AACR-NCI-EORTC: Sunitinib Shows Early Promise in Liver Cancer

SAN FRANCISCO, Oct. 26 -- Sunitinib (Sutent) appears to be effective in advanced hepatocellular cancer, according to a small study.A preliminary analysis showed antitumor activity, including an average 39% decrease in tumor blood vessel permeability after two weeks of sunitinib therapy, Andrew X. Zhu, M.D., Ph.D., of Massachusetts General Hospital Cancer Center and Harvard, and colleagues, reported here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.
Although it is too early to say whether the findings are relevant to inhibition of the tumor itself, Dr. Zhu called them "very, very encouraging."
"We know that hepatocellular carcinoma is very vascular," Dr. Zhu said. "We have actually postulated that antiangiogenesis may be a very important strategy to inhibit the cancer growth in this type of malignancy."
Hepatocellular cancer has been associated in previous studies with increased levels of angiogenic factors, which sunitinib is designed to block.
Sunitinib is FDA approved only for treatment of advanced renal cell carcinoma and gastrointestinal stromal tumor, and a similar receptor tyrosine kinase inhibitor, sorafenib (Nexavar), is under review by the FDA for treatment of hepatocellular carcinoma after demonstrating improved survival in clinical trials.
So, the researchers evaluated efficacy, toxicity, and angiogenic parameter changes with sunitinib among 31 patients with unresectable or metastatic measurable hepatocellular carcinoma who had undergone no more than one prior chemotherapy regimen and had adequate organ function.
Participants in the phase II study received sunitinib at 37.5 mg a day for four weeks followed by a standard six-week cycle regimen. They were evaluated with dynamic contrast-enhanced MRI and multiplex protein array.
After an average follow-up of 15 months from enrollment, the average progression-free survival was four months. This is "in the same neighborhood" as the 4.5-month median progression-free survival seen in the trial of sorafenib for hepatocellular carcinoma, Dr. Zhu said.
Cancer stabilized in 10 patients for at least three months, and one patient had a partial response.
There were also preliminary signs of antiangiogenic activity in the subset of patients who were evaluated for these endpoints.
Vascular endothelial growth factor (VEGF) levels had increased in 14 of 18 patients on day 15. Levels of placental growth factor (PIGF) increased in all 18 patients.
However, the basic fibroblast growth factors were decreased in 11 patients on day 15. VEGFR2 was also decreased in 14 of 15 patients. Viable circulating progenitor cells evaluated by flow cytometry in fresh whole blood samples were also decreased (P<0.01), which "may affect angiogenesis more profoundly," Dr. Zhu said.
"The key for us is determining whether any of the changes are relevant to the antiangiogenesis pathway," he said.
The treatment was generally well tolerated, he added, with less than 20% of patients experiencing grade 3 toxicity in any category. These included 16% leukopenia, 16% lymphopenia, 10% fatigue, 19% elevated aspartate transaminase (AST), 6% elevated alanine transaminase (ALT), 6% skin rash, 6% hand-foot syndrome, and 6% thrombocytopenia.
The only grade 4 toxicity was thrombocytopenia in 6% of patients.
"Sunitinib administered in the current dose schedule can be safely given with close monitoring in the majority of hepatocellular carcinoma patients," the researchers said.
"Sunitinib clearly is modifying the disease in this specific patient population," Dr. Zhu concluded. But, he noted, "whether this drug will eventually prove to be effective in hepatocellular carcinoma clearly requires rigorous testing in future large studies."
The study was funded by Pfizer, manufacturer of sunitinib. Dr. Zhu reported no relevant conflicts of interest. Primary source: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics
Source reference: Zhu AX, et al "Efficacy, safety, and changes in angiogenic markers following sunitinib monotherapy in patients with advanced hepatocellular carcinoma: Experience from a phase II study" AACR-NCI-EORTC meeting 2007; Abstract PR7.