Trastuzumab duocarmazine* (SYD985; Synthon) is a novel antibody-drug conjugate composed of the recombinant humanized anti-epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab linked, via a cleavable linker, to the duocarmycin prodrug seco-duocarmycin-hydroxybenzamide-azaindole, also known as seco-DUBA.
The investigational agent is being developed by Synthon, a pharmaceutical company based in The Netherlands, is part of a wave of HER2-directed antibody-drug conjugates under clinical investigation for HER2 amplified but also HER2 expressing but not amplified breast tumors. 
As part of the development program, the U.S. Food & Drug Administration (FDA) granted Fast Track designation for its trastuzumab duocarmazine (SYD985). This designation is for treating patients diagnosed with HER2-positive metastatic breast cancer (MBC) that has progressed during or after at least two HER2-targeting treatment regimens for locally advanced or metastatic disease or progressed during or after [ado-]trastuzumab emtansine treatment.
U.S. FDA Fast Track designation is one of four programs that are intended to facilitate and expedite the development and review of new drugs to address the unmet medical needs in the treatment of a serious or life-threatening condition.
Mechanism of Action
Following administration, the trastuzumab moiety binds to HER2 on the tumor cell surface. This triggers the endocytosis of this agent after which the linker is cleaved inside the tumor cell by proteases at the dipeptide valine-citrulline (vc), and releases the active moiety agent.
While most of the payloads used in ADCs prevent tubulin polymerization during cell division, trastuzumab duocarmazine is using a different linker-drug technology, applying valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA) based on synthetic duocarmycin analogs. These synthetic duocarmycin analogs bind to the minor groove of DNA, alkylates adenine at the N3 position, and subsequently cause irreversible alkylation of DNA, disrupts the nucleic acid architecture, which eventually leads to tumor cell death.
In addition, trastuzumab induces antibody-dependent cell-mediated cytotoxicity (ADCC) against tumor cells that overexpress HER2.
Duocarmycins are able to exert their mode of action at any phase in the cellular cycle, whereas tubulin binders will only attack tumor cells when they are in a mitotic phase. Growing evidence suggests that DNA damaging agents, including duocarmycins, are more efficacious in tumor cell killing than tubulin binders, particularly in solid tumors.
Although based on natural products, the proprietary ADC linker-drug technology developed by Synthon uses fully synthetic duocarmycin analogs. The unique design of the selectively cleavable linker connecting the antibody to the duocarmycin drug leads to high stability in circulation and induces the efficient release of the cytotoxin in the tumor.
In various preclinical studies, trastuzumab duocarmazine showed promising anti-tumor activity. Based on the positive results of these preclinical studies, the researchers developed a Phase I study (SYD985.001; NCT02277717)
In this first-in-human Phase I dose-escalation and dose-expansion study, researchers assessed the safety and activity of trastuzumab duocarmazine in patients with advanced solid tumors. 
The dose-escalation part of the study included 39 patients between 18 years and older who were enrolled in one of three academic medical centers in Belgium, The Netherlands, and the United Kingdom. All participating patients were diagnosed with locally advanced or metastatic solid tumors with variable HER2 status who were refractory to standard cancer treatment.
In addition, the researchers enrolled 146 patients 18 years and older in one of 15 hospitals in Belgium, The Netherlands, Spain, and the United Kingdom to participate in the dose-expansion phase of the study. These patients were diagnosed with breast, gastric, urothelial, or endometrial cancer with at least HER2 immunohistochemistry 1+ expression and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST).
The participating patients received trastuzumab duocarmazine intravenously on day 1 of each 3-week cycle. In the separate dose-escalation phase of the investigational agent was given at doses of 0·3 mg/kg to 2·4 mg/kg (3 + 3 design) until disease progression or unacceptable toxicity.
In this part of the study, the primary endpoint of the dose-escalation phase was to assess the safety and ascertain the recommended Phase II dose, which would be the dose used in the dose-expansion phase. Then, the primary endpoint of the dose-expansion phase was the proportion of patients achieving an objective response, which was either a complete response or partial response, as assessed by the investigator using RECIST version 1.1.
In the dose-escalation phase of the study, the trial results showed a number of adverse events, including one dose-limiting toxic effect leading to death from pneumonitis which occurred at the highest administered dose of 2.4 mg/kg.
