Background: Pexa-Vec is a vaccinia virus engineered to express granulocyte-macrophage colony stimulating factor (GM-CSF), thereby stimulating direct oncolysis, tumor vascular disruption and anti-tumor immunity (Nat Rev Cancer 2009). Pexa-Vec was shown to replicate in metastatic tumors following intratumoral (IT) or intravenous (IV) administration (Lancet Oncol 2008; Nature 2011). Preclinical and clinical data suggest that Pexa-Vec-induced acute vascular disruption sensitizes tumors to anti-angiogenic effects of sorafenib (Mol Ther 2011). Methods: Treatment-refractory HCC patients received Pexa-Vec for 3 weeks (Day 1 IV, Day 8 IT and Day 22 IT) followed by sorafenib at Day 25. The primary objective of the study was to determine the safety of Pexa-Vec followed by sorafenib. Secondary objectives include disease control rate based on mRECIST and Choi (hypodensity) response criteria after Pexa-Vec only (Day 25) and after sorafenib initiation (Week 6 and 12). Optional assessments included response by positron-emission tomography (PET). Data summarized prior to database lock. Results: Enrollment is completed: 25 patients of which 20 were refractory to sorafenib. The treatment regimen was well-tolerated. Transient flu-like symptoms, including fever (n=23; 92%), chills (n=19; 76%), headache and nausea (n=10; 40%), abdominal pain and lymphopenia (n=10; 40%) were the most common adverse events following Pexa-Vec. Sorafenib toxicities were consistent with the expected profile. After Pexa-Vec alone the Choi tumor response rate was 47%. Following subsequent sorafenib therapy, 75% had Choi responses, including 81% of sorafenib-failure patients. The mRECIST disease control rate was 62% with Pexa-Vec alone and 59% following initiation of sorafenib. Two of 4 patients evaluable for PET response exhibited decreased PET signal after Pexa-Vec. Conclusions: Pexa-Vec was well-tolerated and associated with Choi tumor responses and disease control in patients with advanced HCC. Subsequent sorafenib was well-tolerated and associated with Choi responses. Further trials of Pexa-Vec in HCC patients are warranted.
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