Disitamab vedotin represents a specific class of cancer treatments known as antibody-drug conjugates, or ADCs. This innovative therapy is engineered to deliver a potent cell-killing agent directly to cancer cells. By precisely targeting diseased cells, disitamab vedotin aims to minimize harm to healthy tissues throughout the body. It offers a more focused approach compared to traditional chemotherapy, which often affects both cancerous and healthy cells indiscriminately.
How Disitamab Vedotin Works
Disitamab vedotin targets cancer cells. It consists of three main components: a targeted antibody, a chemotherapy payload, and a linker connecting them. The antibody, called disitamab, acts as a guidance system engineered to recognize and attach to human epidermal growth factor receptor 2 (HER2). HER2 is a protein often found in elevated amounts on the surface of certain cancer cells, driving their growth and spread.
Once the disitamab antibody binds to the HER2 protein on a cancer cell, the entire antibody-drug conjugate is internalized into the cell through receptor-mediated endocytosis. After internalization, the chemical linker, a valine-citrulline (VC) linker, is cleaved by enzymes within the cell’s lysosomes.
This cleavage releases the active chemotherapy payload, monomethyl auristatin E (MMAE), directly inside the cancer cell. MMAE is a powerful anti-mitotic agent that disrupts microtubules, structures necessary for cell division. By interfering with microtubule assembly, MMAE halts the cancer cell’s ability to divide and multiply, ultimately leading to its programmed death.
Cancers Treated With Disitamab Vedotin
Disitamab vedotin has shown promise in managing advanced or metastatic urothelial carcinoma, a type of bladder cancer. The drug is also applied in cases of gastric cancer, including those affecting the gastroesophageal junction.
This therapy is indicated for cancers that are HER2-positive or express HER2 at low levels, meaning the cancer cells have detectable amounts of this protein on their surface. For example, in urothelial carcinoma, HER2 overexpression has been linked to tumor progression. In gastric cancer, disitamab vedotin has been conditionally approved for HER2-positive cases that have already undergone at least two prior systemic chemotherapy treatments. The drug’s application extends to breast cancer, particularly in HER2-positive and HER2-low advanced cases.
Clinical Trial Efficacy and Results
Clinical trials have evaluated disitamab vedotin’s effectiveness using specific measures. Objective response rate (ORR) is the percentage of patients whose tumors shrink or disappear. Progression-free survival (PFS) is the time a patient lives with the disease without it worsening.
In HER2-positive metastatic urothelial carcinoma, disitamab vedotin demonstrated an ORR of 50.5% in combined Phase II trials, with a median PFS of 5.9 months and a median overall survival (OS) of 14.2 months. A Phase III trial combining disitamab vedotin with toripalimab for first-line HER2-expressing urothelial carcinoma showed significant improvements in PFS and OS compared to standard chemotherapy, achieving an ORR of 73.2%, a median PFS of 9.3 months, and a median OS of 33.1 months. Preliminary data from a study combining disitamab vedotin with pembrolizumab in urothelial carcinoma indicated an investigator-assessed ORR of 61.1% in all patients and 76.9% in HER2-low patients.
For heavily pretreated HER2-expressing advanced gastric cancer, a Phase II study reported an ORR ranging from 18.1% to 23.6%, with a median PFS of 3.8 to 4.1 months and a median OS of 7.6 months. In HER2-overexpressing gastric or gastroesophageal junction cancer, a combination of disitamab vedotin with tislelizumab and S-1 achieved a confirmed ORR of 89.4%, a median PFS of 12.7 months, and an 18-month OS rate of 72.7%. Early results from first-line treatments combining disitamab vedotin with toripalimab and chemotherapy or trastuzumab in HER2-expressing gastric cancers have also shown high response rates.
In HER2-positive advanced breast cancer, real-world data indicated an ORR of 29.6% and a median progression-free survival of 5.9 months in patients previously treated with trastuzumab. A Phase I/Ib study reported ORRs of 42.9% for HER2-overexpression and 33.3% for HER2-low breast cancer, with corresponding median PFS values of 5.7 months and 5.1 months. A Phase III study in HER2-positive advanced breast cancer with liver metastasis, after prior trastuzumab and taxane treatments, showed disitamab vedotin significantly improved PFS to a median of 9.9 months compared to 4.9 months in the control group.
Common Side Effects and Safety
Like other cancer treatments, disitamab vedotin can cause various side effects. Common experiences include fatigue, nausea, vomiting, and diarrhea. Patients may also experience hair loss, or alopecia, and peripheral neuropathy, manifesting as numbness or tingling in the hands and feet.
Blood-related side effects, such as leukopenia (low white blood cell count) and neutropenia (low neutrophil count), are observed, along with elevated liver enzymes. More serious, though less frequent, side effects involve ocular toxicity, which can lead to blurred vision, dry eyes, and corneal abnormalities like pseudomicrocysts. Infusion-related reactions, such as fever, chills, or rash, can occur during administration. Patients receiving this therapy are closely monitored by their medical team to identify and manage these events.