Patients with cervical cancer don't have many options. Merck's Keytruda became one of them in 2018, but the checkpoint inhibitor only works in patients whose tumors express PD-L1, and, even then, the FDA greenlighted the drug on the strength of just a 14% response rate. Enter Seattle Genetics and Genmab's antibody-drug conjugate (ADC) tisotumab vedotin, which shrank tumors in one-quarter of patients with advanced cervical cancer and stopped tumor growth in half of them.
The results, unveiled Monday at the virtual meeting of the European Society for Medical Oncology, tee up an FDA filing for the treatment, which could help patients whose disease has worsened despite receiving other treatment and who have run out of options.
The phase 2 data come from 101 patients whose cancer had come back or spread to other places in the body after first-line therapy. Nearly all the patients had metastases outside the pelvic region (94%), and more than half had received the chemo drug cisplatin and radiation. Another 63% had been treated with doublet chemotherapy and Roche’s blockbuster Avastin.
Tisotumab vedotin shrank tumors to some degree in 79% of the patients, reducing tumor size enough in 24% of patients for them to be considered responders. It kept patients alive for a median of 12.1 months and staved off cancer a median of 4.2 months. Patients’ responses lasted a median of 8.3 months.
“Some patients haven’t even reached the median duration of response. It’s something that we are very proud of,” Clay Siegall, CEO of Seattle Genetics, said.
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The trial, called InnovaTV 204, was a single-arm study, so there is no direct comparator for the data, but a look at historical cases shows survival rates to be “considerably shorter” that the performance Seattle Genetics’ drug put up.
“Based on historical comparisons, a median overall survival of 12.1 months is very satisfying,” Siegall said. The company, along with Genmab, plans to seek accelerated approval for the treatment.
“There are not a lot of good therapies for these patients. They can get chemotherapy, but the response rate is pretty low, often in the 10, 12, 14% range,” Siegall said. “It’s a disease that has a bad prognosis—two-year survival is low and there aren’t a lot of alternatives. It’s a very different thing than we were looking at with Adcetris,” he added, referring to the blood cancer ADC that became Seattle Genetics' first approved drug.
The partners tested tisotumab vedotin as a single agent to see whether it could make a dent in this hard-to-treat patient group, but they eventually want to combine it with other cancer meds to see if they can do even better. A key factor for those combinations will be the treatment’s safety.
Most of the drug’s side effects were mild, with 38% of patients experiencing alopecia, or hair loss; 30% getting nose bleeds; and 27% feeling nausea. One patient died from septic shock, which the investigators deemed related to the treatment.
Some patients also reported eye-related side effects, with 26% developing conjunctivitis, 23% getting dry eye and 11% experiencing keratitis, or inflammation of the cornea. Investigators had flagged these concerns in a phase 1 study, and Seattle Genetics was prepared this time around.
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“Working with ophthalmologists and oncologists, we devised a simple plan for this trial which used prophylactic steroid eye drops and some cold compresses on the eye ahead of therapy. Eye toxicities were greatly ameliorated,” Siegall said. “We think it is no longer a limiting factor to trying to get this approved.”
Beyond cervical cancer, the partners are testing tisotumab vedotin in ovarian cancer and an undisclosed group of “other solid tumors.” The treatment’s drug component is the same one used in Adcetris and the company’s new bladder cancer med Padcev, which disrupts the microtubule infrastructure—commonly called the railways of the cell and used for moving organelles around as well as to support the cell and give it shape. The antibody piece, tisotumab, targets tissue factor, a protein abundant in cervical cancer and other solid tumors.