Table 2:
Outcomes from included studies on the benefit of second-line systemic therapy following sorafenib
| Study | Treatment allocation | N (evaluated) | Median OS (months) | Median TTP (months) | Median PFS (months) | ORR No. (%) | Terminated early? |
|---|---|---|---|---|---|---|---|
| Regorafenib + BSC vs. placebo + BSC | |||||||
| Bruix, 2017 (41) | Regorafenib + BSC | 379 | 10.6 | 3.2 | 3.1 | 40 (11) | No |
| Placebo + BSC | 194 | 7.8 | 1.5 | 1.5 | 8 (4) | ||
| HR 0.63; 95% CI 0.50–0.79; p <0.0001 | HR 0.44; 95% CI 0.36–0.55; p <0.0001 | HR 0.46; 95% CI 0.37–0.56; p <0.0001 | p = 0.0047 | ||||
| Cabozantinib vs. placebo | |||||||
| Abou-Alfa, 2018 (44) | Cabozantinib | 470 | 10.2 | NR | 5.2 | 18 (4) | Yes, for efficacy |
| Placebo | 237 | 8.0 | 1.9 | 1 (<1) | |||
| HR 0.76; 95% CI 0.63–0.92; p = 0.005 | HR 0.44; 95% CI 0.36–0.52; p <0.001 | p = 0.009 | |||||
| Ramucirumab + BSC vs. placebo + BSC | |||||||
| REACH – Zhu, 2015 (38) | Ramucirumab + BSC | 283 (277) | 9.2 | 3.5 | 2.8 | 20 (7) | No |
| Placebo + BSC | 282 (276) | 7.6 | 2.6 | 2.1 | 2 (<1.0) | No | |
| HR 0.87; 95% CI 0.72–1.05; p = 0.14 | HR 0.59; 95% CI 0.49–0.72; p <0.0001 | HR 0.63; 95% CI 0.52–0.75; p <0.0001 | p <0.0001 | ||||
| REACH-2, 2019 (40) | Ramucirumab | 197 | 8.5 | 2.8 | 9 (5) | ||
| Placebo + BSC | 95 | 7.3 | 1.6 | 1 (1) | |||
| HR 0.710; 95% CI 0.53–0.95; p = 0.0199 | HR 0.452; 95% CI 0.34–0.60; p <0.0001 | p = 0.1697 | |||||
| ADI-peg 20 + BSC vs. placebo + BSC | |||||||
| Abou-Alfa, 2018 (37) | ADI-peg 20 + BSC | 424 | 7.8 | NR | 2.6 | 2 (<1.0) | No |
| Placebo + BSC | 211 | 7.4 | 2.6 | 6 (2.8) | |||
| HR 1.022; 95% CI 0.847–1.233; p = 0.884 | HR 1.175; 95% CI 0.964–1.432; p = 0.075 | p = NR | |||||
| S-1 vs. placebo | |||||||
| S-CUBE, 2017 (45) | S-1 | 222 | 11.1 | 2.6 | 2.6 | 12 (5) | No |
| Placebo | 111 | 11.2 | 1.4 | 1.4 | 1 (1) | ||
| HR 0.86; 95% CI 0.067–1.10; p = 0.220 | HR 0.59; 95% CI 0.46–0.76; p <0.0001 | HR 0.60; 95% CI 0.46–0.77; p <0.0001 | p = 0.068 | ||||
| Brivanib + BSC vs. placebo + BSC | |||||||
| BRISK-PS – Llovet, 2013 (46) | Brivanib + BSC | 263 (261) | 9.4 | 4.2 | NR | 10 | No |
| Placebo + BSC | 132 (131) | 8.2 | 2.7 | 2 | |||
| HR 0.89; 95% CI 0.69–1.15; p = 0.3307 | HR 0.56; 95% CI 0.42–0.76; p <0.001 | p = 0.0030 | |||||
| Tivantinib vs. placebo | |||||||
| Santoro, 2013 (47) | Tivantinib | 71 | 6.6 | 1.6 | 1.5 | 3 | No |
| Placebo | 36 | 6.2 | 1.4 | 1.4 | 0 | ||
| HR 0.90; 95% CI 0.57–1.40; p = 0.63 | HR 0.64; 90% CI†, 0.43–0.94; p = 0.04 | HR 0.67; 95% CI 0.44–1.04; p = 0.06 | |||||
| Rimassa, 2018 (48) | Tivantinib | 226 | 8.4 | 2.4 | 2.1 | NR | No |
| Placebo | 114 | 9.1 | 3.0 | 2.0 | |||
| HR 0.97; 95% CI 0.75–1.25; p = 0.81 | HR 0.96; 95% CI 0.74–1.25; p = 0.76 | HR 0.96; 95% CI 0.75–1.22; p = 0.72 | |||||
| RO5137382/GC33 vs. placebo | |||||||
| Yen, 2014 (49), abstract | RO5137382/GC33 | 121 | 6.8 | 2.9 | 2.6 | NR | No |
| Placebo | 64 | 6.7 | 1.7 | 1.5 | |||
| p = 0.99 | p = 0.85 | p = 0.87 | |||||
| Everolimus + BSC vs. placebo + BSC | |||||||
| Zhu, 2014 (50) | Everolimus + BSC | 362 | 7.6 | NR | NR | 2.2 | No |
| Placebo + BSC | 184 | 7.3 | NR | 1.6 | |||
| HR 1.05; 95% CI 0.86–1.27; p = 0.68 | HR 0.93; 95% CI 0.75–1.15; p = ns | p = NR | |||||
| Pembrolizumab + BSC vs. placebo + BSC | |||||||
| Finn, 2019 (51) | Pembrolizumab + BSC | 278 | 13.9 | 3.8 | 3.0 | 51 (18.3) | No |
| Placebo + BSC | 135 | 10.6 | 2.8 | 2.8 | 6 (4.4) | ||
| HR 0.78; 95% CI 0.61–1.00; p = 0.0238‡ | HR 0.69; 95% CI 0.54–0.88; p = 0.0011 | HR 0.71; 95% CI 0.57–0.90; p = 0.0022‡ | p = 0.00007 | ||||
†
Note this is a 90% confidence interval
‡
Did not meet pre-specified boundaries for statistical significance set prior to the start of the trial
OS = Overall survival; TTP = Time to progression; PFS = Progression-free survival; ORR = Objective response rate; BSC = Best supportive care; HR = Hazard ratio; CI = Confidence interval; NR = Not reported; ns = Not significant