COMMENTARY ON:Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, Hsu CH, Hu TH, Heo J, Xu J, Lu L, Chao Y, Boucher E, Han KH, Paik SW, Robles-Aviña J, Kudo M, Yan L, Sobhonslidsuk A, Komov D, Decaens T, Tak WY, Jeng LB, Liu D, Ezzeddine R, Walters I, Cheng AL. J Clin Oncol. 2013 Oct 1;31(28):3517–24. Reprinted with permission. © (2014) American Society of Clinical Oncology. All rights reserved.http://www.ncbi.nlm.nih.gov/pubmed/23980084Abstract: PURPOSE: Brivanib is a dual inhibitor of vascular-endothelial growth factor and fibroblast growth factor receptors that are implicated in the pathogenesis of hepatocellular carcinoma (HCC). Our multinational, randomized, double-blind, phase III trial compared brivanib with sorafenib as first-line treatment for HCC.PATIENTS AND METHODS: Advanced HCC patients who had no prior systemic therapy were randomly assigned (ratio, 1:1) to receive sorafenib 400mg twice daily orally (n=578) or brivanib 800mg once daily orally (n=577). Primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and safety.RESULTS: The primary end point of OS noninferiority for brivanib versus sorafenib in the per-protocol population (n=1150) was not met (hazard ratio [HR], 1.06; 95.8% CI, 0.93 to 1.22), based on the prespecified margin (upper CI limit for HR⩽1.08). Median OS was 9.9months for sorafenib and 9.5months for brivanib. TTP, ORR, and DCR were similar between the study arms. Most frequent grade 3/4 adverse events for sorafenib and brivanib were hyponatremia (9% and 23%, respectively), AST elevation (17% and 14%), fatigue (7% and 15%), hand-foot-skin reaction (15% and 2%), and hypertension (5% and 13%). Discontinuation as a result of adverse events was 33% for sorafenib and 43% for brivanib; rates for dose reduction were 50% and 49%, respectively.CONCLUSION: Our study did not meet its primary end point of OS noninferiority for brivanib versus sorafenib. However, both agents had similar antitumor activity, based on secondary efficacy end points. Brivanib had an acceptable safety profile, but was less well-tolerated than sorafenib.ANDBrivanib 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. Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, Kang YK, Assenat E, Lim HY, Boige V, Mathurin P, Fartoux L, Lin DY, Bruix J, Poon RT, Sherman M, Blanc JF, Finn RS, Tak WY, Chao Y, Ezzeddine R, Liu D, Walters I, Park JW. J Clin Oncol. 2013 Oct 1;31(28):3509–16. Reprinted with permission. © (2014) American Society of Clinical Oncology. All rights reserved.http://www.ncbi.nlm.nih.gov/pubmed/23980090Abstract: PURPOSE: Brivanib is a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma (HCC). An unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who cannot tolerate it. This multicenter, double-blind, randomized, placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib.PATIENTS AND METHODS: In all, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib 800mg orally once per day plus best supportive care (BSC) or placebo plus BSC. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), and disease control rate based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and safety.RESULTS: Median OS was 9.4months for brivanib and 8.2months for placebo (hazard ratio [HR], 0.89; 95.8% CI, 0.69 to 1.15; P=.3307). Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 (95% CI, 0.63 to 1.04; P=.1044). Exploratory analyses showed a median time to progression of 4.2months for brivanib and 2.7months for placebo (HR, 0.56; 95% CI, 0.42 to 0.76; P<.001), and an mRECIST ORR of 10% for brivanib and 2% for placebo (odds ratio, 5.72). Study discontinuation due to treatment-related adverse events (AEs) occurred in 61 brivanib patients (23%) and nine placebo patients (7%). The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension (17%), fatigue (13%), hyponatremia (11%), and decreased appetite (10%).CONCLUSION: In patients with HCC who had been treated with sorafenib, brivanib did not significantly improve OS. The observed benefit in the secondary outcomes of TTP and ORR warrants further investigation.Hepatocellular carcinoma (HCC) remains a major health problem worldwide, and is the sixth most common cancer and third leading cause of cancer-related mortality globally [[1]Jemal A. Bray F. Center M.M. Ferlay J. Ward E. Forman D. Global cancer statistics.CA Cancer J Clin. 2011; 61: 69-90Crossref PubMed Scopus (30015) Google Scholar]. The development of systemic agents in advanced hepatocellular carcinoma (HCC) has been a challenge. The results of the SHARP study and approval of sorafenib in 2007 was a giant step-forward in our management of the disease and how we design and conduct studies for this population [[2]Llovet J.M. Ricci S. Mazzaferro V. Hilgard P. Gane E. Blanc J.F. et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390Crossref PubMed Scopus (8747) Google Scholar]. However, since then we have been mired in numerous negative phase III studies [[3]Llovet J.M. Hernandez-Gea V. Hepatocellular carcinoma: reasons for phase III failure and novel perspectives on trial design.Clin Cancer Res. 2014; 20: 2072-2079Crossref PubMed Scopus (302) Google Scholar]. One of the first agents to be evaluated in the post sorafenib era was brivanib, an oral, potent selective inhibitor of both the fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) family of receptors (Table 1) [[4]Bhide R.S. Cai Z.W. Zhang Y.Z. Qian L. Wei D. Barbosa S. et al.Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor.J Med Chem. 2006; 49: 2143-2146Crossref PubMed Scopus (135) Google Scholar]. Laboratory evidence suggests that both pathways play a role in the pathogenesis of HCC and, in context of the FGFR family, in the resistance to VEGF driven angiogenesis [[5]Chou T. Finn R.S. Brivanib: a review of development.Future Oncol. 2012; 8: 1083-1090Crossref PubMed Scopus (22) Google Scholar]. Despite encouraging phase II data, enpoints were not met in two randomised phase III registration studies (Table 2). To avoid similar disappointment in the future, we should look carefully at these studies to identify potential flaws in trial design and assumptions. Given that these are two different populations of patients, the front-line and second-line groups should be considered separately.Table 1Brivanib targeted tyrosine kinases and inhibition profile. Open table in a new tab Table 2Comparison of brivanib’s efficacy in phase II and phase III studies.∗Modified WHO criteria per independent radiology review.^Modified RECIST criteria.n.r., not disease control TTP, time to progression median overall Open table in a new tab Brivanib was evaluated in two phase II studies of patients with advanced The front-line study patients with advanced HCC were treated in the study with the primary objective survival and progression survival and the secondary of response median progression and overall and safety Finn R.S. F. et study of brivanib as first-line therapy in patients with advanced hepatocellular Cancer Res. 2011; PubMed Scopus Google Scholar]. the modified Criteria the progression survival rate was (95% CI, median was (95% CI, time to progression was (95% CI, and median overall survival was (95% CI, Given the control from SHARP these that brivanib is an active in compared to the in to sorafenib in However, the brivanib study In that these efficacy were compared to the sorafenib phase III study Kang Qin S. et and safety of sorafenib in patients in the with advanced hepatocellular carcinoma: a phase III double-blind, placebo-controlled Oncol. PubMed Scopus Google a median OS of to the median OS of in the sorafenib in that study. to the adverse with brivanib were with and most common and the reaction common with sorafenib, is with approval for front-line the brivanib study was and evaluated brivanib in patients with progression on of prior therapy R.S. Kang Lim Walters et study of brivanib as second-line therapy in patients with advanced hepatocellular Cancer Res. 2012; PubMed Scopus Google Scholar]. this was an study. patients were of prior sorafenib, and the and Median TTP per criteria was (95% CI, median (95% CI, and median OS was (95% CI, the first in a population of HCC patients, for that had prior sorafenib, we were a median OS of a that not have been from the SHARP or the between median OS and median One have that the median OS sorafenib was from the SHARP study and 4 in the and the OS of with brivanib was in a population of patients with a unmet both phase II studies included an of response the modified RECIST criteria for HCC in an to the of brivanib Llovet J.M. RECIST (mRECIST) for hepatocellular PubMed Scopus Google Scholar]. these in phase III randomised studies were with brivanib in a front-line study a study and a third in with first randomised second-line phase III study in the post sorafenib era to was the BRISK-PS study J.M. Decaens T. Raoul Boucher E. Kudo Chang et in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS Clin Oncol. PubMed Scopus Google Scholar]. This was a phase placebo control study of 395 patients randomised that had progressed on or sorafenib or were intolerant to sorafenib. The primary for the study was OS with a ratio of for the study to be considered were based on for sorafenib discontinuation and in front-line HCC studies as and the of vascular the study was for these was an the control in the of patients that had vascular was the that the of patients had In baseline not included in the but a negative prognostic factor in was in patients brivanib. This study its primary median OS was with brivanib, with placebo with brivanib (HR, 0.89; 95.8% CI, this was not median OS in the phase III study was similar to that in the phase II for this population to progression was