Systemic Therapies in Hepatocellular Carcinoma
Systemic Therapies in Hepatocellular Carcinoma
Fourteen studies investigating sorafenib in combination with other treatments included a total of 470 patients, with a similar patient populations as the sorafenib-only studies, but with a smaller number of patients.
These studies collected better OS, TTP and DCR results than those observed in the sorafenib-only trials, even though a direct comparison between all these studies seems difficult to assess. Sorafenib in combination with other agents does not show excessive toxicity, but the HFS seems to be much more frequent, especially sorafenib in combination with fluorouracil and derivates. Furthermore, addition of erlotinib to sorafenib did not provide additional benefit to patients with unresectable liver cancer versus sorafenib alone in the Phase III trial.
The most common cause of death in HCC is due to tumor recurrence and metastasis. Clinical outcomes have not met expectations, despite positive results obtained in preclinical studies with VEGF inhibitors. Sorafenib is the only drug that has been shown to improve survival significantly in HCC patients. Recently, a VEGF inhibitor called sunitinib has shown survival benefits in HCC patients but not in the HCV patients.
Sunitinib malate (SU11248, Sutent®; Pfizer, NY, USA) is an oral multikinase inhibitor that targets several tyrosine kinases receptors, such as VEGF-1/2 and PDGFR-α/β, and is implicated in HCC proliferation and angiogenesis. In addition, it was defined as an inhibitor of c-kit, Fit-3 and RET.
Sunitinib was approved for treatment of gastrointestinal stromal tumors after progression or intolerance to imatinitib mesylate.
It has already demonstrated preliminary anti-tumoral activity and an acceptable safety profile in different Phase II trials for patients with advanced HCC. However, despite the other tumor types, sunitinib seems to have more toxic side effects in HCC. Due to more treatment-related toxicities when using the 50-mg dose, in most planned trials, a 37.5-mg dose has been used.
In any case, sorafenib therapeutic effects are transient so additional treatments are warranted.
In the Huynh et al. study (xenograft models), the authors wanted to compare the effectiveness of sunitinib relative to sorafenib. Both are strong inhibitors of tyrosine kinases proteins, which are involved in tumor growth, angiogenesis and metastasis, reporting suppressed tumor growth, angiogenesis, cell proliferation and induced apoptosis in both HCC models, orthotopic and ectopic, for both drugs.
However, the anti-tumoral effectiveness of sorafenib was greater when administered at the dose of 50 mg/kg than sunitinib at a dose of 40 mg/kg. Futhermore, sorafenib inhibited p-eIF4E Ser209 and p-p38 Thr180/Tyr182, and reduced survivin expression. This was not seen with sunitinib. In addition, the anti-tumoral properties and the proapoptotic effects of sorafenib (upregulation of fast migrating Bin and ASK1, plus downregulation of survivin) was greater than sunitinib. These data seem to confirm the apparently higher efficacy of sorafenib in anti-tumoral activity, if it were compared with sunitinib.
Huynh concludes that the anti-tumoral effect of sunitinib is inferior to sorafenib, in both ectopic and orthotopic models of human HCC. However, these observations should be verified in humans. Concomitant liver function, liver disease and the local liver environment have a huge impact on treatment outcomes.
Sunitinib antiproliferative action on HCC cell lines, either in vitro, or in xenograft and orthotopic models was studied by Bagi et al. in order to evaluate the effect of local liver vasculature on drug efficacy. The in vitro studies used human cancer cell lines Huh7.5, Hep3B and SK-Hep-1, whereas, in in vivo studies, mice carried Huh7.5 cells either in the subcutaneous or intrahepatic compartment. Drug exposure and treatment regimens were the same in both tumors. In the Huh7.5 cell lines sunitinib can mildly inhibit proliferation. It can also promote the expression of p53 in p53-wildtype cell line SK-hep-1 and can increase the expression of elements of the cell cycle (S-phase and sub-G1) in the Hep3B cell line. HCC tumors manifest their heterogeneity in a different response to sunitinib in HCC cell lines, which probably explains the discrepancy between preclinical and clinical results. Comparing sunitinib effects on the models, the in vivo results show that it is much less effective against intrahepatic tumors compared with xenograft models. Sunitinib affects large, solid, intrahepatic tumors, as shown by histological data, but unopposed local growth of the small turmors and the development of distant micrometastases seems to be a problem with these types of VEGF inhibitors. There is no doubt that both xenograft and orthotopic models are limited, but they can add value in understanding tumor biology to plan treatment paradigms for these types of patients.
