What Is Trastuzumab-Deruxtecan (T-DXd)?
Trastuzumab-Deruxtecan (T-DXd) is an investigational drug currently being studied in clinical trials. It is a type of medication known as an antibody-drug conjugate (ADC), which combines a targeted antibody with a chemotherapy drug.
The antibody component of T-DXd is designed to specifically identify and attach to HER2, a protein often found in high amounts on the surface of certain cancer cells. Once bound, it delivers a chemotherapy drug called DXd directly into the cancer cell. DXd works by inhibiting topoisomerase I, an enzyme essential for cancer cell growth and division, which ultimately leads to the death of the tumor cell.
Clinical trials are currently investigating Trastuzumab-Deruxtecan for various cancers, including breast cancer, colon cancer, colorectal cancer, and rectal cancer, particularly in their metastatic or adenocarcinoma forms.
Uses and Conditions Under Study
Trastuzumab-Deruxtecan (T-DXd) is currently under investigation in clinical trials for its potential to treat several types of cancer, particularly those that may express the HER2 protein. The drug's targeted approach aims to deliver chemotherapy directly to cancer cells, potentially reducing harm to healthy tissues.
- Breast Cancer: This includes both early-stage and metastatic forms of breast cancer, which is a common cancer originating in the breast tissue. T-DXd is being studied in two clinical trials for breast cancer, including those specifically for metastatic breast cancer. The rationale for its use stems from its ability to target HER2-positive cells, a characteristic found in a subset of breast cancers, offering a precise way to deliver its cytotoxic payload.
- Colorectal and Rectal Cancers: These cancers affect the large intestine (colon) or the rectum. The specific conditions under study include colon cancer adenocarcinoma, metastatic colon cancer, colorectal adenocarcinoma, colorectal cancer, rectal adenocarcinoma, and metastatic rectal cancer. Trastuzumab-Deruxtecan is being evaluated in one clinical trial for these gastrointestinal cancers. By targeting HER2, T-DXd aims to provide a focused treatment approach for these cancers, especially in cases where the cancer has spread or is of the adenocarcinoma type, which is a common form of colorectal cancer.
Dosing
Trastuzumab-Deruxtecan (T-DXd) is administered as an intravenous (IV) infusion. The drug is supplied as a solution for direct infusion into a vein.
In the ongoing clinical trials, the investigational dose of Trastuzumab-Deruxtecan is consistently 5.4 mg per kilogram of body weight. This dose is given intravenously as an infusion over approximately 90 minutes (with a 10-minute variability) on day 1 of each treatment cycle.
The standard treatment schedule involves administering the drug every three weeks. For specific conditions, such as hormonal-receptor-positive breast cancer, T-DXd may be given in combination with endocrine therapy. This combination regimen is planned for up to 16 cycles or until the disease progresses, whichever occurs first. Patients participating in these trials receive their medication under strict medical supervision according to the specific trial protocol.
Side Effects
The most common side effect reported by patients taking Trastuzumab-Deruxtecan (T-DXd) was nausea. In a clinical study involving patients with HER2-positive metastatic breast cancer, 73.1% of patients receiving Trastuzumab-Deruxtecan (T-DXd) experienced nausea, compared to 35.8% of patients receiving trastuzumab emtansine (T-DM1).
Other common side effects, comparing Trastuzumab-Deruxtecan (T-DXd) to trastuzumab emtansine (T-DM1), included:
- Fatigue: 48.0% of patients on Trastuzumab-Deruxtecan (T-DXd) experienced fatigue, compared to 42.1% on T-DM1.
- Alopecia (hair loss): 45.4% of patients on Trastuzumab-Deruxtecan (T-DXd) experienced alopecia, compared to 15.6% on T-DM1.
- Vomiting: 38.0% of patients on Trastuzumab-Deruxtecan (T-DXd) experienced vomiting, compared to 17.5% on T-DM1.
- Constipation: 34.7% of patients on Trastuzumab-Deruxtecan (T-DXd) experienced constipation, compared to 23.4% on T-DM1.
- Diarrhea: 30.2% of patients on Trastuzumab-Deruxtecan (T-DXd) experienced diarrhea, compared to 19.5% on T-DM1.
- Decreased appetite: 29.8% of patients on Trastuzumab-Deruxtecan (T-DXd) experienced decreased appetite, compared to 16.2% on T-DM1.
A serious side effect associated with Trastuzumab-Deruxtecan (T-DXd) is interstitial lung disease (ILD) or pneumonitis. This occurred in 15.2% of patients receiving Trastuzumab-Deruxtecan (T-DXd) in the same study, compared to 3.1% of patients receiving T-DM1. Fatal cases of ILD/pneumonitis occurred in 0.8% of patients on Trastuzumab-Deruxtecan (T-DXd).
