Table 1.
First line therapy (FDA-approved and Phase III investigations in advanced HCC).
| Therapy | Target | OR (HR) | Note | Clinical Phases [40] * | Reference and ClinicalTrials.gov |
|---|---|---|---|---|---|
|
Atezolizumab +
Bevasizumab |
PD-L1, VEGF | 0.58 (HR 0.42–0.79) | OS > 17 months, normalizes tumor vasculature to starve tumors | Approved, III | NCT03434379 [50] |
| Nivolumab | PD-1 | 0.85 (0.72–1.02) | Well-tolerated in advanced HCC | Approved, III (sorafenib) | NCT02576509 [51] |
| Lenvatinib | FGFR1-4, VEGFR1-3, RET, c-KIT and PDGFRα | 0.85 (0.72–1.02) | Safety and tolerability profiles | Approved, III non-inferiority trial | NCT01761266 [52] |
| Erlotinib + Sorafenib | EGFR + VEGFR1-3, RET, KIT PDGFRa/b | 0.92 (0.78–1.11) | Adding erlotinib to sorafenib did not improve survival | III | NCT0901901 [53] |
| Linifanib | FGFR | 1.05 (0.90–1.22) | TTP and ORR favored linifanib | III | [54] |
| Brivanib | VEGFR | 1.07 (0.94–1.23) | OS, TTP, ORR, DCR, and mRECIST | III | NCT00858871 [55] |
|
Y90 (SIRveNIB) (Yttrium-90 resin microspheres) |
Radiation | 1.12 (0.88–1.42) | SIRveNIB trial, locoregional selective internal radiation therapy (SIRT) | III (approved for colon cancer) | NCT01135056 [56] |
| Y90 (SARAH) | Radiation | 1.15 (0.94–1.41) | Sorafenib vs. Radioembolization in Advanced Hepatocellular carcinoma (SARAH) trial, yttrium-90 (Y-90) resin microspheres | III | [57,58,59] |
| 2nd line treatment (FDA-approved and Phase III investigations in advanced HCC) | |||||
| Regorafenib | VEGFR1-3, RET, KIT PDGFRa/b. FGFR1/2. Raf | Regorafenib 0.63 (0.50–0.79) |
Approved | NCT01774344 [60] | |
| Ramucirumab | VEGFR2 | 0.71 (0.53–0.95) | In advanced HCC with AFP > 400 ng/mL | Approved | NCT02435433 |
| Cabozantinib | EGFR2, MET, RON, RET, TIE2, TAMkinases | 0.76 (0.63–0.92) | CELESTIAL trial, HCC progression on prior sorafenib | Approved | NCT01908426 [61] |
| Pembrolizumab | PD-1 | 0.78 (0.61–0.99) | 1 Q3W + BSC 8.3% | Approved | NCT02702401 [62] |
| Brivanib | PD-1 | 0.89 (0.69–1.15) | BRISK-FL study | III | NCT00858871 [55]; NCT00825955 [63] |
| Tivantinib | MET | 0.97 (0.75–1.25) | METIV-HCC | III | NCT01755767 [64] |
| Everolimus | mTOR (mTORC1 complex) | 1.95 (0.86–1.27) | EVOLVE-1 | III | NCT01035229 [65] |
| Sorafenib | VEGFR1-3, Raf, PDGFRb, KIT, Fit-3 | 0.69 (0.55 to 0.87) | Sorafenib HCC Assessment Randomized Protocol (SHARP) trial | Approved | NCT00105443 [66,67] |
|
Nivolumab ±
ipilimumab |
PD-1 and CTLA-4 | Neoadjuvant | II | NCT03222076 | |
* Current systemic therapies for HCC: approved in unselected populations [40].