Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE)

Abstract

Pexastimogene devacirepvec (Pexa-Vec) is a vaccinia virus-based oncolytic immunotherapy designed to preferentially replicate in and destroy tumor cells while stimulating anti-tumor immunity by expressing GM-CSF. An earlier randomized Phase IIa trial in predominantly sorafenib-naïve hepatocellular carcinoma (HCC) demonstrated an overall survival (OS) benefit. This randomized, open-label Phase IIb trial investigated whether Pexa-Vec plus Best Supportive Care (BSC) improved OS over BSC alone in HCC patients who failed sorafenib therapy (TRAVERSE). 129 patients were randomly assigned 2:1 to Pexa-Vec plus BSC vs. BSC alone. Pexa-Vec was given as a single intravenous (IV) infusion followed by up to 5 IT injections. The primary endpoint was OS. Secondary endpoints included overall response rate (RR), time to progression (TTP) and safety. A high drop-out rate in the control arm (63%) confounded assessment of response-based endpoints. Median OS (ITT) for Pexa-Vec plus BSC vs. BSC alone was 4.2 and 4.4 months, respectively (HR, 1.19, 95% CI: 0.78-1.80; p = .428). There was no difference between the two treatment arms in RR or TTP. Pexa-Vec was generally well-tolerated. The most frequent Grade 3 included pyrexia (8%) and hypotension (8%). Induction of immune responses to vaccinia antigens and HCC associated antigens were observed. Despite a tolerable safety profile and induction of T cell responses, Pexa-Vec did not improve OS as second-line therapy after sorafenib failure. The true potential of oncolytic viruses may lie in the treatment of patients with earlier disease stages which should be addressed in future studies. ClinicalTrials.gov: NCT01387555 ARTICLE HISTORY

mRECIST for HCC: Performance and novel refinements

“…48,49 In a phase II study of 104 patients who received pembrolizumab monotherapy in second line after sorafenib, the use of immune-related RECIST (irRE-CIST) did not affect response rate or time to response compared to mRECIST; however median PFS was 7.0 months (95% CI 4.9-8.0) when assessed by irRECIST vs. 3.2 months (95% CI 2.2-4.1) when registered according to mRECIST. 49 In a recent phase IIb study 70 investigating a vaccinia virus-based oncolytic immunotherapy -pexastimogene devacirepvec -in advanced HCC, changes to mRECIST were implemented because the tested treatment induces a flare response with swelling and oedema. 71 These changes included the concept of confirmation at 4 weeks, either based on a further increase in size or additional signs of progression such as the emergence of new lesions.…”

“…71 These changes included the concept of confirmation at 4 weeks, either based on a further increase in size or additional signs of progression such as the emergence of new lesions. 70 Overall, in order to address assessment of response to checkpoint inhibitors or immunotherapies in HCC, we recommend evaluation by CT/ MRI at 8-12 weeks after treatment, as opposed to the classic 6-8 weeks for tyrosine kinase inhibi-…”

Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer

“…Oncolytic viruses selectively infect and lyse tumor cells, triggering an immunological response to TAA. GM-CSF production from infected tumor cells has been suggested as an additional immunostimulatory mechanism [ 151 , 152 ]. Initially encouraging reports in predominantly sorafenib-naïve HCC patients suggested a significantly improved OS for the application of the oncolytic pox virus vaccine JX-594.…”

“…However, a subsequent randomized multicenter Phase IIb trial failed to show a difference in OS for JX-594 as a second-line HCC therapy after sorafenib failure. In JX-594-treated patients, a T cell response against vaccinia, β-galactosidase and TAA was noted, however, without improving patient survival [ 151 ]. Hypothesizing that vaccinia virus-based immunotherapy-mediated immune activation may resolve the immunosuppressive TME and pave the way for a sorafenib response, the PHOCUS phase III trial (NCT02562755) investigated sorafenib versus vaccinia virus-based immunotherapy and subsequent sorafenib application [ 154 ].…”

Immunotherapy for Hepatocellular Carcinoma: A 2021 Update

“…The most common adverse reaction was flu-like syndrome with fever, rigor, and vomiting, which occurred in all patients within the first few days after treatment in a dose-dependent manner [ 98 ]. However, in patients who had been previously treated with sorafenib (NCT01387555), the median OS was not significantly different in patients treated with JX-594, 4.2 months, compared to best supportive care, 4.4 months, [HR 1.19 (95% CI: 0.78–1.80); p = 0.428) [ 99 ]. Currently, a phase III study (NCT02562755) is ongoing comparing JX-594, followed by sorafenib versus sorafenib alone [ 124 ].…”