Table 3.
Representative clinical trials of ICI-based systemic therapy for unresectable HCC
| Study | Mechanism of action | Treatment (no. of subjects) | Overall survival (OS)/ Progression-free survival (PFS) (months) (median/ 95% C.I.) | Hazard ratios | Objective response rate (%, 95% C.I.) RECIST 1.1/ modified REICST |
|---|---|---|---|---|---|
| ICI-based combination | |||||
| Finn, 2020; Cheng 2021 (IMBrave150) | Anti-PDL1 plus anti-VEGF | Atezolizumab 1200 mg + bevacizumab 15 mg/kg Q3W (336) |
19.2 (17.0–23.7)/ 6.9 (5.7–8.6) |
OS: 0.66 (0.52–0.85) p < 0.001# |
30.0 (25.0–35.0)/ 33.2 (28.1–38.6) |
| Multikinase inhibitor (MKI) | Sorafenib 400 mg BID (165) |
13.4 (11.4–16.9)/ 4.3 (4.0–5.6) |
PFS: 0.65 (0.53–0.81) p < 0.001# |
11.0 (7.0–17.0)/ 13.3 (8.4–19.6) | |
| Ren, 2021 (ORIENT-32) | Anti-PD1 plus anti-VEGF | Sintilimab 200 mg + bevacizumab biosimilar 15 mg/kg Q3W (380) |
Not reached/ 4.6 (4.1–5.7) |
OS: 0.57, (0.43–0.75) p < 0.0001# |
21 (17–25)/ 24 (20–29) |
| MKI | Sorafenib 400 mg BID (191) |
10.4 (8.5–NE) / 2.8 (2.7–7.0) |
PFS: 0.56, 9 (0.46–0.70) p < 0.0001# |
4 (2–8)/ 8 (4–13) |
|
| Kelley, 2022 (COSMIC-312) | Anti-PDL1 plus MKI | Atezolizumab 1,200 mg Q3W + cabozantinib 40 mg QD (432) |
15.4 (13.7–17.7)/ 6.8 (5.6–8.3) |
OS: 0.90 (0.69–1.18) p = 0.44 |
11.0 (8.1–14.2)/ NA |
| MKI | Sorafenib 400 mg BID (217) |
15.5 (12.1–NE)/ 4.2 (2.8–3.2) |
PFS: 0.63, (0.44–0.91) p = 0.0012# |
4.0 (1.6–7.1)/ NA |
|
| Abou-Alfa, 2022 (HIMALAYA) | Anti-PDL1 plus anti-CTLA4 | Durvalumab 1500 mg Q4W + Tremelimumab 300 mg 1 dose (393) |
16.4 (14.2–19.6)/ 3.78 (3.68–5.32) |
OS: 0.78 (0.65–0.93) p = 0.0035# |
20.1/ NA |
| MKI | Sorafenib 400 mg BID (389) |
13.8 (12.3–16.1)/ 3.6 (3.2–3.8) |
PFS: 0.90, (0.77–1.05) p = NS |
5.1/ NA |
|
| Finn, 2022 (LEAP-002) | Anti-PD1 plus MKI | Pembrolizumab 200 mg Q3W + Lenvatinib 8 mg (BW < 60 kg) or 12 mg (BW ≥ 60 kg) QD (395) |
21.2 (19.0–23.6)/ 8.2 (6.4- 8.4) |
OS: 0.84, (0.70–0.99) p = 0.0227 |
26.1/ 40.8 |
| MKI | Lenvatinib 8 mg (BW < 60 kg) or 12 mg (BW ≥ 60 kg) QD (399) |
19.0 (17.2–21.7)/ 8.0 (6.3–8.2) |
PFS: 0.83, (0.71–0.97) p = 0.0466 |
17.5/ 34.1 |
|
| Qin, 2022 | Anti-PD1 plus MKI | Camrelizumab (200 mg Q2W + rivoceranib 250 mg QD (272) |
22.1 (19.1–27.2)/ 5.6 (5.5- 6.3) |
OS: 0.62, (0.49–0.80) p < 0.0001# |
25.4 (20.3–31.0)/ 33.1 (27.5–39.0) |
| MKI | Sorafenib 400 mg BID (271) |
15.2 (13.0–18.5)/ 3.7 (2.7–3.7) |
