Table 5.
Molecular-targeted therapies
| Drugs | Types | Indication | Details of clinical trials | Side effects | Extra information | Reference |
|---|---|---|---|---|---|---|
| First and only US FDA approved systemic therapy in 2007 | ||||||
| Sorafenib | Oral multi-tyrosine kinase inhibitor of VEGFR, platelet-derived growth factor receptor and Raf | Patients with well-preserved liver function and with advanced tumours/those tumours progressing upon loco-regional therapies | Sorafenib HCC Assessment Randomized Protocol (SHARP) trial • Median overall survival: 10.7 months with sorafenib and 7.9 months with placebo • 31% decrease in relative risk of death • Median time to radiologic progression: 5.5 months with sorafenib and 2.8 months with placebo Phase III study in Asia • Overall survival: 6.5 months with sorafenib and 4.2 months with placebo |
Hand-foot skin reactions (8%–16%) Diarrhea (8%–9%) Weight loss Hypophosphataemia Fatigue | Currently being tested • As an adjuvant after resection or complete local ablation for initial stages • In combination with chemoembolization for intermediate stages • In combination with Erlotinib/systemic doxorubicin in advanced stages • As first line treatment for Child–Pugh B patients |
50 |
| Under clinical development and clinical trials | ||||||
| Brivanib alaninate | Oral VEGFR and FGFR tyrosine kinase inhibitor | Phase II studies • Median overall survival: 10 months in first line patients with advanced tumor and 9.8 months in second line treated group Phase III studies • Median overall survival: 9.4 months with brivanib and 8.2 months with placebo • Median time to progression: 4.2 months for brivanib and 2.7 months for placebo |
Hypertension (17%) Fatigue (13%) Hyponatremia (11%) Decreased appetite (10%) | Currently being tested in three phase III clinical trials • First line blinded to sorafenib • Second line blinded to placebo • In combination with chemoembolization |
3 | |
| Bevacizumab | Recombinant, humanised monoclonal antibody against VEGF | Monotherapy • Median time to regression of 6.5 months • Objective responses of 10% With EGFR targeting agents • Median survival of 15 months for mixed HCC patient populations With chemotherapy (gemcitabine, oxaliplatin, capecitabine-based regimes) • Objective responses of 10–20% • Median survivals of 9–10 months |
Approved for colorectal cancer, non-small cell lung cancer, and breast carcinoma treatment No phase III investigations | 3, 51 | ||
| Sunitinib | Multi-targeted tyrosine kinase inhibitor and PDGFR | Presently not recommended for treatment of HCC | • Used in phase II & III clinical trials for HCC treatment • Median overall survival times of 7.9 months • Median relative dose intensity, 66.6% vs sorafenib, 71.3% |
Thrombocytopenia (29.7%) Neutropenia (25.7%) Bleeding (37.1%) Diarrhea led to dose reductions as a result of thrombocytopenia (6.7%), hand-foot syndrome (6.5%), and neutropenia (4.0%) | • Blockade of angiogenic receptors and reduces HCC development • GIST after disease progression on or intolerance to imatinib mesylate • Show anti-tumor activity in three phases II studies of patients with advanced HCC |
3, 38, 51, 52 |
| Erlotinib | Tyrosine kinase inhibitor of the EGFR | Maintenance treatment of patients with locally advanced or metastatic NSCLC whose disease has not progressed after four cycles of platinum-based, 1st line chemotherapy | • Phases I, I–II, II, III are under evaluation • Survival times of 15.6 months • Survival times of 6.8 months • Median of 13 and 6.3 months in 2 single-arm studies • Response rate of 25% and <10% in single-arm studies |
• Being tested in phase III pivotal trials for regulatory approval | 36, 52, 53 | |
| Linifanib | Tyrosine kinase inhibitor targeting PDGFR and VEGF | • Phases II, III are under evaluation | • Being tested in phase III pivotal trials for regulatory approval • Effective in the treatment of the HCC with an acceptable safety profile in a single-arm phase II clinical trial |
38, 52 | ||
| Tivantinib | Oral MET receptor tyrosine kinase inhibitor | • Has synergistic effect against HCC when added to sorafenib • Used as a second-line agent for the treatment of HCC in previously unresectable HCC who progressed or could not tolerate first-line systemic therapy |
38 | |||
| Rapamycin (sirolimus) and its analogs (temsirolimus and everolimus) | Growth factors and proliferative pathway inhibitors (mTOR inhibitor) | Tested in preclinical and early clinical investigation | Everolimus • Used for kidney cancer therapy • Being tested in phase III for • a second line indication |
3 | ||
| Vatalanib, axitinib, cediranib | Anti-angiogenic | Being tested at early clinical investigation | 3 | |||
Abbreviations: US FDA, United States Food and Drug Administration; VEGFR, vascular endothelial growth factor receptor; FGFR, fibroblast growth factor; PDGFR, platelet derived growth factor receptor; Raf, rapidly accelerated fibrosarcoma; EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor; GIST, gastrointestinal stromal tumor; NSCLC, non-small cell lung cancer; HCC, hepatocellular carcinoma.