Copyright
©The Author(s) 2015.
World J Gastroenterol. May 14, 2015; 21(18): 5445-5453
Published online May 14, 2015. doi: 10.3748/wjg.v21.i18.5445
Published online May 14, 2015. doi: 10.3748/wjg.v21.i18.5445
Table 1 Overview of important clinical trials
| First author, Journal (Year) | Study design | Enrollment period | Drugs | Patients | No. Pts |
| Santoro, BJC (2013) | Phase I, open-label, single-arm study (full-text), NCT00802555 | 2009.3- 2010.11 completed | Tivantinib | Advanced HCC, Child-Pugh A cirrhosis, previously treated with sorafenib or other therapy | 21 |
| Santoro, Lancet Oncol (2013) | Phase II double-blind, placebo-controlled, RCT (full-text), NCT00988741 | 2009.10.8- 2011.8.25 completed | Tivantinib vs placebo | Advanced HCC with or without MET-high tumors, who had progressed on or were unable to tolerate first-line systemic therapy | 107 |
| Verslype/Cohn, JCO (2012, May/Feb) | Phase II randomized discontinuation trial (abstract), NCT00940225 | Completed | PR: Continued open-label cabozantinib; SD: Cabozantinib vs placebo; PD: Discontinued | Advanced HCC, ≤ 1 prior systemic regimen, Child-Pugh A | 41 |
| Novartis Pharmaceuticals | Phase II, open label, single-arm study (registration), NCT01737827 | Ongoing | INC280 | Advanced HCC which could not be suitable for treatment with locoregional therapies or has progressed following locoregional therapy, c-MET pathway dysregulation | 56 |
| Novartis Pharmaceuticals | Phase II, double-blind, placebo-controlled RCT (registration), NCT01964235 | Suspended | INC280 vs placebo | Adult patients with advanced HCC after progression or intolerance to sorafenib treatment, c-MET pathway dysregulation | 69 |
| Merck KGaA | Phase Ib/II, single-arm, trial (registration), NCT02115373 | Ongoing | MSC2156119J | Advanced HCC, MET+, Child-Pugh A, who have failed sorafenib treatment | 48 |
| Qin, JCO (2014) | Phase Ib/II RCT (abstract), NCT01988493 | Ongoing | Phase II: MSC2156119J vs sorafenib | Asian patients, MET-positive, advanced HCC, Child-Pugh A | 158 |
| O'Neil, JCO (2013) | Phase Ib/II, open-label, study (abstract), NCT01271504 | Ongoing | Phase Ib: Golvatinib plus sorafenib; Phase II: Golvatinib plus sorafenib vs sorafenib alone | Advanced HCC | 13 |
| Yau, JCO (2012) | Phase I/II trial (abstract), NCT00920192 | Ongoing | Foretinib | Advanced HCC | 13 |
| Santoro, JCO (2013) | Phase III, double-blind, RCT (abstract), NCT01755767 | Ongoing | Tivantinib vs placebo | MET diagnostic-high inoperable HCC treated with one prior systemic therapy | 303 |
| Abou-Alfa, JCO (2014) | Phase III, double-blind, RCT (abstract), NCT01908426 | Ongoing | Cabozantinib vs placebo | Advanced HCC who have received prior sorafenib | 760 |
Table 2 Adverse events related to tivantinib: An overview of data from phase I and II trials n (%)
| Adverse event | Rosen, (2011) n = 79 | Yap, (2011) n = 51 | Yamamoto, (2013) n = 47 | Santoro, (2013) n = 21 | Santoro, (2013) n = 71 | |||||
| All grades | Grade≥3 | All grades | Grade≥3 | All grades | Grade≥3 | All grades | Grade≥3 | All grades | Grade≥3 | |
| Pancytopenia | NA | NA | NA | NA | NA | NA | NA | NA | 2 (2.8) | 2 (2.8) |
| Leukocytopenia | NA | 1 (1.3) | 2 (3.9) | 1 (2.6) | 22 (46.8) | 8 (17.0) | 8 (38) | 4 (19) | 5 (7.0) | 3 (4.2) |
| Neutropenia | NA | 2 (2.5) | 5 (9.8) | 4 (7.8) | 15 (31.9) | 9 (19.1) | 11 (52) | 8 (38) | 20 (28.2) | 12 (16.9) |
| Anemia | 6 (7.6) | 3 (3.8) | 3 (5.9) | 0 (0) | 12 (25.5) | 5 (10.6) | 10 (48) | 5 (24) | 11 (15.5) | 8 (11.3) |
| Thrombocytopenia | NA | 1 (1.3) | 2 (3.9) | 1 (2.6) | NA | NA | 3 (14) | 0 (0) | 6 (8.5) | 4 (4.9) |
| Lymphopenia | NA | NA | 2 (3.9) | 0 (0) | 7 (14.9) | 1 (2.1) | 2 (10) | 0 (0) | NA | NA |
