Research Progress on Trastuzumab-Duocarmazin

ADCs (antibody-drug conjugates), monoclonal antibodies linked to potent chemotherapy drugs, have emerged as a successful targeted cancer treatment. Trastuzumab-duocarmazine, a third-generation HER2-targeted ADC, is under development for unmet needs in HER2-targeted therapy. Here, we review the biology, development, efficacy and safety of trastuzumab-duocarmazine.

What Is Trastuzumab-Duocarmazine?

Trastuzumab-double carmazine is an ADC that conjugates the antibody trastuzumab to a cytotoxic double carmazine-based payload with a cleavable linker. The target of trastuzumab-double carmazine, HER2, is an overexpressed driver factor in certain breast cancers and other cancers, which has been found to be a carcinogen. Binding of trastuzumab-biscarbamazine to HER2-positive tumor cells is followed by internalization of the ADC into the cells by endocytosis. After the linker is cleaved, the cytotoxic biscarbamazine derivative is released from the antibody. Dicarboxymycin then binds to the minor groove of DNA which results in lethal DNA alkylation and, ultimately, tumor cell death. In addition to the activities described above, Trastuzumab-double carmazine also possesses the natural capacity to mediate antibody-dependent cytotoxicity (ADCC), which is carried by trastuzumab. The targeted delivery of these highly potent cytotoxins, as well as antibody-mediated immune responses, are therefore expected to translate into greater anti-tumor activity with diminished systemic toxicity compared to conventional chemotherapy.

Early-Phase Clinical Development

Phase I Dose Escalation and Dose Expansion Trials

The first-in-human clinical trial of trastuzumab-double carmazine is a phase I study in patients with locally advanced or metastatic HER2-positive solid tumors, designed to assess its safety, determine the recommended phase II dose, and seek early evidence of efficacy.

Key findings from this trial included:

Safety and tolerability: Recommended phase II dose was defined as 1.2 mg/kg IV every 3 weeks. Most common toxicities included fatigue, conjunctivitis, dry eye and other ocular side effects, indicative of a novel toxicity profile with duocarmycin payload delivery.

Activity in other tumor types: Among HER2-positive metastatic breast cancer patients, ORR was approximately 33%. Objective responses were also observed in patients with HER2-low breast cancer. Responses were seen in patients who had previously received other HER2-directed therapies, including T-DM1.

Expanding indications: Partial responses were also seen in gastric, urothelial and endometrial cancers which also expressed HER2. While these results are very early, they are very encouraging, and show that trastuzumab-duocarmazine can produce objective tumor responses in heavily pretreated patients, and across multiple tumor types with variable HER2 expression.

Phase III TULIP Trial: A Milestone in Development

The primary clinical development milestone for trastuzumab-duocarmazine is the Phase III TULIP trial. TULIP is a global, open-label, randomized phase III trial in patients with unresectable locally advanced or metastatic HER2-positive breast cancer who have been treated with at least two HER2-targeted therapies, or whose disease has progressed after treatment with trastuzumab emtansine.

Safety and Tolerability

The safety profile of trastuzumab-duocarmazine was generally manageable but distinct from other HER2 ADCs:

• Ocular toxicity (e.g., keratitis, conjunctivitis, dry eye) was a frequent adverse event and was responsible for a higher rate of treatment discontinuation in the experimental arm compared to physician's choice treatment.
• Other significant events included neutropenia and general chemotherapy-related side effects. Grade ≥3 adverse events have been reported in just over 50% of patients.

As a result of these safety findings, there has been greater focus on implementing preventative ocular monitoring and management in clinical development programs.

Comparative Landscape: Trastuzumab-Duocarmazine vs. Other HER2 ADCs

ADCs are an exciting area of development at the moment, and are being driven forward by some very strong agents, such as trastuzumab deruxtecan. They are not the focus of this review, but it is useful to establish where trastuzumab-duocarmazine may sit with respect to them:

Trastuzumab deruxtecan has shown high clinical activity in HER2-positive and HER2-low metastatic breast cancer and has been broadly approved and utilized.

In contrast to first-generation ADCs, they are similar in mechanism of action but have distinct characteristics in payload chemical structure, linker design, and bystander killing effect. These differences underpin their efficacy and toxicity profiles.

Duocarmycin Antibodies

Duocarmycin Antigen