Transgene’s partner in the trial, SillaJen, said that the administration of various anticancer therapies to nonresponding patients — used in the salvage setting — could have skewed the trial results.3

“The end point was overall survival — I think it’s possible the trial failed because patients moved onto second-line therapies. It will be interesting to see what second-line therapies the patients received and whether this might have affected the outcomes,” said Dr Wong.

The Korea Biomedical Review article reported that 63 of 203 patients on the Pexa-Vec and sorafenib regimen received rescue or salvage therapies, compared with 76 out of 190 in the control arm.

“I think we should be very conscious that the SillaJen communication is their analysis of the trial. We are in the process of determining this. That is their data but not our analysis,” said Dr Brandely, announcing that Transgene expects to release more details of their analysis later in September 2019.

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Relatively few oncolytic viral therapies have made it to phase 3 trials, so it is difficult to say whether this termination is an unusual occurrence with oncolytic viral therapies — but it is not rare for companies to terminate phase 3 trials early when interim analyses show uninspiring results.

“A lot of time when early studies show positivity, phase 3 [trials] do fail. It will be very critical for the investigators to go back to the data and look at immune profiles; biomarkers for response or resistance,” said Dr Wong.

Immunotherapies also pose a unique challenge for preclinical testing in animal models as even mice, which are commonly used, have key difference from humans.

“The immune system of rodents is much stronger than ours — small animals tolerate much more therapy — it’s a general problem with preclinical models for testing immunotherapies. Everybody has the same problem; our preclinical models are not always predictive [of] what will happen in patients,” said Dr Altomonte.

Pexa-Vec displayed promising phase 2 trial results, but in a reasonably low number of patients. Perhaps a little hasty to move on to phase 3?

“We have very convincing phase 2 data showing high vs low dose of Pexa-Vec was very beneficial, and[it was] legitimate to go and start the phase 2 trial. When we started the trial, there was no competition. When we started the trial, it was the right decision. I think it was sound to move from phase 2 to phase 3,” said Dr Brandeley.

“It might just be the wrong indication for this virus — maybe it will work very well for something else. It is difficult to figure this out at this stage,” said Dr Altomonte.

Combining immune checkpoint inhibitors with oncolytic viral therapies is a very hot topic of research currently, with several trials investigating this in multiple indications, Pexa-Vec itself is also currently involved in a clinical trial with immune checkpoint inhibitor nivolumab4 and in early August 2019, SillaJen announced new trials for people with a variety of primary cancers that have metastasized to the liver.5

“Cancer immunity is so complex, [there is] not just 1 component — in the cancer immunity cycle, you have to release antigens, present them properly, activate and prime T cells, [and] T cells have to infiltrate the tumor. There are multiple steps here — this is why people are looking more and more at combination therapies, [as] targeting [just] 1 step in this pathway will perhaps not be very helpful,” said Dr Wong.

Advanced HCC is essentially incurable, with most patients surviving for less than a year, even with treatment. And, nivolumab is only associated with a 20% objective response rate.6

“I think combination treatment will be very key here; even PD-1 inhibitors alone don’t have great responses in liver cancer, but combinations are the next thing that people are looking at. Pexa-Vec itself appears to be well tolerated, so it will be interesting to see how it fares when combined with other immunotherapies,” said Dr Wong.

“Testing it in other indications makes sense; they’ve developed it such a long way, they are pretty confident it does something. I think, to be honest, everything is going to be a combination therapy,” said Dr Altomonte.

References

  1. ClinicalTrials.gov. Hepatocellular Carcinoma Study Comparing Vaccinia Virus Based Immunotherapy Plus Sorafenib vs Sorafenib Alone (PHOCUS). NCT02562755. Accessed September 10, 2019.
  2. Heo J, Reid T, Ruo L. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med. 2013;19(3):329-336.
  3. Taylor, P. Pharmaphorum. Sillajen explains Pexa-Vec trial failure – it was the rescue meds. Published August 6, 2019. Accessed September 10, 2019.
  4. ClinicalTrials.gov. A Trial to Evaluate the Safety and Efficacy of the Combination of the Oncolytic Immunotherapy Pexa-Vec With the PD-1 Receptor Blocking Antibody Nivolumab in the First-line Treatment of Advanced Hepatocellular Carcinoma (HCC). NCT03071094. Accessed September 10, 2019.
  5. Sae-im J. Korea Biomedical Review. SillaJen remains confident about Pexa-Vec’s value, despite trial failure. Updated August 5, 2019. Accessed September 10, 2019.
  6. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492-2502.