Orthotopic models are particularly useful in enhancing our knowledge of the role of organ vasculature in local metastasis development and tumor resistance to antiangiogenic treatments.
Thus, recently, sunitinib efficacy/safety assessment studies have been suspended due to an unfavorable risk–benefit relationship of its administration (SUN 1170 Phase III open-label study), in comparison to sorafenib.
Linifanib (ABT-869) is a multitargeted tyrosine kinase inhibitor that inhibits multiple members of the VEGFR and PDGFR families. In a xenograft model of HCC, ABT-869 significantly reduced tumor burden. Interim Phase II results in patients with advanced HCC showed a median TTP of 3.7 months with ABT-869 treatment and a safety profile consistent with angiogenesis inhibition. In the Toh et al. study, the authors demonstrate that linifanb as a single agent was found to be clinically active in patients with advanced HCC, with an acceptable safety profile.
Tivantinib (ARQ 197) is a new oral selective MET inhibitor that acts by blocking growth and inducing apoptosis in human tumor cell lines that express MET. MET is a tyrosine kinase receptor involved in tumor development and metastatic progression, which is encoded by a MET proto-oncogene. When binding to HGF, MET activates the RAS–MAPK and PI3K–AKT signaling pathways. Tivantinib anti-tumor activity was demonstrated in murine xenograft models and its efficacy was confirmed in a panel of HCC cell lines. The inhibitory effect on MET activity and downstream pathways was also demonstrated in tumor biopsy samples gained before and after tivantinib treatment. Ultimately, preclinical studies on tivantinib combination with sorafenib have shown good therapeutic opportunities for the additive and synergistic activity of these drugs, as freshly confirmed by a Phase I clinical trial in HCC.
A Phase II trial in patients who were surgically and pharmacologically untreatable with previous therapeutic options was performed by Santoro et al. For this multicenter, randomized, placebo-controlled, double-blind, Phase II study, patients with advanced HCC and Child–Pugh A cirrhosis who were untreatable with other options were enrolled. We randomly allocated patients 2:1 to receive tivantinib (360 mg twice a day) or placebo until progression of the disease. An amendment of tivantinib dose (from 360 to 240 mg) was necessary for the high incidence of grade 3 or worse neutropenia during the treatment. Randomization was carried out centrally, stratified by Eastern Cooperative Oncology Group performance status and vascular invasion, and the primary end point was TTP, according to an independent radiological review in the intention-to-treat population. MET expression on tumor samples was estimated using immunohistochemistry (high expression was regarded as grade ≥2 in ≥50% of tumor cells). Tivantinib was received by 71 patients, of which 38 received a dose of 360 mg twice daily and 33 received 240 mg twice daily. Placebo was received by 36 patients. At the time of analysis, 46 (65%) patients in the tivantinib group and 26 (72%) in the placebo group demonstrated disease progression. Patients treated with tivantinib had a longer TTP (1.6 months [95% CI: 1.4–2.8]) than placebo patients (1.4 months [95% CI: 1.4–1.5]; hazard ratio: 0.64, 90% CI: 0.43–0.94; p = 0.04). Patients with a high MET expression had a longer TTP if treated with tivantinib instead of placebo (2.7 months [95% CI: 1.4–8.5] for 22 MET-high patients on tivantinib vs 1.4 months [95% CI: 1.4–1.6] for 15 MET-high patients on placebo). Neutropenia and anemia were observed with more frequency in the tivantinib group with the following rates: 14 versus 0% (placebo group) and 8 versus 0% (placebo group), respectively. Furthermore, the administration of a higher dosage (360 vs 240 mg) of tivantinib seems to lead to higher rates of neutropenia and anemia (21 vs 6%, respectively) and to higher death rates for severe neutropenia.
