[PD Test]Oncolytic immunotherapy promising in sorafenib-refractory HCC

Asian patients with advanced hepatocellular carcinoma (HCC) refractory to sorafenib may benefit from an investigational oncolytic immunotherapy known as JX-594, as it showed antitumor activity in a recent phase II trial.

“JX-594 consists of a vaccinia virus backbone engineered to target solid tumors both systemically and locally. It is armed with the granulocyte-macrophage colony-stimulating factor [GM-CSF] gene for induction of immune attack on cancer, and the Lac-Z gene for monitoring,” said Dr. Jeong Heo of the Pusan National University School of Medicine, Pusan, Korea, at the Asian Pacific Association for the Study of the Liver (APASL) Liver Week 2013 held recently in Singapore.

JX-594 has a novel multi-pronged mechanism of action. It works by direct infection and destruction of cancer cells, immune-mediated killing, and tumor vascular shutdown that occurs within 5 days of treatment. [Nat Rev Cancer 2009;9:64-71; Sci Transl Med 2013;5:185ra63; Cancer Res 2013;73:1265-1275]

In a phase II trial of 25 Korean patients with advanced HCC (sorafenib failure, n=20; sorafenib naïve, n=5), JX-594 demonstrated anti-tumor activity with similar response rates in both sorafenib-refractory and sorafenib-naïve patients. [International Liver Cancer Association Annual Meeting 2012; abstract 2012-1304]

“Patients in the trial were first treated with an intravenous [IV] dose of JX-594, followed by intra-tumoral [IT] doses of JX-594 at weeks 1 and 3, and sorafenib from week 4,” said Heo. “Most patients were heavily pretreated and had extensive tumor burden at baseline.”

Response rate (RR) was 47 percent for JX-594 (IV followed by IT), increasing to 75 percent when this was followed by sorafenib. Disease control rate (DCR) was 62 and 59 percent, respectively, for the two regimens.

“For patients failing sorafenib, RR was 43 percent for IV/IT JX-594 and 80 percent for IV/IT JX-594 followed by sorafenib. DCR was 65 and 59 percent, respectively,” Heo reported.

Median survival was 9.1 months for all evaluable patients and 17.3 months for sorafenib-naïve patients.

“JX-594 was well tolerated, with flu-like symptoms being the most common adverse effects,” said Heo. “Toxicities of sorafenib were consistent with previous reports.”

More recently, Heo and colleagues conducted a phase II trial to determine the optimal dose of JX-594, given by IT injection in up to 5 nodules, in 30 patients with heavily-pretreated advanced HCC (sorafenib naïve, 80 percent). [Nat Med 2013;19:329-336]

“DCR at week 8 was the same for high-dose and low-dose JX-594 [47 and 46 percent],” he noted. “RR and DCR were equivalent at injected and distant non-injected tumors at both doses.”

However, survival was significantly related to dose (median, 14.1 months for high dose vs 6.7 months for low dose; hazard ratio, 0.39; p=0.020).

“A phase IIb trial is ongoing to investigate the effect of JX-594 in HCC patients failing sorafenib,” he said.