| Fatigue | 11 (13.9) | 1 (1.3) | 10 (19.6) | 1 (2.6) | 19 (40.4) | 1 (2.1) | 6 (29) | 1 (5) | 7 (9.9) | 3 (4.2) |
| Anorexia | NA | NA | 4 (7.8) | 0 (0) | 8 (17.0) | 2 (4.3) | 8 (38) | 0 (0) | 7 (9.9) | 1 (1.4) |
| Nausea | 11 (13.9) | 1 (1.3) | 7 (13.7) | 0 (0) | 4 (8.5) | 0 (0) | NA | NA | 2 (2.8) | 1 (1.4) |
| Vomiting | 8 (10.1) | 1 (1.3) | 7 (13.7) | 0 (0) | NA | NA | 3 (14) | 0 (0) | 4 (5.6) | 0 (0) |
| Diarrhoea | 5 (6.3) | NA | 5 (9.8) | 0 (0) | NA | NA | 6 (29) | 0 (0) | 5 (7.0) | 0 (0) |
| Constipation | NA | NA | 2 (3.9) | 0 (0) | NA | NA | NA | NA | NA | NA |
| Dyspepsia | NA | NA | 1 (2.6) | 0 (0) | NA | NA | NA | NA | NA | NA |
| Dysphagia | NA | NA | 1 (2.6) | 0 (0) | NA | NA | NA | NA | NA | NA |
| Alopecia | NA | NA | 1 (2.6) | 0 (0) | 4 (8.5) | 0 (0) | 4 (19) | 0 (0) | 3 (4.2) | 0 (0) |
| Asthenia | NA | NA | NA | NA | 1 (1.3) | NA | 10 (48) | 2 (10) | 8 (11.3) | 1 (1.4) |
| Abdominal pain | NA | NA | NA | NA | NA | NA | NA | NA | 1 (1.4) | 1 (1.4) |
| Hepatic failure | NA | 1 (1.3) | NA | NA | NA | NA | NA | NA | NA | NA |
| ALT increased | NA | NA | NA | NA | 3 (6.4) | 0 (0) | NA | NA | NA | NA |
| AST increased | NA | 1 (1.3) | NA | NA | NA | NA | NA | NA | NA | NA |
| ALP increased | NA | 1 (1.3) | NA | NA | NA | NA | NA | NA | NA | NA |
| Hypokalemia | NA | NA | 1 (2.6) | 0 (0) | NA | NA | NA | NA | NA | NA |
| Dehydration | NA | 1 (1.3) | NA | NA | NA | NA | NA | NA | NA | NA |
| Hyperammonaemia | NA | 1 (1.3) | NA | NA | NA | NA | NA | NA | NA | NA |
| Hyponatraemia | NA | 1 (1.3) | NA | NA | NA | NA | NA | NA | NA | NA |
| Hyperbilirubinemia | NA | NA | NA | NA | NA | NA | 3 (14) | 1 (5) | NA | NA |
| Rash | NA | NA | 6 (11.8) | 0 (0) | 3 (6.4) | 0 (0) | NA | NA | NA | NA |
| Pruritus | NA | NA | 1 (2.6) | 0 (0) | NA | NA | NA | NA | 2 (2.8) | 0 (0) |
| Hot flush | NA | NA | 2 (3.9) | 0 (0) | NA | NA | NA | NA | NA | NA |
| Hand-foot syndrome | NA | NA | 1 (2.6) | 1 (2.6) | NA | NA | NA | NA | NA | NA |
| Mucosal inflammation | NA | NA | 2 (3.9) | 2 (3.9) | NA | NA | NA | NA | NA | NA |
| Tongue discoloration | NA | NA | 3 (5.9) | 0 (0) | NA | NA | NA | NA | NA | NA |
| Peripheral oedema | NA | NA | NA | NA | NA | NA | 3 (14) | 0 (0) | NA | NA |
| Weight loss | NA | NA | 3 (5.9) | 0 (0) | NA | NA | NA | NA | NA | NA |
| Pyrexia | NA | NA | 1 (2.6) | 0 (0) | NA | NA | NA | NA | 4 (5.6) | 0 (0) |
| Sepsis | NA | NA | NA | NA | NA | NA | NA | NA | 5 (7.0) | 5 (7.0) |
| Prolonged QTc | NA | NA | NA | NA | 3 (6.4) | 0 (0) | NA | NA | NA | NA |
| Bradycardia | NA | NA | NA | NA | 2 (4.3) | 0 (0) | NA | NA | 8 (11.3) | 1 (1.4) |
Table 3 Current status of MET inhibitors for the treatment of advanced hepatocellular carcinoma
| First-line therapy of advanced HCC |
| INC280: A phase II sing-arm trial (NCT01737827) |
| MSC2156119J vs sorafenib: A phase II RCT (NCT01988493) |
| Golvatinib plus sorafenib vs sorafenib alone: A phase II RCT (NCT01271504) |
| Foretinib: A phase II sing-arm trial (NCT00920192) |
| Second-line therapy of advanced HCC |
| Tivantinib vs placebo: A phase II RCT (NCT00988741) |
| Tivantinib vs placebo: A phase III RCT (NCT01755767) |
| Cabozantinib vs placebo: A phase II randomized discontinuation trial (NCT00940225) |
| Cabozantinib vs placebo: A phase III RCT (NCT01908426) |
| INC280 vs placebo: A phase II RCT (NCT01964235) |
| MSC2156119J: A phase II sing-arm trial (NCT02115373) |
- Citation: Qi XS, Guo XZ, Han GH, Li HY, Chen J. MET inhibitors for treatment of advanced hepatocellular carcinoma: A review. World J Gastroenterol 2015; 21(18): 5445-5453
- URL: https://www.wjgnet.com/1007-9327/full/v21/i18/5445.htm
- DOI: https://dx.doi.org/10.3748/wjg.v21.i18.5445