In conclusion, tivantinib may provide an option for second-line treatment in patients affected by advanced HCC with well-compensated cirrhosis, especially if they have MET-high tumors. MET can represent an important prognostic and predictive biomarker in this type of patient. Further studies of tivantinib in a biomarker-selected patient population are warranted.
The Trojan and Zeuzem paper covers the preclinical data, the Phase I studies of monotherapy or in combination with sorafenib, and a Phase II study of second-line systemic treatment in patients with advanced HCC. The tivantinib safety profile and MET expression diagnostic role are mentioned. Tivantinib was shown to improve progression-free survival (PFS) and OS in the highly expressed MET group versus placebo, as a second choice treatment (Phase II study) while MET overexpression was considered a negative prognostic factor. Tivantinib in combination with sorafenib seems to be a promising therapy. AEs are represented by hematological toxicity, asthenia and loss of appetite. Tivainib safety was examinated in the Santoro et al. Phase Ib study of a population of patients with Child's A or B cirrhosis, previously treated for HCC. They were administered a twice-daily dose of 360 mg, until toxicity effects or disease progression were observed. Common drug-related AEs detected in 21 HCC patients were neutropenia, anemia, asthenia, leukopenia, anorexia, diarrhea and fatigue. Drug-related decline of liver function or performance status was not observed except for a Child's B cirrhosis patient that experienced a bilirubin increase. Four patients had serious AEs, one of them suffering a neutropenia-related death. Compared with the previous study, there were more hematologic toxicities but those were promptly treated. In nine out of 16 evaluable patients (56%), the best response was stable disease (median: 5.3 months). Median TTP was 3.3 months. In conclusion, tivantinib demonstrated a manageable safety profile and preliminary anti-tumor activity in patients with HCC and Child's A or B cirrhosis.
Studies on Sorafenib Combined With Other Treatments
Fourteen studies investigating sorafenib in combination with other treatments included a total of 470 patients, with a similar patient populations as the sorafenib-only studies, but with a smaller number of patients.
These studies collected better OS, TTP and DCR results than those observed in the sorafenib-only trials, even though a direct comparison between all these studies seems difficult to assess. Sorafenib in combination with other agents does not show excessive toxicity, but the HFS seems to be much more frequent, especially sorafenib in combination with fluorouracil and derivates. Furthermore, addition of erlotinib to sorafenib did not provide additional benefit to patients with unresectable liver cancer versus sorafenib alone in the Phase III trial.
Sunitinib
The most common cause of death in HCC is due to tumor recurrence and metastasis. Clinical outcomes have not met expectations, despite positive results obtained in preclinical studies with VEGF inhibitors. Sorafenib is the only drug that has been shown to improve survival significantly in HCC patients. Recently, a VEGF inhibitor called sunitinib has shown survival benefits in HCC patients but not in the HCV patients.
Sunitinib malate (SU11248, Sutent®; Pfizer, NY, USA) is an oral multikinase inhibitor that targets several tyrosine kinases receptors, such as VEGF-1/2 and PDGFR-α/β, and is implicated in HCC proliferation and angiogenesis. In addition, it was defined as an inhibitor of c-kit, Fit-3 and RET.
Sunitinib was approved for treatment of gastrointestinal stromal tumors after progression or intolerance to imatinitib mesylate.
It has already demonstrated preliminary anti-tumoral activity and an acceptable safety profile in different Phase II trials for patients with advanced HCC. However, despite the other tumor types, sunitinib seems to have more toxic side effects in HCC. Due to more treatment-related toxicities when using the 50-mg dose, in most planned trials, a 37.5-mg dose has been used.
In any case, sorafenib therapeutic effects are transient so additional treatments are warranted.