significantly with brivanib as as secondary objective response rate and disease control assessed The effect of brivanib was similar as in the phase II studies and was a rate of dose and and a discontinuation rate of secondary to the BRISK-FL study did not meet its primary of in OS compared to sorafenib Qin S. Park Poon Raoul Philip et sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL Clin Oncol. PubMed Scopus Google Scholar]. This study patients and randomised in a to brivanib or sorafenib and as the SHARP vascular and study median OS with brivanib was similar as in the phase II in phase III and However, this did not significantly from the sorafenib survival of (HR, 1.06; 95.8% CI, and the HR 95% CI of to the BRISK-PS secondary were similar mRECIST in the BRISK-FL the ORR with sorafenib of with mRECIST was than that in the SHARP study RECIST the of brivanib was similar to the phase II the of dose and was similar between the two were with brivanib due to adverse 43% with brivanib as compared to 33% with sorafenib. This for development in systemic is not as as in The failure of in this population this Kang Lin Park Kudo Qin S. et versus sorafenib in advanced hepatocellular results of a randomized phase III Clin Oncol. PubMed Scopus Google we from the development of control are not for phase III studies but for phase II as be that a randomised phase II study have the of brivanib to sorafenib in the front-line the BRISK-FL study less In for the BRISK-PS a randomised phase II study have a of the survival of the placebo and identify factors survival in the and in the front-line not be in the second-line from vascular is an in the second-line two of sorafenib progression J. F. A. A. et survival of patients with advanced hepatocellular carcinoma: for second-line trial PubMed Scopus Google Lu et of patients with advanced hepatocellular carcinoma who first-line systemic 2014; PubMed Scopus Google of was the for a second-line study is a for benefit in with targeted the SHARP study and these that response RECIST mRECIST with in HCC and further of need to be In is time to agents in To no agents in this brivanib, have been to improve on sorafenib in the front-line or improve survival in the second-line This is not to these agents not have than placebo in the front-line but as need to do than sorafenib or at do as with a profile. sorafenib, we need to both a and to agents with a similar of this development in HCC has from the of the disease and its on of response to be in an for sorafenib, we to in HCC with we need not trial and design but we need to patients most to benefit from a of has as a to and COMMENTARY Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, Hsu CH, Hu TH, Heo J, Xu J, Lu L, Chao Y, Boucher E, Han KH, Paik SW, Robles-Aviña J, Kudo M, Yan L, Sobhonslidsuk A, Komov D, Decaens T, Tak WY, Jeng LB, Liu D, Ezzeddine R, Walters I, Cheng AL. J Clin Oncol. 2013 Oct 1;31(28):3517–24. Reprinted with permission. © (2014) American Society of Clinical Oncology. All rights PURPOSE: Brivanib is a dual inhibitor of vascular-endothelial growth factor and fibroblast growth factor receptors that are implicated in the pathogenesis of hepatocellular carcinoma (HCC). Our multinational, randomized, double-blind, phase III trial compared brivanib with sorafenib as first-line treatment for AND METHODS: Advanced HCC patients who had no prior systemic therapy were randomly assigned (ratio, 1:1) to receive sorafenib 400mg twice daily orally (n=578) or brivanib 800mg once daily orally (n=577). Primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and The primary end point of OS noninferiority for brivanib versus sorafenib in the per-protocol population (n=1150) was not met (hazard ratio [HR], 1.06; 95.8% CI, 0.93 to 1.22), based on the prespecified margin (upper CI limit for HR⩽1.08). Median OS was 9.9months for sorafenib and 9.5months for brivanib. TTP, ORR, and DCR were similar between the study arms. Most frequent grade 3/4 adverse events for sorafenib and brivanib were hyponatremia (9% and 23%, respectively), AST elevation (17% and 14%), fatigue (7% and 15%), hand-foot-skin reaction (15% and 2%), and hypertension (5% and 13%). Discontinuation as a result of adverse events was 33% for sorafenib and 43% for brivanib; rates for dose reduction were 50% and 49%, Our study did not meet its primary end point of OS noninferiority for brivanib versus sorafenib. However, both agents had similar antitumor activity, based on secondary efficacy end points. Brivanib had an acceptable safety profile, but was less well-tolerated than sorafenib. AND 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. Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, Kang YK, Assenat E, Lim HY, Boige V, Mathurin P, Fartoux L, Lin DY, Bruix J, Poon RT, Sherman M, Blanc JF, Finn RS, Tak WY, Chao Y, Ezzeddine R, Liu D, Walters I, Park JW. J Clin Oncol. 