A brand new type of cancer drug that acts as a ‘Trojan horse’ to get inside tumor cells has shown promise in patients with six different cancer types. In patients with advanced, drug-resistant cancers, over a quarter with cervical and bladder tumors, and nearly 15% with ovarian and lung tumors, responded to the new treatment. A team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust led a phase I/II global clinical trial of nearly 150 patients, with a variety of cancer types who had stopped responding to standard treatments. TV is made up of a toxic drug attached to the tail end of a monoclonal antibody. The innovative new drug, called tisotumab vedotin (or TV for short), releases a toxic drug to kill cancer cells from within. Tissue factor (TF) is the main physiological initiator of coagulation and is involved in angiogenesis, cell adhesion, motility and cell survival. It is therefore linked with worse cancer prognosis. Utilizing a cleavable linker technology, the antibody firstly goes looking for the TF receptor, present at high levels on the surface of many cancers cells. Binding to tissue factor draws the drug auristatin E inside cancer cells, where it can kill them by stopping replication.
The researchers found that a significant minority of cancer patients responded to the drug, with their tumors either shrinking or stopping growing. They saw responses in 27% of patients with bladder cancer, 26.5% with cervical cancer, 14% ovarian cancer, 13% with oesophageal, 13% with non-small cell lung and 7% with endometrial cancer (although not in any men with prostate cancer). Responses lasted an average of 5.7 months, and up to 9.5 months in some patients. The main side effects reported from the study were nose bleeds, fatigue, nausea and eye problems – but halfway through the trial the researchers adjusted the protocol to reduce these eye-related effects. The trial initially recruited 27 patients to assess safety and establish the right dose, before expanding to a further 120 patients primarily to look at whether the drug was hitting the right target but also at what effect it had on tumors. The majority of patients in the early trial had advanced stage cancer (spread locally or metastasis) that had already been treated with, and became resistant to, an average of three different types of treatment. Biopsy samples taken at the start of the trial are currently being analyzed for expression of tissue factor on tumor cells to see if it could be used as a marker to select patients most likely to respond to the drug.
The results have been so positive the drug has now moved forward to phase II trials in uterine cancer and will be tested in a range of additional solid tumor cancers. TV is now being trialed in other cancer types including bowel, pancreatic, squamous cell lung and head and neck, as well as in a phase II trial as a second-line treatment for cervical cancer. Professor Johann de Bono, Consultant Medical Oncologist Professor at The Royal Marsden NHS Foundation Trust, said: “What is so exciting about this treatment is that its mechanism of action is completely novel – it acts like a Trojan horse to sneak into cancer cells and kill them from the inside. Our early study shows that it has the potential to treat a large number of different types of cancer, and particularly some of those with very poor survival rates. TV has manageable side effects, and we saw some good responses in the patients in our trial, all of whom had late-stage cancer that had been heavily pre-treated with other drugs and who had run out of other options. We have already begun additional trials of this new drug in different tumor types and as a second-line treatment for cervical cancer, where response rates were particularly high. We are also developing a test to pick out the patients most likely to respond.”
The study had been funded by Genmab and Seattle Genetics and is now published in The Lancet Oncology journal.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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