Table 1. Clinical trials of targeted therapies and immunotherapeutic agents in the second-line setting of advanced HCC.
| Drug | Molecular target | NCT number (trial name) | Phase | Patients | Population | Overall survival | Indication | Date | Ref |
|---|---|---|---|---|---|---|---|---|---|
| Molecular targeted therapies | |||||||||
| Brivanib | VEGFR & FGFR inhibitor | NCT00825955 (BRISK-PS) | III | 395 | Prior sorafenib | 9.4 vs. 8.2 mo (P=0.3307) | Negative result | 2009–2011 | (36) |
| Everolimus | mTOR inhibitor | NCT02614183 (EVOLVE-1) | III | 546 | Prior sorafenib | 7.6 vs. 7.3 mo (P=0.68) | Negative result | 2010–2012 | (37) |
| Tivantinib | MET inhibitor | NCT01755767 (METIV-HCC) | III | 340 | MET-high HCC with prior sorafenib | 8.4 vs. 9.1 mo (P=0.81) | Negative result | 2012–2015 | (38) |
| Ramucirumab | VEGFR inhibitor | NCT01140347 (REACH) | III | 565 | Prior sorafenib | 9.2 vs. 7.6 mo (P=0.14) | Not significant | 2010–2013 | (39) |
| NCT02435433 (REACH-2) | III | 292 | AFP high (≥400 ng/mL) HCC with prior sorafenib | 8.5 vs. 7.3 mo (P=0.0199) | Positive top-line result | Ongoing | (40) | ||
| Regorafebin | Multi-targeted TKI | NCT01774344 (RESORCE) | III | 573 | Prior sorafenib | 10.6 vs. 7.8 mo (P<0.001) | FDA approval in 2017 as second-line treatment | 2013–2015 | (11) |
| Cabozantinib | Multi-targeted TKI | NCT01908426 (CELESTIAL) | III | 707 | Prior sorafenib | 10.2 vs. 8.0 mo (P<0.001) | Positive result | 2013–2017 | (41) |
| Immunotherapy agents | |||||||||
| Nivolumab | PD-1 inhibitor | NCT01658878 (CheckMate040) | I/II | 262 | Sorafenib naive: n=80, sorafenib progressed: n=182 | Sorafenib progressed group: 15–15.6 mo |
FDA accelerated approval in 2017 as second-line treatment. Carry on with first-line setting clinical trials (Checkmate459) | 2012–2016 | (12) |
| Pembrolizumab | PD-1 inhibitor | NCT02702401 (Keynote-240) | III | 408 | Prior sorafenib | NA | Promising phase II results (Keynote-224) | Ongoing | (42) |
| Durvalumab | PD-L1 inhibitor | NCT01693562 | I/II | 40 | Predominantly HCC with prior sorafenib | 13.2 mo | Promising result | Ongoing | (43) |
FDA, U S Food and Drug Administration; FGFR, fibroblast growth factor receptor; HCC, hepatocellular carcinoma; MET, N-methyl-N-nitrosoguanidine human osteosarcoma transforming gene; mTOR, mammalian target of rapamycin; PD-1, programmed cell death protein 1; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor.