A first patient has started treatment in a Phase II study designed to evaluate the safety and efficacy of [vic-] trastuzumab duocarmazine, also known as SYD985, in patients with HER2-expressing recurrent, advanced or metastatic endometrial (uterine) cancer.

According to GLOBOCAN, an estimated 382,069 new cases and 89,929 deaths were attributed worldwide to endometrial cancer in 2018. In the same year, endometrial cancer was the second most common and fourth leading cause of global deaths due to gynecological cancer [1]. Metastatic endometrial cancer remains incurable. [2][3] For advanced/metastatic disease, platinum-based chemotherapy is the preferred first-line treatment. And only a few therapeutic agents have demonstrated to produce meaningful response rates in the second-line setting, highlighting a need for new therapies in advanced, recurrent, metastatic endometrial cancer.[4]

Investigational drug
The trial drug, [vic-] trastuzumab duocarmazine is an investigational antibody-drug conjugate or ADC being developed by Byondis, an independent biopharmaceutical research and development company based in Nijmegen, The Netherlands.

The open-label, single-arm, phase II study is designed to evaluate the safety and efficacy of [vic-] trastuzumab duocarmazine in patients with HER2-expressing recurrent, advanced or metastatic endometrial carcinoma who previously progressed on or after first-line platinum-based chemotherapy.  The study is expected to enroll approximately 60 patients in up to 40 clinical sites in the United States, Europe, and Asia-Pacific.

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Participating patients receive [vic-] trastuzumab duocarmazine once every three weeks (Q3W) until disease progression or unacceptable toxicity. Patients who have had two or more lines of chemotherapy for advanced/metastatic disease are not eligible.

The study’s primary endpoint is objective response rate (ORR), which is the proportion of patients with an assessed best overall response of complete response or partial response. Secondary endpoints include progression-free survival (PFS), overall survival (OS) and treatment-emergent adverse events (AEs).

Impressed by its potential
“My team and I are excited to participate in the Phase II study of the investigational antibody-drug conjugate [vic-]trastuzumab duocarmazine in HER2-expressing advanced endometrial cancer,” noted Alessandro D. Santin, M.D., Yale Cancer Center professor of obstetrics, gynecology, and reproductive sciences, will serve as principal investigator for the Yale study site.

Alessandro D. Santin, MD, is an oncologist who cares for patients with endometrial and other gynecologic cancers. Photo courtesy: © 2020 Yale Medicine

“We had the opportunity to study the potential of [vic-] trastuzumab duocarmazine in our preclinical models for endometrial cancer and were impressed by its potential. This ADC combines the ‘double punch’ of anti-HER2 antibody trastuzumab with a powerful duocarmycin-based cytotoxin – a combination that could prove beneficial for patients whose disease has progressed,” Santin, an endometrial cancer expert, added.

Santin says his research, which primarily explores cancers of the ovary, endometrium, and cervix, as well as tumor immunology and immunotherapy, is driven by his team’s desire to find better treatments for patients with hard to treat cancers representing major unmet medical need.

About 20 years ago, Santin’s lab discovered the connection between some types of an aggressive form of endometrial cancer, known as Uterine Serous Carcinoma (USC), and HER2 expression. And in 2018, preliminary data from a Phase II study by Santin and his team led to the inclusion of the chemotherapy-trastuzumab combination for new treatment of women with HER2-positive USC in the National Comprehensive Cancer Network (NCCN) guidelines. More recently, Clinical Cancer Research published the final results of this same study, which confirmed trastuzumab with chemotherapy improves survival rates for women with USC whose tumors expressed high levels of the HER2 protein.[5][6]

Specific anti-tumor activity
Byondis’ [vic-] trastuzumab duocarmazine which includes the same antibody as ado-trastuzumab emtansine (Kadcyla®; T-DM1; Genentech/Roche) and [fam] trastuzumab deruxtecan-nxki  (Enhertu®; DS-8201a; Daiichi Sankyo and AstraZeneca) has excellent targeting and specific anti-tumor activity against HER2. But in contrast to trastuzumab emtansine, which has a non-reducible thioether linker, N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC, designated MCC after conjugation) and releases the Lys-linker-payload to kill the cells, trastuzumab duocarmazine has a cleavable linker and a duocarmycin prodrug payload known as seco-DUBA, is effective in the picomolar range.[7][8]

As a result, [vic-] trastuzumab duocarmazine has a similar targetability in comparison to trastuzumab emtansine, but, at the same time, also reduces trastuzumab emtansine resistance and demonstrates improved efficacy in heterogeneous tumors.

