Transgene, a France-based biotech company, has reported that 1 of its immunotherapy agents, called Pexastimogene Devacirepvec (Pexa-Vec), has failed an interim futility analysis in patients with advanced liver cancer. The phase 3 PHOCUS trial,1 which was being run in partnership with South Korean biotech company SillaJen, has been ordered to stop enrolling patients into the study after the analysis by the Independent Data Monitoring Committee (IDMC) revealed that the study was unlikely to meet its primary objective.

“The first-line treatment of liver cancer is a very difficult indication to treat; the only drug which demonstrates superiority over chemotherapy or no treatment is sorafenib. Patients are refractory to all kinds of therapy,” Maud Brandely, MD, PhD, chief medical officer at Transgene, told Cancer Therapy Advisor.

The study was designed to assess the addition of Pexa-Vec to the current standard of treatment, sorafenib. Patients were randomized into 1 of 2 arms: those who received 3 biweekly intratumoral injections of Pexa-Vec followed by sorafenib, and those who received sorafenib alone. However, the trial was halted after recruitment of just under two-thirds of the 600-patient goal.

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“Many times a drug that’s shown a benefit in a small number of well-selected patients at a single or small number of centers — it does not show the same benefit [across] 200 centers. We have not been able to demonstrate any improved clinical benefit [of Pexa-Vec] so far,” said Dr Brandely.

The trial began recruiting in 2015 after a successful phase 2 trial yielded an overall survival benefit of 14.1 months. These results were released during a period in which sorafenib had few competitors.2

“I think the trial was designed a while ago. At this time, we only had sorafenib, but we now have a number of therapies in development,” said Kit Wong, MD, assistant professor in the department of medicine in the division of oncology at the University of Washington, Seattle.

Pexa-Vec is a modified vaccinia poxvirus, engineered to express granulocyte-macrophage colony-stimulating factor (GM-CSF), as is typical for many oncolytic viral therapies. Additionally, it has the thymidine kinase gene deleted, which theoretically should preferentially target cancer cells with mutated RAS or P53 genes.

So what may have been behind the failure of the phase 3 trial for this indication?

“Hepatocellular carcinoma [HCC] is a very challenging target; there’s been very little progress over the years. Patients are often diagnosed at a very late stage; no matter how great your therapy is, it is always going to be a challenge,” said Jennifer Altomonte, MD, principal investigator at Klinik und Poliklinik für Innere Medizin II, Munich, Germany. “If they’d focused on an easier target, they may have had better success with the therapy — but if it had worked, it would have provided a great benefit to patients,” she added.

“The liver is a very immunosuppressive environment; there are a lot of steps to create an immune response. In HCC, T cells highly express immunosuppressive markers … even though you are presenting all of these antigens, the immune environment and tumor environment suppresses an immune response,” said Dr Wong.