IMbrave 050: A Phase III Trial of Atezolizumab Plus Bevacizumab in High-Risk Hepatocellular Carcinoma after Curative Resection or Ablation

Figures & data

Infographic: A PDF version of this infographic is available as supplemental material.

Figure 1. Interaction between VEGF and the cancer immunity cycle.

Reproduced with permission from [36] © Elsevier (2018).

Table 1. Summary of results from randomized trials evaluating atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.

End point	GO30140: Arm F		IMbrave 150
	Atezolizumab (n = 59)	Atezolizumab + bevacizumab (n = 60)	Sorafenib (n = 165)	Atezolizumab + bevacizumab (n = 336)
Median duration of follow-up	6.6 months	6.7 months	8.6 months
PFS events, n (%)	35 (58)	39 (66)
Median PFS, months (95% CI)	3.4 (1.9–5.2)	5.6 (3.6–7.4)	4.3 (4.0–5.6)	6.8 (5.7–8.3)
Stratified PFS HR (CI)	0.55 (80% CI: 0.40–0.74) p = 0.0108		0.59 (95% CI: 0.47–0.76) p ≤ 0.0001
Median OS, months (95% CI)	NE (8.3, NE)	NE (8.2, NE)	13.2 (10.4, NE)	NE
Stratified OS HR (CI)	0.78 (80% CI: 0.5–1.2)		0.58 (0.42–0.79) p = 0.0006
ORR, % (95% CI)	17 (8–29)	20 (11–32)	12 (7–18.0)	27 (23–33)
Difference in ORR (p-value)	3% (p-value NR)		15% (p < 0.0001)
Ongoing response, n (%)	8 (80)	12 (100)	13 (68)	77 (87)

HR: Hazard ratio; ITT: Intent-to-treat; NE: Not estimable; NE: Not Evaluable; NR: Not Reported; NS: Not significant; ORR: Overall response rate; OS: Overall survival; PFS: Progression-free survival.

Table 2. Immune mechanisms implicated in hepatocellular carcinoma recurrence following curative resection or ablation.

Immune cells/checkpoints	Findings in HCC	Ref.
Infiltration of immune effectors
Immunoscore	↑ CD3^+/CD8^+ infiltration associated with ↓ recurrence	[44]
NKT cells & IFN-γ	↓NKT cells and IFN-γ independently predict recurrence and survival	[46]
Immune gene signatures	Multiple immune gene signatures associated with the prognosis of resected HCC	[47]
Accumulation of immunosuppressive cells
Tregs	↑Tregs associated with ↓ OS and DFS	[48] [49]
MDSCs	↑ MDSCs correlated with early recurrence after resection ↑ PD-L1^+ MDSCs in HCC	[50] [51] [52]
Macrophages	↑ peritumoral MΦ associated with recurrence and poor survival after hepatectomy	[53] [54]
Upregulation of negative immune checkpoints
PD-L1	↑PD-L1 associated with high-risk factors for recurrence Unclear impact on recurrence/survival	[55] [56] [57]

DFS: Disease-free survival; HCC: Hepatocellular carcinoma; MDSC: Myeloid derived suppressor cell; OS: Overall survival.

Figure 2. IMbrave 050 study design.

Diagnosis of HCC by radiological criteria and/or pathological confirmation.

CR: Complete response by imaging; EASL: European Association for the Study of the Liver; HCC: Hepatocellular carcinoma; IRF: Independent review facility; MWA: Microwave ablation; q3w: Every 3 weeks; R0: Absence of microscopic tumor invasion of the resection margin; RFA: Radiofrequency ablation; R: Randomization.

Table 3. Criteria for high risk of hepatocellular carcinoma recurrence.

Curative treatment	Criteria
Resection	Up to three tumors, with largest tumor >5 cm regardless of vascular invasion (microvascular invasion or macrovascular invasion of Vp1/Vp2) or poor tumor differentiation (Grade 3 or 4) Four or more tumors, with largest tumor ≤5 cm regardless of vascular invasion (microvascular invasion or macrovascular invasion of Vp1/Vp2) or poor tumor differentiation (Grade 3 or 4) Up to three tumors, with largest tumor ≤5 cm with vascular invasion (microvascular invasion or macrovascular invasion of Vp1/Vp2) and/or poor tumor differentiation (Grade 3 or 4)
Ablation	Single tumor >2 cm but ≤5 cm Multiple tumors (up to four tumors), all ≤5 cm

Table 4. Definition of types of vascular invasion in hepatocellular carcinoma.