“As we near the completion of enrollment in our Phase III study of SYD985 in metastatic HER2- positive breast cancer, we are pleased to examine its possible contribution to improving patient outcome in advanced endometrial cancer, another difficult disease with unmet need,” noted Marco Timmers, Ph.D., Chief Executive Officer of Byondis.

I-Spy-2 TRIAL
Only last week [vic-] trastuzumab duocarmazine was selected for a new investigational treatment arm in its ongoing I-SPY 2 TRIAL™ for neoadjuvant treatment of locally advanced breast cancer.

The I-SPY 2 TRIAL is a standing phase II randomized, controlled, multicenter study aimed at rapidly screening promising treatments in specific subgroups of women with newly-diagnosed, high-risk, locally advanced breast cancer (Stage II/III).

Clinical trial
SYD985 in Patients With HER2-expressing Recurrent, Advanced or Metastatic Endometrial Carcinoma – NCT04205630
Phase I Study of SYD985 With Niraparib in Patients With Solid Tumors – NCT04235101
First-in-human Study With the Antibody-drug Conjugate SYD985 to Evaluate Safety and Efficacy in Cancer Patients – NCT02277717
SYD985 vs. Physician’s Choice in Participants With HER2-positive Locally Advanced or Metastatic Breast Cancer (TULIP) – NCT03262935

Reference
[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. (2018) 68:394–424. doi: 10.3322/caac.21492, https://acsjournals.onlinelibrary.wiley.com/doi/full/10.3322/caac.21492
[2] National Comprehensive Cancer Network, Endometrial Cancer (Version 1.2020), http://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf
[3] Colombo N, Creutzberg C, Amant F et al., “ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer: diagnosis, treatment, and follow-up,” Annals of Oncology 2016; 27:16-41, https://www.annalsofoncology.org/article/S0923-7534(19)35337-2/pdf
[4] Bestvina CM, Fleming GF, “Chemotherapy for Endometrial Cancer in Adjuvant and Advanced Disease Settings,” The Oncologist 2016;21:1250-1259, https://theoncologist.onlinelibrary.wiley.com/doi/epdf/10.1634/theoncologist.2016-0062
[6] Fader AN, Roque DM, Siegel E et al., “Randomized Phase II Trial of Carboplatin-Paclitaxel Versus Carboplatin-Paclitaxel-Trastuzumab in Uterine Serous Carcinomas That Overexpress Human Epidermal Growth Factor Receptor 2/neu,” Journal of Clinical Oncology 36, no. 20 (October 2018): pp. 2044-2051, https://doi.org/10.1200/jco.2017.76.5966
[6] Fader AN, Roque DM, Siegel E et al., Randomized Phase II Trial of Carboplatin-Paclitaxel Compared with Carboplatin-Paclitaxel-Trastuzumab in Advanced (Stage III–IV) or Recurrent Uterine Serous Carcinomas that Overexpress HER2/Neu (NCT01367002): Updated Overall Survival Analysis, Clinical Cancer Research (June 2020), https://doi.org/10.1158/1078-0432.CCR-20-0953
[7] Xu Z, Guo D, Jiang Z, et al. Novel HER2-Targeting Antibody-Drug Conjugates of Trastuzumab Beyond T-DM1 in Breast Cancer: Trastuzumab Deruxtecan(DS-8201a) and (Vic-)Trastuzumab Duocarmazine (SYD985). Eur J Med Chem. 2019;183:111682. doi:10.1016/j.ejmech.2019.111682
[8] Kaplon H, Reichert JM. Antibodies to watch in 2019. MAbs. 2019;11(2):219-238. doi:10.1080/19420862.2018.1556465