2013 Oct 1;31(28):3509–16. Reprinted with permission. © (2014) American Society of Clinical Oncology. All rights PURPOSE: Brivanib is a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma (HCC). An unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who cannot tolerate it. This multicenter, double-blind, randomized, placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib. AND METHODS: In all, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib 800mg orally once per day plus best supportive care (BSC) or placebo plus BSC. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), and disease control rate based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and Median OS was 9.4months for brivanib and 8.2months for placebo (hazard ratio [HR], 0.89; 95.8% CI, 0.69 to 1.15; P=.3307). Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 (95% CI, 0.63 to 1.04; P=.1044). Exploratory analyses showed a median time to progression of 4.2months for brivanib and 2.7months for placebo (HR, 0.56; 95% CI, 0.42 to 0.76; P<.001), and an mRECIST ORR of 10% for brivanib and 2% for placebo (odds ratio, 5.72). Study discontinuation due to treatment-related adverse events (AEs) occurred in 61 brivanib patients (23%) and nine placebo patients (7%). The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension (17%), fatigue (13%), hyponatremia (11%), and decreased appetite In patients with HCC who had been treated with sorafenib, brivanib did not significantly improve OS. The observed benefit in the secondary outcomes of TTP and ORR warrants further Hepatocellular carcinoma (HCC) remains a major health problem worldwide, and is the sixth most common cancer and third leading cause of cancer-related mortality globally [[1]Jemal A. Bray F. Center M.M. Ferlay J. Ward E. Forman D. Global cancer statistics.CA Cancer J Clin. 2011; 61: 69-90Crossref PubMed Scopus (30015) Google Scholar]. The development of systemic agents in advanced hepatocellular carcinoma (HCC) has been a challenge. The results of the SHARP study and approval of sorafenib in 2007 was a giant step-forward in our management of the disease and how we design and conduct studies for this population [[2]Llovet J.M. Ricci S. Mazzaferro V. Hilgard P. Gane E. Blanc J.F. et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390Crossref PubMed Scopus (8747) Google Scholar]. However, since then we have been mired in numerous negative phase III studies [[3]Llovet J.M. Hernandez-Gea V. Hepatocellular carcinoma: reasons for phase III failure and novel perspectives on trial design.Clin Cancer Res. 2014; 20: 2072-2079Crossref PubMed Scopus (302) Google Scholar]. One of the first agents to be evaluated in the post sorafenib era was brivanib, an oral, potent selective inhibitor of both the fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) family of receptors (Table 1) [[4]Bhide R.S. Cai Z.W. Zhang Y.Z. Qian L. Wei D. Barbosa S. et al.Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor.J Med Chem. 2006; 49: 2143-2146Crossref PubMed Scopus (135) Google Scholar]. Laboratory evidence suggests that both pathways play a role in the pathogenesis of HCC and, in context of the FGFR family, in the resistance to VEGF driven angiogenesis [[5]Chou T. Finn R.S. Brivanib: a review of development.Future Oncol. 2012; 8: 1083-1090Crossref PubMed Scopus (22) Google Scholar]. Despite encouraging phase II data, enpoints were not met in two randomised phase III registration studies (Table 2). To avoid similar disappointment in the future, we should look carefully at these studies to identify potential flaws in trial design and assumptions. Given that these are two different populations of patients, the front-line and second-line groups should be considered WHO criteria per independent radiology RECIST not disease control TTP, time to progression median overall Brivanib was evaluated in two phase II studies of patients with advanced The front-line study patients with advanced HCC were treated in the study with the primary objective survival and progression survival and the secondary of response median progression and overall and safety Finn R.S. F. et study of brivanib as first-line therapy in patients with advanced hepatocellular Cancer Res. 2011; PubMed Scopus Google Scholar]. the modified Criteria the progression survival rate was (95% CI, median was (95% CI, time to progression was (95% CI, and median overall survival was (95% CI, Given the control from SHARP these that brivanib is an active in compared to the in to sorafenib in However, the brivanib study In that these efficacy were compared to the sorafenib phase III study Kang Qin S. et and safety of sorafenib in patients in the with advanced hepatocellular carcinoma: a phase III double-blind, placebo-controlled Oncol. PubMed Scopus Google a median OS of to the median OS of in the