The latest findings from both the STORM and HeiLivCa trials were conclusive that the multikinase inhibitor sorafenib—the current standard of care for treatment of patients with inoperable advanced liver cancer—does not increase recurrence-free survival in hepatocellular carcinoma (HCC) in the adjuvant setting, according to reports presented at the International Liver Cancer Association (ILCA) 2014 Annual Conference.
“Negative outcomes like these need to be presented,” ILCA President Peter R. Galle, MD, PhD, Professor of Medicine and Director of the First Department of Internal Medicine at University of Mainz, noted in an email after the meeting. “Both studies were well-performed, sufficiently large, and clearly negative—thus, sorafenib for adjuvant therapy and as a bridge for those on the transplant list won't play a role.”
The latest data from the STORM trial, presented during the plenary session at the ILCA meeting as well as at the 2014 American Society of Clinical Oncology Annual Meeting, showed that sorafenib does not improve recurrence-free survival for patients with hepatocellular carcinoma in the adjuvant setting (ASCO Abstract 4006).
“Sorafenib is the sole drug approved for management of advanced HCC cases,” study author Josep M. Llovet, MD, said in an email. Llovet is Professor of Research at Institució Catalana de Recerca i Estudis Avançats of the Barcelona Clinic Liver Cancer Group of the Liver Unit at IDIBAPS-Hospital Clínic, University of Barcelona, and Professor of Medicine and Director of the Liver Cancer Program at Icahn School of Medicine at Mount Sinai. “We estimated that it would be a potentially effective treatment in cases of dissemination after resection.”
The trial included 1,114 patients who had surgical resection or local ablation with curative intent and had an intermediate or high recurrence risk—with Child-Pugh scores of five to seven, ECOG PS 0, and no residual disease (confirmed by CT or MRI testing). The patients were randomized to receive oral sorafenib (400 mg, twice daily) or placebo.
The data showed no differences in recurrence-free survival, time to recurrence, or overall survival for the two groups. Patients receiving sorafenib had a shorter median treatment duration (12.5 vs. 22.2 months) and lower mean daily dose (578 mg vs. 778 mg). And discontinuation rates with sorafenib were higher due to treatment-emergent adverse events—24 percent of patients taking sorafenib compared with seven percent of the patients receiving the placebo.
The most common grade 3-4 adverse events for patients receiving sorafenib were hand-foot skin reactions (28%), hypertension (7%), and diarrhea (6%).
“The fact that the final results are negative represents a halt in the development of agents in this setting,” Llovet said—noting that it will now likely be several years before a new agent is approved for the indication. “This is an unmet need.”
Also presented during the meeting's plenary session were the latest data from the HeiLivCa trial. That data showed no statistically significant difference in time to progression of disease for patients treated with transarterial chemoembolization (TACE) plus sorafenib compared with patients treated with TACE plus placebo after neo-adjuvant treatment before liver transplant; and the safety profile of the patients receiving sorafenib was slightly inferior to that of the placebo group.
“Time to progression was similar after neoadjuvant treatment with TACE and sorafenib before liver transplant compared with treatment with TACE and placebo,” the study's lead author, Katrin Hoffmann, MD, Attending Surgeon in the Department of General and Transplantation Surgery at Ruprecht-Karls-University in Heidelberg, Germany, said via email. “And tumor response, progression-free survival, and time to liver transplantation were comparable. This trial gives no evidence on the indication of sorafenib for HCC before liver transplantation.”
The trial included 50 patients with hepatocellular carcinoma from four centers in Germany, who were awaiting liver transplantation. The patients were randomly assigned to receive TACE plus either sorafenib (2 × 200 mg) twice a day or placebo (given continuously). TACE was scheduled every four to six weeks and continued until complete de-vascularization or until transplant.
The median time of treatment was 124.5 days for patients in the sorafenib group and 171 days for those in the placebo group. Five patients in the sorafenib group underwent liver transplant as did 12 patients in the placebo group.
The data showed that 14 patients in the study developed tumor progression—seven had received treatment with sorafenib and seven had received the placebo, with time to progression similar for both groups. The results of tumor response, progression-free survival, and time to liver transplant were also similar in both treatment groups.
The incidence of adverse events were similar for both groups, occurring in 23 of the 26 patients in the placebo group (92%) compared with 23 of 24 in the sorafenib group (96%). Four patients in the placebo group (16%) and 12 in the sorafenib group (50%) had severe treatment-related adverse events. And eight patients (6 in the sorafenib group, 2 in the placebo group) had dose reductions or temporarily discontinued treatment due to treatment-related adverse events; and seven patients (6 receiving sorafenib, 1 receiving placebo) discontinued the study because of treatment-related adverse events.
The most frequent, treatment-related adverse events, Hoffmann noted, were thrombocytopenia, diarrhea, and hand-foot-skin reactions.
Sorafenib Not the HCC ‘Wonder Drug’
Asked for his perspective for this article, Robert J. Mayer, MD, Faculty Vice President for Academic Affairs at Dana Farber Cancer Institute, Faculty Associate Dean for Admissions and Stephen B. Kay Family Professor of Medicine at Harvard Medical School, said that the findings from these studies do not close the door for sorafenib—“but I would say it is not the wonder drug that is going to reverse all the horrors and difficulties of hepatocellular cancer, and we need to continue looking for better and more effective therapies.”
Sorafenib is the standard of care for treating patients with advanced hepatocellular cancer—“and it remains the standard of care because it remains as good a treatment as we have,” Mayer, an OT Editorial Board member, explained in a telephone interview. “But it's disappointing that sorafenib did not add benefit when combined with TACE, and it's even more disappointing that it didn't have adjuvant effect.”
When initial data came out on the efficacy of sorafenib in HCC (OT 8/10/07 issue), the mechanism behind that effectiveness was not clear, Mayer continued. That study—the SHARP trial—was a large, randomized controlled trial, which showed that patients with advanced hepatocellular cancer who had never received prior therapy did live longer after being treated with sorafenib—“but interestingly enough, their tumors didn't shrink.”
It could be hypothesized that sorafenib was blocking blood nodules, which stopped tumor growth and led to prolonged survival in patients—“but it was not completely clear what was happening,” he said. “Now, the results of these two abstracts raise some questions about the long-term biological significance of the molecule [sorafenib], and also raise some questions as to what exactly the function of sorafenib is—and the extent of that function—in the SHARP study, where it may have had far less of an anti-tumor effect than was initially thought.”
The Future of Sorafenib
Despite the unknowns, Mayer said these latest findings still do not change the role of sorafenib for patients with advanced disease. “Sorafenib has been approved for this purpose appropriately by the Food and Drug Administration. Sorafenib is still the standard of care [for patients with advanced HCC], but it is not an optimal standard of care.
“The findings will likely diminish the enthusiasm of people devoting a great deal more time to investigating different ways to give sorafenib. And it probably will open the door to future studies with non-sorafenib containing treatment plans,” he said.