For the first time in a late stage trial, a virus-based cancer drug is showing some promising early results. The news that Amgen’s melanoma drug talimogene laherparepvec (TVEC) has met the primary goal of a Phase 3 trial may revive interest in what has proved to be a rather elusive drug technology.
The company reports that 16% of the patients who received TVEC experienced tumor shrinkage that persisted for six months compared with only 2% in a control group that received a treatment based on GM-CSF, a protein that stimulates the immune system.
This statistically significant difference in “durable response rate (DRR), defined as the rate of complete or partial response lasting continuously for at least six months”, means the trial has met its primary endpoint, says the company in a statement released to the press this week.
Results on whether the drug improves overall survival, a key secondary endpoint of the trial, are expected later this year, says Amgen.
According to the New York Times, a spokeswoman for the drug company says it is too early to say if they are going to file for regulatory approval based on these trial results.
Antoni Ribas, a melanoma specialist at the University of California, Los Angeles, told the newspaper that 16% is not that high and the treatment the new drug was compared to would not typically be used to treat melanoma.
Another reason TVEC might not be that successful as a melanoma drug, says Ribas, is that it has to be injected directly into tumors, and only one third of patients with advanced melanomas have tumors on or near the skin, where they can be injected, whereas in the majority of patients the tumors have spread to more inaccessible places like the brain or the liver.
Melanoma is by far the most aggressive and most serious type of skin cancer, of which there are several.
Although fewer than 5% of skin cancers are melanoma, it accounts for the vast majority of skin cancer deaths.
Since the early 1970s, malignant melanoma incidence has increased significantly, for example an average 4% every year in the United States.
According to the World Health Organization (WHO), a large body of evidence suggests the risk of malignant melanoma ties with genetic and personal characteristics, and a person’s UV exposure behaviour.
TVEC is based on an oncolytic virus. Oncolytic viruses target and kill tumor cells while leaving healthy cells intact.
Once the virus gains entry to the host cancer cell it takes over the cell machinery so it makes copies of the virus. Eventually, there are so many virus copies the cell bursts open, releasing them to infect other cells and causing the “anti-cancer” infection to spread.
Researchers first became interested in the treatment potential of oncolytic viruses nearly two decades ago.
But what looks promising on the lab bench is proving difficult to translate into clinical success, for several reasons. One problem is getting the oncolytic virus to enter deep tumors and penetrate enough cancer cells to be effective, without having repeatedly to inject huge quantities into the patient.
TVEC is designed to attack melanoma from two angles: by directly destroying tumor cells, and by stimulating the immune system to do the same.
The oncolytic virus TVEC is based on is herpes simplex, the type that causes cold sores. The virus has been genetically modified to infect only cancer cells and leave healthy ones intact.
TVEC has also been genetically modified to carry a gene for GM-CSF, a protein that stimulates the growth of white blood cells in the immune system.
To be effective, TVEC has to be injected directly into tumors.
The trial was a global, randomized, open-label, Phase 3 trial designed to test the safety and efficacy of TVEC compared to a control therapy in over 400 patients with unresected stage IIIB, IIIC or IV melanoma.
The control therapy was treatment with GM-CSF.
The patients were randomly assigned 2:1 to receive either TVEC, injected directly into lesions every two weeks, or GM-CSF injected into the skin, for the first 14 days of each 28 day cycle.
Treatment could take up to 18 months.
Amgen says additional information about trial results will be submitted at the 2013 Annual Meeting of ASCO (American Society of Clinical Oncology), which takes place in Chicago May 31 to June 4.
In a recent online issue of the Journal of Virology, researchers report that a modified Newcastle disease virus has the potential to kill prostate cancer cells while leaving normal cells intact. They say the modified virus is ready for preclinical tests on animals, and possibly phase I human trials.
Written by Catharine Paddock PhD