Clinical Trial Results
HER2-Positive Metastatic Breast Cancer (DESTINY-Breast03)
The NCT03529158 study, known as DESTINY-Breast03, evaluated Trastuzumab-Deruxtecan (T-DXd) in patients with HER2-positive metastatic breast cancer who had previously received treatment with trastuzumab and a taxane. Patients were randomly assigned to receive either Trastuzumab-Deruxtecan (T-DXd) or trastuzumab emtansine (T-DM1).
Trastuzumab-Deruxtecan (T-DXd) significantly improved progression-free survival (PFS), meaning the time patients lived without their cancer getting worse. The median PFS was not reached for patients treated with Trastuzumab-Deruxtecan (T-DXd), indicating that more than half of these patients had not experienced disease progression at the time of analysis. In contrast, the median PFS for patients treated with T-DM1 was 6.8 months. At 12 months, 75.8% of patients on Trastuzumab-Deruxtecan (T-DXd) were alive without disease progression, compared to 34.1% of patients on T-DM1.
The objective response rate (ORR), which measures the percentage of patients whose tumors shrank or disappeared, was also significantly higher with Trastuzumab-Deruxtecan (T-DXd). 79.7% of patients on Trastuzumab-Deruxtecan (T-DXd) experienced an objective response, compared to 34.2% of patients on T-DM1. Complete responses, where all signs of cancer disappeared, were observed in 16.1% of patients receiving Trastuzumab-Deruxtecan (T-DXd) versus 8.7% of those receiving T-DM1.
HER2-Low Metastatic Breast Cancer (DESTINY-Breast04)
The NCT03734029 study, known as DESTINY-Breast04, investigated Trastuzumab-Deruxtecan (T-DXd) in patients with HER2-low metastatic breast cancer who had previously received chemotherapy. Patients were randomized to receive either Trastuzumab-Deruxtecan (T-DXd) or physician's choice chemotherapy.
In patients with hormone receptor-positive, HER2-low breast cancer, Trastuzumab-Deruxtecan (T-DXd) extended progression-free survival. The median PFS was 10.1 months for patients treated with Trastuzumab-Deruxtecan (T-DXd), compared to 5.4 months for those on chemotherapy.
Trastuzumab-Deruxtecan (T-DXd) also improved overall survival (OS) in this patient group. The median OS was 23.4 months for patients receiving Trastuzumab-Deruxtecan (T-DXd), compared to 16.8 months for those receiving chemotherapy.
The objective response rate in the hormone receptor-positive, HER2-low population was 52.3% for patients treated with Trastuzumab-Deruxtecan (T-DXd), versus 16.3% for those on chemotherapy.
Currently Recruiting Trials
For patients interested in participating in clinical research for Trastuzumab-Deruxtecan, two studies are currently recruiting. These trials aim to further understand the drug's effectiveness in different cancer types.
One ongoing Phase 2 study, NCT07407465, sponsored by Gruppo Oncologico del Nord-Ovest, is investigating Trastuzumab-Deruxtecan in combination with capecitabine and bevacizumab. This trial aims to assess the activity of this regimen as a first-line treatment for patients with HER-2 positive metastatic or locally advanced unresectable colorectal cancer. Conditions being studied include colorectal cancer, colorectal adenocarcinoma, rectal adenocarcinoma, rectal cancer, and metastatic colon cancer. The study plans to enroll 42 participants to evaluate the overall response rate.
Another trial, a Phase 3 study designated NCT06643585, is sponsored by Prof. Wolfgang Janni. This randomized, open-label, multi-center study compares Trastuzumab-Deruxtecan to standard of care therapy in patients with early breast cancer who experience a molecular relapse. It focuses on individuals with intermediate to high-risk HER2-positive or HER2-low early breast cancer, specifically those participating in the SURVIVE trial. This larger study seeks to enroll 180 participants.
Where to Participate
Currently, specific locations for participating in Trastuzumab-Deruxtecan clinical trials are not yet listed. However, general eligibility criteria for these studies typically include adults between 18 and 75 years of age, of any gender. It is important to note that these trials are not designed for healthy volunteers or children, focusing instead on patients with specific medical conditions.
Development Timeline
The clinical development of Trastuzumab-Deruxtecan began on September 21, 2023, with the initiation of its first trial. Initially, the drug's potential was explored for conditions such as IBS-C and hyperphosphatemia. However, the research pipeline quickly expanded to focus on various oncological conditions.
To date, a total of 3 clinical trials have been launched, aiming to enroll 250 participants across different studies. These trials are progressing through Phase 2 and Phase 3 stages, reflecting significant advancements in its investigation. Multiple sponsors, including Gruppo Oncologico del Nord-Ovest, MedSIR, and Prof. Wolfgang Janni, have contributed to driving this research. Trastuzumab-Deruxtecan is now being investigated for conditions such as metastatic breast cancer, colon cancer metastatic, colorectal adenocarcinoma, and rectal cancer. The latest trial is projected to conclude by February 12, 2026, highlighting ongoing efforts to understand its full therapeutic potential.