Since a JX-594 phase 2 single agent trial was underway in advanced HCC patients who had not received prior sorafenib, we were able to follow patient safety and tumor response on standard sorafenib once tumors progressed following JX-594. Three such patients were identified, and all three patients learn more exhibited rapid (2.5 weeks) and marked tumor necrosis (up to 100% of the viable tumor mass) and responses on sorafenib. Of note, sorafenib alone has not been described to induce necrotic Choi or mRECIST responses to date, although modest necrosis induction has been described in a minority of patients.16 Finally, 15 consecutive HCC historical and concurrent control patients on sorafenib alone at the same institutions were retrospectively assessed, and no Choi or mRECIST responses were noted (0 of 15).

A fourth JX-594-treated patient (metastatic, poor prognosis RCC) from a separate phase 1 trial was treated with a similar small molecule angiogenesis inhibitor (sunitinib); this patient had a durable complete response lasting over 4 years (still on-going). JX-594 is expected to be cleared within weeks and dramatic responses in injected tumors long after completion of JX-594 therapy have not been observed to date. Therefore based on the data presented here, we hypothesize that JX-594 therapy may sensitize HCC tumors to sorafenib and potentially other VEGFR inhibitors (i.e., a therapeutic class effect). A randomized controlled trial of sorafenib alone versus JX-594 followed by sorafenib is required to validate this hypothesis. Additional nonclinical and clinical studies should be performed to confirm these findings.

Only three patients were evaluated in this study; it is not yet clear whether these patients are representative of the HCC population at large. In addition, while mRECIST and Choi responses have not been reported with sorafenib alone, it is possible that on future study sorafenib responses will be demonstrated. A phase 2 trial of JX-594 followed by sorafenib has been initiated in patients with advanced HCC. JX-594 treatment is followed by standard sorafenib initiated 1 week after the final JX-594 injection. Promising interim safety and efficacy data has been reported.19 Of note, objective tumor responses have been reported for patients who have documented resistance to, and tumor progression on, sorafenib monotherapy.

A prospective randomized trial will be required to confirm that JX-594 followed by sorafenib leads to superior response rate and survival duration compared Dacomitinib to either agent alone in HCC patients; planning for such a trial is underway. In addition, if the ability of JX-594 to resensitize sorafenib-refractory tumors to sorafenib is confirmed, a randomized trial of JX-594 followed by sorafenib versus best supportive care may be indicated in this patient population. Similar trials can be envisioned with other inhibitors of the VEGFR pathway in development.