In the Huynh et al. study (xenograft models), the authors wanted to compare the effectiveness of sunitinib relative to sorafenib. Both are strong inhibitors of tyrosine kinases proteins, which are involved in tumor growth, angiogenesis and metastasis, reporting suppressed tumor growth, angiogenesis, cell proliferation and induced apoptosis in both HCC models, orthotopic and ectopic, for both drugs.
However, the anti-tumoral effectiveness of sorafenib was greater when administered at the dose of 50 mg/kg than sunitinib at a dose of 40 mg/kg. Futhermore, sorafenib inhibited p-eIF4E Ser209 and p-p38 Thr180/Tyr182, and reduced survivin expression. This was not seen with sunitinib. In addition, the anti-tumoral properties and the proapoptotic effects of sorafenib (upregulation of fast migrating Bin and ASK1, plus downregulation of survivin) was greater than sunitinib. These data seem to confirm the apparently higher efficacy of sorafenib in anti-tumoral activity, if it were compared with sunitinib.
Huynh concludes that the anti-tumoral effect of sunitinib is inferior to sorafenib, in both ectopic and orthotopic models of human HCC. However, these observations should be verified in humans. Concomitant liver function, liver disease and the local liver environment have a huge impact on treatment outcomes.
Sunitinib antiproliferative action on HCC cell lines, either in vitro, or in xenograft and orthotopic models was studied by Bagi et al. in order to evaluate the effect of local liver vasculature on drug efficacy. The in vitro studies used human cancer cell lines Huh7.5, Hep3B and SK-Hep-1, whereas, in in vivo studies, mice carried Huh7.5 cells either in the subcutaneous or intrahepatic compartment. Drug exposure and treatment regimens were the same in both tumors. In the Huh7.5 cell lines sunitinib can mildly inhibit proliferation. It can also promote the expression of p53 in p53-wildtype cell line SK-hep-1 and can increase the expression of elements of the cell cycle (S-phase and sub-G1) in the Hep3B cell line. HCC tumors manifest their heterogeneity in a different response to sunitinib in HCC cell lines, which probably explains the discrepancy between preclinical and clinical results. Comparing sunitinib effects on the models, the in vivo results show that it is much less effective against intrahepatic tumors compared with xenograft models. Sunitinib affects large, solid, intrahepatic tumors, as shown by histological data, but unopposed local growth of the small turmors and the development of distant micrometastases seems to be a problem with these types of VEGF inhibitors. There is no doubt that both xenograft and orthotopic models are limited, but they can add value in understanding tumor biology to plan treatment paradigms for these types of patients.
Orthotopic models are particularly useful in enhancing our knowledge of the role of organ vasculature in local metastasis development and tumor resistance to antiangiogenic treatments.
Thus, recently, sunitinib efficacy/safety assessment studies have been suspended due to an unfavorable risk–benefit relationship of its administration (SUN 1170 Phase III open-label study), in comparison to sorafenib.
Linifanib
Linifanib (ABT-869) is a multitargeted tyrosine kinase inhibitor that inhibits multiple members of the VEGFR and PDGFR families. In a xenograft model of HCC, ABT-869 significantly reduced tumor burden. Interim Phase II results in patients with advanced HCC showed a median TTP of 3.7 months with ABT-869 treatment and a safety profile consistent with angiogenesis inhibition. In the Toh et al. study, the authors demonstrate that linifanb as a single agent was found to be clinically active in patients with advanced HCC, with an acceptable safety profile.
Tivantinib
Tivantinib (ARQ 197) is a new oral selective MET inhibitor that acts by blocking growth and inducing apoptosis in human tumor cell lines that express MET. MET is a tyrosine kinase receptor involved in tumor development and metastatic progression, which is encoded by a MET proto-oncogene. When binding to HGF, MET activates the RAS–MAPK and PI3K–AKT signaling pathways. Tivantinib anti-tumor activity was demonstrated in murine xenograft models and its efficacy was confirmed in a panel of HCC cell lines. The inhibitory effect on MET activity and downstream pathways was also demonstrated in tumor biopsy samples gained before and after tivantinib treatment. Ultimately, preclinical studies on tivantinib combination with sorafenib have shown good therapeutic opportunities for the additive and synergistic activity of these drugs, as freshly confirmed by a Phase I clinical trial in HCC.
