icon-folder.gif   Conference Reports for NATAP  
  62th Annual Meeting of the American Association for the Study of Liver Diseases San Francisco 2011 Nov 6-9 Back grey_arrow_rt.gif
Liver Cancer Therapy Positive in Early Trials
  By Charles Bankhead, Staff WriterMedPage Today
Published: November 14, 2011

SAN FRANCISCO -- Patients with advanced hepatocellular carcinoma (HCC) appeared to gain a survival benefit when treated with the higher of two doses of an investigational oncolytic virus, results of a small, phase II trial showed.

Treatment with the higher dose of JX-594 was associated with a median overall survival of 13.8 months as compared with 6.7 months in patients who received a lower dose.

Action Points

· Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

· Explain that the high dose of an investigational poxvirus significantly prolonged overall survival in patients with heavily pretreated hepatocellular carcinoma compared to a lower dose.

· Note that the mechanism of action of this agent is twofold: Targeted direct oncolysis and granulocyte stimulating factor expression, which, in turn, causes anti-tumor immunity and tumor "vascular shutdown."

Subgroup analysis showed a consistent survival benefit in patients who had prior exposure to chemotherapy for HCC and in patients who had multiple tumors.

The findings have provided impetus for larger phase IIb and phase III randomized clinical trials, as reported here at the American Association for the Study of Liver Diseases.

"This is the first demonstration of a benefit in survival with gene or virotherapy in cancer," said Tony Reid, MD, PhD, of the University of California San Diego.

"The safety of JX-594 has been documented in studies of intravenous and intratumoral administration involving more than 120 patients," he added.

JX-594 is the first member of a new class of targeted oncolytic poxvirus. The agent causes tumor necrosis via selective oncolysis and induction of granulocyte macrophage-colony stimulating factor, resulting in "vascular shutdown" and tumoral anti-immunity, said Reid.

Preliminary clinical studies of the poxvirus demonstrated replication, transgene expression, and evidence of response in patients with advanced liver cancer treated with intravenous or intratumoral administration (Lancet Oncol 2008; 9: 533-542, Nature 2011; 477: 99-102).

Reid presented findings from a randomized trial involving 30 patients with heavily pretreated advanced HCC. The patients were randomized to one of two doses of JX-594: 1 x 109 plaque forming units (pfu) or 1 x 108 pfu. The poxvirus was administered via three intratumoral injections separated by two-week intervals.

Patients randomized to the higher dose had received an average of 4.7 prior therapeutic interventions, and patients in the low-dose arm had received an average of 2.2 prior interventions. Prior treatment included systemic therapy in 38% of the high-dose group and 7% of the low-dose group.

A majority of patients in both groups had virus-related liver cancer. About half of the patients had four or more visible tumors.

Overall, 54% of patients had evidence of a necrotic response by modified Choi criteria at eight weeks, and the proportion of responding patients did not differ significantly between the high- and low-dose groups. Reid said that 52% of the patients had stable disease at eight weeks.

The twofold increase in overall survival in the high-dose arm reached statistical significance (P=0.029). Patients with a history of prior systemic therapy had a median overall survival of 13.8 months in the high-dose arm versus an expected three months from historical data, said Reid. Patients with multiple tumors had a median overall survival of 13.5 months with the higher dose of JX-594 versus 4.3 months with the lower dose (P=0.019).

Adverse events that occurred in at least 30% of patients consisted of fever, chills, injection-site pain, vomiting, nausea, abdominal pain, headache, anorexia, and fatigue. Few events reached grade 3 severity, and no grade 4-5 adverse events occurred.

The phase IIb trial of JX-594 has already begun. Reid said the phase IIb trial has an accrual target of 120 patients with advanced HCC that is refractory to sorafenib (Nexavar). The patients will be randomized 2:1 to JX-594 plus best supportive care (BSC) or to BSC alone.

The phase III trial will evaluate JX-594 as first-line therapy for patients with advanced HCC, comparing the oncolytic virus to standard of care.

Both studies have a primary endpoint of overall survival.

Reid had no relevant disclosures.

Primary source: American Association for the Study of Liver Diseases

Source reference:

Heo J, et al "A randomized, controlled phase II trial of JX-594, a targeted, multimechanistic oncolytic poxvirus, in patients with advanced hepatocellular carcinoma, final results" AASLD 2011; Abstract LB-1.