted therapies for locally advanced or metastatic disease or who had progressed on ado-trastuzumab emtansine (T-DM1; Kadcyla).4
The regulatory designation was based off of encouraging findings from the 2-part phase 1 SYD985.001 trial, which showed that the ADC was safe and effective in heavily pretreated patients with HER2-positive metastatic breast cancer.