A Phase II trial in patients who were surgically and pharmacologically untreatable with previous therapeutic options was performed by Santoro et al. For this multicenter, randomized, placebo-controlled, double-blind, Phase II study, patients with advanced HCC and Child–Pugh A cirrhosis who were untreatable with other options were enrolled. We randomly allocated patients 2:1 to receive tivantinib (360 mg twice a day) or placebo until progression of the disease. An amendment of tivantinib dose (from 360 to 240 mg) was necessary for the high incidence of grade 3 or worse neutropenia during the treatment. Randomization was carried out centrally, stratified by Eastern Cooperative Oncology Group performance status and vascular invasion, and the primary end point was TTP, according to an independent radiological review in the intention-to-treat population. MET expression on tumor samples was estimated using immunohistochemistry (high expression was regarded as grade ≥2 in ≥50% of tumor cells). Tivantinib was received by 71 patients, of which 38 received a dose of 360 mg twice daily and 33 received 240 mg twice daily. Placebo was received by 36 patients. At the time of analysis, 46 (65%) patients in the tivantinib group and 26 (72%) in the placebo group demonstrated disease progression. Patients treated with tivantinib had a longer TTP (1.6 months [95% CI: 1.4–2.8]) than placebo patients (1.4 months [95% CI: 1.4–1.5]; hazard ratio: 0.64, 90% CI: 0.43–0.94; p = 0.04). Patients with a high MET expression had a longer TTP if treated with tivantinib instead of placebo (2.7 months [95% CI: 1.4–8.5] for 22 MET-high patients on tivantinib vs 1.4 months [95% CI: 1.4–1.6] for 15 MET-high patients on placebo). Neutropenia and anemia were observed with more frequency in the tivantinib group with the following rates: 14 versus 0% (placebo group) and 8 versus 0% (placebo group), respectively. Furthermore, the administration of a higher dosage (360 vs 240 mg) of tivantinib seems to lead to higher rates of neutropenia and anemia (21 vs 6%, respectively) and to higher death rates for severe neutropenia.
In conclusion, tivantinib may provide an option for second-line treatment in patients affected by advanced HCC with well-compensated cirrhosis, especially if they have MET-high tumors. MET can represent an important prognostic and predictive biomarker in this type of patient. Further studies of tivantinib in a biomarker-selected patient population are warranted.
The Trojan and Zeuzem paper covers the preclinical data, the Phase I studies of monotherapy or in combination with sorafenib, and a Phase II study of second-line systemic treatment in patients with advanced HCC. The tivantinib safety profile and MET expression diagnostic role are mentioned. Tivantinib was shown to improve progression-free survival (PFS) and OS in the highly expressed MET group versus placebo, as a second choice treatment (Phase II study) while MET overexpression was considered a negative prognostic factor. Tivantinib in combination with sorafenib seems to be a promising therapy. AEs are represented by hematological toxicity, asthenia and loss of appetite. Tivainib safety was examinated in the Santoro et al. Phase Ib study of a population of patients with Child's A or B cirrhosis, previously treated for HCC. They were administered a twice-daily dose of 360 mg, until toxicity effects or disease progression were observed. Common drug-related AEs detected in 21 HCC patients were neutropenia, anemia, asthenia, leukopenia, anorexia, diarrhea and fatigue. Drug-related decline of liver function or performance status was not observed except for a Child's B cirrhosis patient that experienced a bilirubin increase. Four patients had serious AEs, one of them suffering a neutropenia-related death. Compared with the previous study, there were more hematologic toxicities but those were promptly treated. In nine out of 16 evaluable patients (56%), the best response was stable disease (median: 5.3 months). Median TTP was 3.3 months. In conclusion, tivantinib demonstrated a manageable safety profile and preliminary anti-tumor activity in patients with HCC and Child's A or B cirrhosis.
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