sorafenib in that study. to the adverse with brivanib were with and most common and the reaction common with sorafenib, is with brivanib. approval for front-line the brivanib study was and evaluated brivanib in patients with progression on of prior therapy R.S. Kang Lim Walters et study of brivanib as second-line therapy in patients with advanced hepatocellular Cancer Res. 2012; PubMed Scopus Google Scholar]. this was an study. patients were of prior sorafenib, and the and Median TTP per criteria was (95% CI, median (95% CI, and median OS was (95% CI, the first in a population of HCC patients, for that had prior sorafenib, we were a median OS of a that not have been from the SHARP or the between median OS and median One have that the median OS sorafenib was from the SHARP study and 4 in the and the OS of with brivanib was in a population of patients with a unmet In both phase II studies included an of response the modified RECIST criteria for HCC in an to the of brivanib Llovet J.M. RECIST (mRECIST) for hepatocellular PubMed Scopus Google Scholar]. these in phase III randomised studies were with brivanib in a front-line study a study and a third in with The first randomised second-line phase III study in the post sorafenib era to was the BRISK-PS study J.M. Decaens T. Raoul Boucher E. Kudo Chang et in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS Clin Oncol. PubMed Scopus Google Scholar]. This was a phase placebo control study of 395 patients randomised that had progressed on or sorafenib or were intolerant to sorafenib. The primary for the study was OS with a ratio of for the study to be considered were based on for sorafenib discontinuation and in front-line HCC studies as and the of vascular the study was for these was an the control in the of patients that had vascular was the that the of patients had In baseline not included in the but a negative prognostic factor in was in patients brivanib. This study its primary median OS was with brivanib, with placebo with brivanib (HR, 0.89; 95.8% CI, this was not median OS in the phase III study was similar to that in the phase II for this population to progression was significantly with brivanib as as secondary objective response rate and disease control assessed The effect of brivanib was similar as in the phase II studies and was a rate of dose and and a discontinuation rate of secondary to the BRISK-FL study did not meet its primary of in OS compared to sorafenib Qin S. Park Poon Raoul Philip et sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL Clin Oncol. PubMed Scopus Google Scholar]. This study patients and randomised in a to brivanib or sorafenib and as the SHARP vascular and study median OS with brivanib was similar as in the phase II in phase III and However, this did not significantly from the sorafenib survival of (HR, 1.06; 95.8% CI, and the HR 95% CI of to the BRISK-PS secondary were similar mRECIST in the BRISK-FL the ORR with sorafenib of with mRECIST was than that in the SHARP study RECIST the of brivanib was similar to the phase II the of dose and was similar between the two were with brivanib due to adverse 43% with brivanib as compared to 33% with sorafenib. This for development in systemic is not as as in The failure of in this population this Kang Lin Park Kudo Qin S. et versus sorafenib in advanced hepatocellular results of a randomized phase III Clin Oncol. PubMed Scopus Google Scholar]. we from the development of control are not for phase III studies but for phase II as be that a randomised phase II study have the of brivanib to sorafenib in the front-line the BRISK-FL study less In for the BRISK-PS a randomised phase II study have a of the survival of the placebo and identify factors survival in the and in the front-line not be in the second-line from vascular is an in the second-line two of sorafenib progression J. F. A. A. et survival of patients with advanced hepatocellular carcinoma: for second-line trial PubMed Scopus Google Lu et of patients with advanced hepatocellular carcinoma who first-line systemic 2014; PubMed Scopus Google of was the for a second-line study is a for benefit in with targeted the SHARP study and these that response RECIST mRECIST with in HCC and further of need to be In is time to agents in To no agents in this brivanib, have been to improve on sorafenib in the front-line or improve survival in the second-line This is not to these agents not have than placebo in the front-line but as need to do than sorafenib or at do as with a profile. sorafenib, we need to both a and to agents with a similar of this development in HCC has from the of the disease and its on of response to be in an for sorafenib, we to in HCC with we need not trial and design but we need to patients most to benefit from a of has as a to and has as a to and
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