Hepatocellular carcinoma is a devastating disease worldwide. Although advances in liver transplantation, surgery, and locoregional therapies have made tumor control or even cure possible for a minority of patients, the majority of patients diagnosed with hepatocellular carcinoma will develop advanced-stage disease for which systemic therapy is the only option.
Unfortunately, cytotoxic chemotherapy has been largely ineffective, and the only agent shown to definitively improve survival has been sorafenib (Nexavar), which targets vascular endothelial growth factor (VEGF) among other signaling pathways.1 Still, the results are far from spectacular, with frequent intolerance to sorafenib and short-lived responses. Therefore, new treatments are desperately needed in hepatocellular carcinoma for both untreated patients as well as those with refractory disease.
Drug Development
Because of the vascular nature of hepatocellular carcinoma and the efficacy of sorafenib, many of the treatments in development have focused on the VEGF pathway, its inhibitors, and its resistance pathways. Fibroblast growth factor (FGF) and its receptors have been shown to drive angiogenesis directly, as well as function as a resistance mechanism for overcoming VEGF inhibition.2,3
Brivanib is a tyrosine kinase inhibitor of both VEGF and FGF receptors and therefore a seemingly ideal candidate drug to be considered for use in hepatocellular carcinoma, either initially or in refractory disease.4 Results in preclinical models with cell lines and xenografts looked promising, and phase II studies in patients with untreated or progressive hepatocellular carcinoma after prior antiangiogenic therapy demonstrated that the majority of patients had disease control with provocative survival times observed.5,6
Consequently, two large phase III studies of brivanib in hepatocellular carcinoma were launched—the BRISK-FL study in first-line therapy and the BRISK-PS study in patients whose disease progressed on or who were intolerant of sorafenib.7,8 Unfortunately, neither study met its endpoint to demonstrate activity of brivanib in hepatocellular carcinoma.
Key Results
In the BRISK-FL study, previously untreated patients were randomly assigned in equal numbers to brivanib or sorafenib. The primary endpoint was noninferiority of overall survival with brivanib compared to sorafenib. This was not demonstrated, although the numeric values were in line with previously observed median survival times (9.9 months for sorafenib and 9.5 months for brivanib).
Probably more importantly, overall rates of adverse events were higher with brivanib, although hand-foot syndrome occurred less frequently with brivanib. Thus, brivanib was less tolerable and resulted in survival inferior to sorafenib, clearly disappointing and echoing the failure of sunitinib (Sutent) to improve upon standard first-line treatment with sorafenib.9
Patients who had been previously treated with sorafenib and were either intolerant of or showing disease progression on that drug were enrolled on the BRISK-PS study and randomly assigned 2:1 to brivanib or placebo. Again, the results were disappointing. Although there was an observed response rate of 10% using the modified RECIST criteria, overall survival was not significantly improved over treatment with placebo.
Interestingly, the survival time for the group treated with placebo was significantly longer than that observed in other second-line studies, and the authors do cite an imbalance in the rate of vascular invasion in the brivanib group (31%) compared to placebo (18%) as a potential confounding factor. Still, a prespecified analysis controlling for all baseline factors failed to reach statistical significance for prolonging overall survival.
Conclusions
Optimizing VEGF blockade and overcoming resistance to blockade are clearly not enough to treat advanced hepatocellular carcinoma. Moving forward, an understanding of other drivers of hepatocellular carcinoma apart from the VEGF pathway that may be synergistic with antiangiogenic drugs will be essential to substantially improve outcomes for patients.
The role of cytotoxic chemotherapy as potentially complementary to sorafenib is under investigation in the ongoing Cancer and Leukemia Group B (CALGB) 80802 study looking at sorafenib with or without doxorubicin. Other traditional chemotherapy regimens such as GEMOX (gemcitabine, oxaliplatin) and FOLFOX (leucovorin, fluorouracil, oxaliplatin) have shown interesting results.
Agents such as cetuximab (Erbitux), erlotinib (Tarceva), everolimus (Afinitor), cabozantinib (Cometriq), tivantinib, and others that do not primarily target angiogenesis are being explored as ways to build on the benefits and limitations seen with sorafenib treatment in hepatocellular carcinoma. ■
Dr. Goff is Assistant Professor of Medicine, Vanderbilt-Ingram Cancer Center, Associate Program Director, Vanderbilt Hematology-Oncology Fellowship Program, Vanderbilt University School of Medicine, Nashville.
Disclosure: Dr. Goff has received research funding from Bristol-Myers Squibb, OSI/Astellas, Roche, Pfizer, Sanofi, and Amgen.
References
1. Llovet JM, Ricci S, Mazzaferro V, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378-390, 2008.
2. Bergers G, Hanahan D: Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592-603, 2008.
3. Uematsu S, Higashi T, Nouso K, et al: Altered expression of vascular endothelial growth factor, fibroblast growth factor-2 and endostatin in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 20:583-588, 2005.
4. Huynh H, Ngo VC, Fargnoli J, et al: Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin Cancer Res14:6146-6153, 2008.
5. Finn RS, Kang YK, Mulcahy M, et al: Phase II, open-label study of brivanib as second-line therapy in patients with advanced hepatocellular carcinoma. Clin Cancer Res 18:2090-2098, 2012.
6. Park JW, Finn RS, Kim JS, et al: Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma. Clin Cancer Res 17:1973-1983, 2011.
7. Johnson PJ, Qin S, Park J-W, et al: Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: Results from the randomized phase III BRISK-FL study. J Clin Oncol 31:3517-3524, 2013.
8. Llovet JM, Decaens T, Raoul J-L, et al: Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol 31:3509-3516, 2013; doi: 10.1200/JCO.2012.47.3009.
9. Cheng A, Kang Y, Lin D, et al: Phase III trial of sunitinib versus sorafenib in advanced hepatocellular carcinoma. J Clin Oncol 29(suppl):Abstract 4000, 2011.
