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.

Keywords: Hepatocellular carcinoma; Pexa-Vec; oncolytic immunotherapy; oncolytic vaccinia; sorafenib.

Figure 1.

CONSORT diagram of sorafenib-pretreated patients with advanced hepatocellular carcinoma in the TRAVERSE study.

Figure 2.

Kaplan-Meier estimates overall survival (OS). OS was computed on all randomized patients. Those patients who had not died or were lost to follow-up at the time of database lock were censored on the last date on which they were known to be alive.

Figure 3.

Overall survival in selected subsets. Hep B, hepatitis B; Hep C, hepatitis C; EtOH, alcohol, NASH, non-alcoholic steatohepatitis; HR, hazard ratio; LCL lower control limit; UCL, upper control limit.

Figure 4.

Patient 211–001 exhibited a response to Pexa-Vec treatment in the injected tumor as demonstrated by CT scans of this patient before (baseline), during (intervention) and 23 weeks after treatment showing a strong reduction in the extent of the tumor at week 23.

Figure 5.

ELISPOT analysis of immune response to vaccinia, β-galactosidase and tumor antigens before (pre-dose) and 6 weeks after treatment (post-dose). Detection of T-cells specific for (a) vaccinia and (c) β-galactosidase peptides for all evaluable patients treated with Pexa-Vec (23 patients for vaccinia [A] and 22 patients for β-galactosidase [C]) and for 10 patients in the control arm (b = vaccinia and d = β-galactosidase peptides) is shown. The y axis represents the SFC/2x10E05 of the sample normalized by subtracting the respective negative pool (NC). The grey diamonds represent the 95% confidence interval. The data points depicted with an x indicate that one of the replicate values for either the sample or the respective negative pool was missing. (e) Detection of T-cells specific for tumor-associated antigen peptides for two patients with detectable responses against MAGE-A1 and MAGE-A3, respectively. Detection of T-cells specific for HCV peptides in HCV positive patients (Supplementary Figure).