Oncolytic Virus Explored in Advanced HCC

Ghassan Abou-Alfa, MD

The findings from the ongoing phase III PHOCUS trial could demonstrate that sorafenib (Nexavar) plus immunotherapy with the oncolytic virus Pexa-Vec is another effective systemic therapy for patients with hepatocellular carcinoma (HCC), explained Ghassan K. Abou-Alfa, MD.

Sorafenib has been the standard of care for a decade, and additional approved agents in the past few years include lenvatinib (Lenvima), nivolumab (Opdivo), and regorafenib (Stivarga). No systemic therapy had been shown to induce sustained improvement in survival prior to the introduction of sorafenib, which was approved by the FDA in 2007 for the treatment of patients with HCC.

However, the data from the phase III REFLECT trial demonstrated the noninferiority in overall survival (OS) with lenvatinib versus sorafenib, which was the basis for the August 2018 FDA approval of lenvatinib in the frontline setting.

“HCC, at the moment, is an extremely hot subject,” said Abou-Alfa, a medical oncologist at Memorial Sloan Kettering Cancer Center. “This is the best news for the patients before anybody else, because therapy was based on literally 1 drug for almost 20 years. For the past 10 years, we have had sorafenib and we've remained with sorafenib without any change.”

Abou-Alfa is the lead investigator of the PHOCUS trial (NCT02562755), which is evaluating the oncolytic immunotherapy Pexa-Vec (pexastimogene devacirepvec; JX-594) followed by sorafenib in comparison with sorafenib alone. Investigators are currently recruiting and hope to enroll 600 patients with advanced HCC who have not received prior systemic therapy.

The primary endpoint of the study is OS, with secondary endpoints focused on time to progression, progression-free survival (PFS), overall response rate, and disease control rate. Investigators will also assess safety, biomarkers, and quality of life.

Pexa-Vec demonstrated an acceptable safety profile and increased OS with the highest dose in results from a previous phase II dose-escalation trial. Findings from this study, which compared 2 doses of Pexa-Vec, showed a response of 15% by modified RECIST criteria and a response by Choi criteria of 62%. The intrahepatic disease control rate was 50%. Median OS was 14.1 months with the high dose versus 6.7 months with the low dose (HR, 0.39; P = .020).

OncLive: Could you provide an overview of the PHOCUS trial?

How could positive results of this study affect clinical practice?

In an interview with OncLive^®, Abou-Alfa discussed the potential of the oncolytic virus Pexa-Vec and other developments in HCC.Abou-Alfa: It's a phase III trial that is looking at a vaccinia virus-based treatment that has a thymidine kinase, which is altered inside the vaccinia that we inject directly into the tumor. Original work has shown there are quite intriguing and evaluable responses in the tumors. However, it was understood that in combination with sorafenib, it will be better. Thus, the current trial is looking at Pexa-Vec followed by sorafenib and randomized against the standard of care, which is sorafenib. The trial is, thankfully, going all over the world and accruing very well. We very much look forward to seeing what the results will be.I don't like to answer speculative questions. It's hard to say what's going to happen with the study.

What are some other key areas of research in HCC right now?

Pexa-Vec causes, number one, direct tumor destruction; number two, the ability of the vaccinia to transmit from 1 place to another and affect other tumors, and add to this the altered immune mechanism with the activation of the G-CSF; and third, the antiangiogenic component makes it a multitargeted approach to therapy. The fact that we are affecting the tumors directly by injecting them, but [also] the ability to transfect other tumors definitely is intriguing. We'll just have to wait for the results.We have 6 trials that have shown positive results. Of that, we already have drugs approved by the FDA, including lenvatinib in the first-line setting, regorafenib in the second-line setting, and the conditional approval for nivolumab in the second-line setting. At the moment, the immediate action is to await results from the large phase III trial of the checkpoint inhibitors: first-line nivolumab, second-line pembrolizumab (Keytruda), and durvalumab (Imfinzi) plus tremelimumab in the first-line setting.

How do clinicians choose between sorafenib and lenvatinib for patients with advanced HCC?

On top of that, the new intriguing component is the combination of tyrosine kinase inhibitors plus checkpoint inhibitors, particularly in view of the data that intrigued everybody: atezolizumab (Tecentriq) plus bevacizumab (Avastin) [in the phase Ib GO30140 study]. This has yet to be proven and we want to see what it means on a larger scale, but hopefully this is where the science will go.[It is a] hard question, no doubt. On one hand, the experience with sorafenib is going to be rather comforting and people might just say, "I know how to use this drug. I know what to expect from it," and move forward with that. Also, there's an advantage for sorafenib followed by regorafenib because it appears to be that you can expand survival in the combination back-to-back.

On the other hand, with lenvatinib [there is a] rather impressive response rate that we have not seen before, which is by RECIST v1.1 about 25% and by modified RECIST close to 40%. These really are very intriguing numbers. The almost tripling of the PFS compared with sorafenib is also intriguing.

One thing that might also be important is the toxicity profile. Toxicities are rather manageable with hypertension as the most common side effect. This is, of course, something that patients would be more willing to accept because it can be controlled with medication. The hand-foot syndrome has remained something of a challenge with sorafenib and regorafenib.

Heo J, Reid T, Ruo L, et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med. 2013;19(3):329-336. doi: 10.1038/nm.3089.