Another patient died during the dose-escalation phase (1.5 mg/kg cohort) due to disease progression. Death was attributed to the patient’s general decline in physical health. Furthermore, the researchers observed grade 3-4 treatment-related adverse events in the dose-escalation phase, including keratitis (n=3) and fatigue (n=2).
Based on the available data, the researchers set the recommended phase II dose was at 1.2 mg/kg.
During the dose-expansion phase of the trial, the treatment-related serious adverse events included 16 (11%) of 146 patients, most commonly infusion-related reactions in 2 patients (1%) and dyspnoea in another 2 patients (1%).
In addition, the most common treatment-related adverse events (grades 1-4) were fatigue in 48 patients (33%), conjunctivitis in 45 patients (31%), and dry eye in 45 patients (31%). Another 104 patients (71%) had at least one ocular adverse event, with grade 3 events reported in 10 (7%) of all participating patients.
While there no patients died from treatment-related adverse events, a total of 4 patients died due to disease progression. This was generally attributed to hepatic failure (n=1), upper gastrointestinal hemorrhage (n=1), neurological decompensation (n=1), and renal failure (n=1).
In the breast cancer dose-expansion cohorts, 16 patients (33%, 95% CI 20·4-48·4) of 48 assessable patients with HER2-positive breast cancer achieved an objective response (OR) according to RECIST.
In addition, nine patients (28%, 95% CI 13·8-46·8) of a total of 32 patients with HER2-low, hormone receptor-positive breast cancer and 6 (40%, 16·3-67·6) of a total of 15 patients with HER2-low, hormone receptor-negative breast cancer achieved an objective response.
Partial response was also observed in 1 patient (6%, 95% CI 0·2-30·2) of 16 patients with gastric cancer, 4 patients (25%, 7·3-52·4) of 16 patients with urothelial cancer, and 5 (39%, 13·9-68·4) of 13 patients with endometrial cancer.
The study showed a manageable safety profile in HER2-positive trastuzumab emtansine-resistant and HER2-low breast cancer.
Overall, the phase I trial with trastuzumab duocarmazine demonstrated notable, positive, clinical activity in heavily pretreated patients with HER2-expressing metastatic cancer and confirmed that the investigational agent could provide substantial benefit to patients with limited or no other treatment options.
Phase III trial
A pivotal Phase III trial, a multi-center, open-label, randomized clinical study comparing the efficacy and safety of trastuzumab duocarmazine to physician’s choice treatment in patients with HER2-positive unresectable locally advanced or metastatic breast cancer enrolled 345 patients in up to 100 sites in the United States, Canada, Europe and Singapore.
This Phase III study, called TULIP®, was designed as a randomized, active-controlled, superiority study in patients with unresectable locally advanced or metastatic HER2-positive breast cancer. These patients had either progression during or after at least two HER2-targeting treatment regimens for locally advanced or metastatic disease or progression during or after (ado-)trastuzumab emtansine treatment.
The eligible patients were randomly assigned (2:1) to receive trastuzumab duocarmazine or physician’s choice treatment (including lapatinib, capecitabine, trastuzumab, vinorelbine and/or eribulin) until disease progression, unacceptable toxicity, or study termination by the researchers. During treatment, patients visited the clinical to assess efficacy, health-related quality of life (QoL), and safety using standardized criteria.
The primary objective of the phase III study is to demonstrate that trastuzumab duocarmazine is superior to the physician’s choice in prolonging progression-free survival (PFS) on the basis of the blinded independent central review of tumor assessment.
The secondary objective includes a comparison of the two treatment groups with respect to overall survival (OS), objective response rate (ORR) on the basis of the blinded independent central review and investigator-assessed PFS as well as patient-reported outcomes (PRO) for health-related quality of life (EORTC QOL C30 & BR23) and safety and tolerability.
In the United States, trastuzumab duocarmazine is known as [vic]trastuzumab duocarmazine.
- 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
 Rinnerthaler G, Gampenrieder SP, Greil R. HER2 Directed Antibody-Drug-Conjugates beyond T-DM1 in Breast Cancer. Int J Mol Sci. 2019 Mar 5;20(5). pii: E1115. doi: 10.3390/ijms20051115.
 Banerji U, van Herpen CML, Saura C, Thistlethwaite F, Lord S, Moreno V, Macpherson IR, et al. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol. 2019 Aug;20(8):1124-1135. doi: 10.1016/S1470-2045(19)30328-6. Epub 2019 Jun 27.