Type of vascular invasion	Definition	Eligible for IMbrave 050
Portal vein
Vp0	No evidence of tumor thrombus invasion	Yes
Vp1	Tumor thrombus distal to but not in the second-order branches	Yes
Vp2	Tumor thrombus in the second-order branches	Yes
Vp3	Tumor thrombus in the first-order branches	No
Vp4	Tumor thrombus in the main trunk or contralateral or both	No
Hepatic vein
Vv0	Absence of tumor thrombus invasion of the hepatic vein	Yes
Vv1	Tumor thrombus invasion of peripheral branches of the hepatic vein	No
Vv2	Tumor thrombus invasion of the right, middle or left hepatic vein, the inferior right hepatic vein, or the short hepatic vein	No
Vv3	Tumor thrombus invasion of the inferior vena cava	No
Microvascular invasion
N/A	Presence of microscopic thrombi within the central hepatic vein, the portal vein or large capsular vessels	Yes

Hegde PS , WallinJJ, MancaoC. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin. Cancer Biol.52, 117–124 (2018).

 PubMed Web of Science ®Google Scholar

Gabrielson A , WuY, WangHet al. Intratumoral CD3 and CD8 T-cell densities associated with relapse-free survival in HCC. Cancer Immunol Res.4(5), 419–430 (2016).

 PubMed Web of Science ®Google Scholar

Xiao YS , GaoQ, XuXNet al. Combination of intratumoral invariant natural killer T cells and interferon-gamma is associated with prognosis of hepatocellular carcinoma after curative resection. PLoS ONE8(8), e70345 (2013).

 PubMed Web of Science ®Google Scholar

Foerster F , HessM, Gerhold-AyAet al. The immune contexture of hepatocellular carcinoma predicts clinical outcome. Sci. Rep.8(1), 5351–5351 (2018).

 PubMedGoogle Scholar

Sun L , XuG, LiaoWet al. Clinicopathologic and prognostic significance of regulatory T cells in patients with hepatocellular carcinoma: a meta-analysis. Oncotarget8(24), 39658–39672 (2017).

 PubMedGoogle Scholar

Gao Q , QiuS-J, FanJet al. Intratumoral balance of regulatory and cytotoxic T Cells Is associated with prognosis of hepatocellular carcinoma after resection. J. Clin. Oncol.25(18), 2586–2593 (2007).

 PubMed Web of Science ®Google Scholar

Gao X-H , TianL, WuJet al. Circulating CD14+HLA-DR-/low myeloid-derived suppressor cells predicted early recurrence of hepatocellular carcinoma after surgery. Hepatol. Res.47(10), 1061–1071 (2017).

 PubMed Web of Science ®Google Scholar

Arihara F , MizukoshiE, KitaharaMet al. Increase in CD14+HLA-DR-/low myeloid-derived suppressor cells in hepatocellular carcinoma patients and its impact on prognosis. Cancer Immunol. Immunother.62(8), 1421–1430 (2013).

 PubMed Web of Science ®Google Scholar

Iwata T , KondoY, KimuraOet al. PD-L1(+)MDSCs are increased in HCC patients and induced by soluble factor in the tumor microenvironment. Sci. Rep.6, 39296 (2016).

 PubMed Web of Science ®Google Scholar

Zhu X-D , ZhangJ-B, ZhuangP-Yet al. High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J. Clin. Oncol.26(16), 2707–2716 (2008).

 PubMed Web of Science ®Google Scholar

Capece D , FischiettiM, VerzellaDet al. The inflammatory microenvironment in hepatocellular carcinoma: a pivotal role for tumor-associated macrophages. BioMed Res. Int.2013, 15 (2013).

 Web of Science ®Google Scholar

Calderaro J , RousseauB, AmaddeoGet al. Programmed death ligand 1 expression in hepatocellular carcinoma: relationship with clinical and pathological features. Hepatology64(6), 2038–2046 (2016).

 PubMed Web of Science ®Google Scholar

Shi F , ShiM, ZengZet al. PD-1 and PD-L1 upregulation promotes CD8+ T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int. J. Cancer128(4), 887–896 (2011).

 PubMed Web of Science ®Google Scholar

Liu G-M , LiX-G, ZhangY-M. Prognostic role of PD-L1 for HCC patients after potentially curative resection: a meta-analysis. Cancer Cell Int.19, 22–22 (2019).

 PubMed Web of Science ®Google Scholar