PFS: 0.52, (0.41–0.65) p < 0.0001# |
5.9 (3.4–9.4)/ 10.0 (6.7–10.2) |
|
| Single-agent ICI | |||||
| Finn, 2020 (KEYNOTE-240) | Anti-PD1 | Pembrolizumab 200 mg Q3W (278) |
13.9 (11.6–16.0)/ 3.0 (2.8–4.1) |
OS: 0.78, (0.61–0.99) p = 0.0238 |
18.3 (14.0–23.4)/NA |
| Placebo | Placebo (135) |
10.6 (8.3–13.5)/ 2.8 (1.6–3.0) |
PFS: 0.71, (0.57–0.90) p = 0.0022 |
4.4 (1.6–9.4)/NA | |
| Yau, 2022 (CheckMate-459) | Anti-PD1 | Nivolumab 240 mg Q2W (371) |
16.4 (13.9–18.4)/ 3.7 (3.1–3.9) |
OS: 0.85, (0.72–1.02) p = 0.075 |
15 (12–19)/NA |
| MKI | Sorafenib 400 mg BID (372) |
14.7 (11.9–17.2)/ 3.8 (3.7–4.5) |
PFS: 0.93, (0.79–1.10) p = NS |
7 (5–10)/NA | |
| Abou-Alfa, 2022 (HIMALAYA) | Anti-PD1 | Durvalumab 1500 mg Q4W (393) |
16.4 (14.2–19.6)/ 3.8 (3.7–5.3) |
OS: 0.78, (0.65–0.93) p = 0.0674 noninferiority |
17.0/NA |
| MKI | Sorafenib 400 mg BID (389) |
13.8 (12.2–16.1)/ 4.1 (3.8–5.5) |
PFS 0.90, (0.77–1.05) p = NS |
5.1/NA | |
| Qin, 2022 (Rationale-301) | Anti-PDL1 | Tislelizumab 200 mg Q3W (342) |
15.9 (13.2–19.7)/ 2.1 (2.1–3.5) |
OS: 0.85, (0.71–1.01) p = 0.0398 noninferiority |
14.3 (10.8–18.5)/NA |
| MKI | Sorafenib 400 mg BID (332) |
14.1 (12.6–17.4)/ 3.4 (2.2–4.1) |
PFS: 1.11, (0.92–1.33) p = NS |
5.4 (3.2–8.4)/NA | |
| Qin, 2022 (KEYNOTE-394) | Anti-PD1 | Pembrolizumab 200 mg Q3W (300) |
15.9 (13.2–19.7)/ 2.1 (2.1–3.5) |
OS: 0.79, (0.63–0.99) p = 0.0180# |
12.7 (9.1–17.0)/ NA |
| Placebo | Placebo (153) |
13.0 (10.5–15.1)/ 2.3 (1.4–2.8) |
PFS: 0.74, (0.60–0.92 p = 0.0032# |
1.3 (0.2–4.6)/ NA |
|
#: statistically significant difference as defined by the trial protocol
1RECIST: the types of response a patient can have been a complete response (CR), a partial response (PR), progressive disease (PD), and stable disease (SD). CR: Disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study
2Modified RECIST: estimating the reduction in “viable tumor volume” for HCC, using the same definition of volume change as RECISIT
3Objective response rate: CR + PR proportion
4Overall survival (OS) is defined as the time from randomization to death; progression-free survival (PFS) is defined as the time from randomization to progression or death. Imaging response assessment will be done according to study protocol and the RECIST.
5QD: once daily; BID: twice daily; Q2W: every 2 weeks; Q3W: every 3 weeks; Q4W: every 4 weeks; NA: not available