Safety and Efficacy of Atezolizumab and Bevacizumab Combination as a First Line Treatment of Advanced Hepatocellular Carcinoma

Figures & data

Table 1 Phase III Trials of Immune-Checkpoint Inhibitor-Based Treatment in the First-Line Setting

Trial Name	Investigated Regimen	Primary Endpoint	Efficacy Results
IMbrave150^Citation10,Citation11	1200 mg of atezolizumab + 15 mg/kg bevacizumab iv q3w vs Sorafenib 400 mg bid po	Co-primary endpoints: OS, PFS	mOS 19.2 months (95% CI, 17.0–23.7) vs 13.4 months (95% CI, 11.0–16.9) HR 0.66 (95% CI, 0.52–0.85; p<0.001) mPFS 6.9 months (95% CI, 5.7–8.6) vs 4.3 months (95% CI, 4.0–5.6) HR 0.65 (95% CI, 0.53–0.81; p<0.001)
ORIENT-32^Citation13	Sintilimab 200 mg + IBI305 15 mg/kg q3w vs Sorafenib 800 mg po	Co-primary endpoints: OS, PFS	mOS not reached vs 10.4 months (95% CI, 8.5–not reached) HR 0.57 (95% CI, 0.43–0.75; p<0.0001) mPFS 4.6 months (95% CI, 4.1–5.7) vs 2.8 months (95% CI, 2.7–3.2) HR 0.56 (95% CI, 0.46–0.70; p<0.0001)
HIMALAYA^Citation14	Tremelimumab 300 mg iv + durvalumab 1500 mg iv q4w (STRIDE) vs Durvalumab 1500 mg iv q4w vs Sorafenib 400 mg bid po	OS for STRIDE vs sorafenib	mOS 16.43 months (95% CI, 14.1–19.5) vs 13.77 months (95% CI, 12.2–16.1) HR for STRIDE vs sorafenib 0.78 (96.02% CI, 0.65–0.93; p=0.0035)
COSMIC-312^Citation18	Cabozantinib 40 mg po + atezolizumab 1200 mg iv q3w vs Sorafenib 400 mg bid po vs Cabozantinib 60 mg po	Dual primary endpoints: OS, PFS of combination therapy vs sorafenib	mOS 15.4 months (96% CI, 13.7–17.7) vs 15.5 months (96% CI, 12.1-NE) HR 0.90 (96% CI, 0.69–1.18; p=0.44) mPFS 6.8 months (99% CI, 5.6–8.3) vs 4.2 months (99% CI, 2.8–7.0) HR 0.63 (99% CI, 0.44–0.91; p=0.0012)
LEAP-002^Citation19	Lenvatinib (8 mg/day or 12 mg/day according to body weight) + pembrolizumab 200 mg iv q3w vs Lenvatinib + placebo	Co-primary endpoints: OS, PFS	mOS 21.2 months (95% CI, 19.0–23.6) vs 19.0 months (95% CI, 17.2–21.7) HR 0.840 (95% CI, 0.708–0.997; p=0.0227) mPFS 8.2 months (95% CI, 6.4–8.4) vs 8.0 months (95% CI, 6.3–8.2) HR 0.867 (95% CI, 0.734–1.024; p=0.0466)
CARES-310^Citation16	Camrelizumab 200 mg iv q2w + rivoceranib 250 mg po vs Sorafenib 400 mg bid po	Co-primary endpoints: OS, PFS	mOS 22.1 months (95% CI, 19.1–27.2) vs 15.2 months (95% CI, 13.0–18.5) HR 0.62 (95% CI, 0.49–0.80; p<0.0001) mPFS 5.6 months (95% CI, 5.5–6.3) vs 3.7 months (95% CI, 2.8–3.7) HR 0.52 (95% CI, 0.41–0.65; p<0.0001)
CheckMate 459^Citation17	Nivolumab 240 mg iv q2w vs Sorafenib 400 mg bid po	OS	mOS 16.4 months (95% CI, 13.9–18.4) vs. 14.7 months (11.9–17.2) HR 0.85 (95% CI, 0.72–1.02; p=0.075)
RATIONALE-301^Citation15	Tislelizumab 200 mg iv q3w vs Sorafenib 400 mg bid po	OS (non inferiority)	mOS 15.9 months (5% CI, 13.2–19.7) vs 14.1 months (95% CI, 12.6–17.4) HR 0.85 (95.003% CI, 0.712–1.019; p=0.039)

Abbreviations: HCC, hepatocellular carcinoma; iv, intravenously; q3w, every 3 weeks; vs, versus; bid, twice a day; po, per os; OS, overall survival; PFS, progression-free survival; mOS, median overall survival; mPFS, median progression-free survival; q4w, every 4 weeks; HR, hazard ratio; NE, not estimable.

Table 2 Efficacy of Currently Approved First-Line Treatment Options for Advanced HCC

Drugs	Sorafenib^Citation4	Lenvatinib^Citation6	Atezolizumab Plus Bevacizumab^Citation11	Durvalumab Plus Tremelimumab (STRIDE)^Citation14
Median OS, months (95% CI)	10.7 (9.4–13.3)	13.6 (12.1–14.9)	19.2 (17.0–23.7)	16.4 (14.2–19.6)
HR (95% CI)	0.69 (0.55–0.87)	0.92 (0.79–1.06)	0.66 (0.52–0.85)	0.78 (0.65–0.93)
P value	<0.001	–	<0.001	0.0035
Median PFS, months	5.5 (4.1–6.9)	7.4 (6.9–8.8)	6.9 (5.7–8.6)	3.8 (3.7–5.3)
HR (95% CI)	0.58 (0.45–0.74)	0.66 (0.57–0.77)	0.65 (0.53–0.81)	0.90 (0.77–1.05)
P value	<0.001	<0.0001	<0.001	–
ORR, %	2.0	24.1	30.0	20.1
DCR, %	43.0	75.5	74.0	60.1

Abbreviations: Abbreviations: OS, overall survival; HR, hazard ratio; 95% CI, 95% confidence interval; PFS, progression free survival; ORR, objective response DCR, disease control rate.

Figure 1 Mechanism of action of atezolizumab and bevacizumab. Atezolizumab and bevacizumab act on a positive feedback loop made of VEGF released by tumor cells and inhibitory cytokines produced by MDSCs and T-reg cells. The inhibitory cytokines in turn increase the expression of PD-L1 on tumor cells inducing immune system inhibition.

Note: Created with BioRender.com.

Abbreviations: HCC, hepatocellular carcinoma; IL-10, interleukin 10; MHC-I, major histocompatibility complex I; MDCSs, medullary dendritic stem cells; PD1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PD-L2, programmed cell death protein ligand 2; TCR, T-cell receptor; TGF-beta, transforming growth factor β; VEGF, vascular endothelial growth factor.

Table 3 Efficacy Outcomes of the Phase III IMbrave150 Trial (Updated Analysis)¹¹

Outcome	Atezolizumab + Bevacizumab (n=336)	Sorafenib (n=156)	Hazard Ratio	P value
Overall survival (months)
Median (95% CI)	19.2 (17.0–23.7)	13.4 (11.4–16.9)	0.66 (0.42–0.85)	p<0.001
Progression-free survival (months)
Median (95% CI)	6.9 (5.7–8.6)	4.3 (4.0–5.6)	0.65 (0.53–0.81)	p<0.001
Confirmed ORR per RECIST 1.1, % (95% CI)	29.8 (24.8–35.0)	11.3 (6.9–17.3)	-	-
Complete response, n (%)	25 (7.7)	1 (0.6)
Partial response, n (%)	72 (22.1)	17 (10.7)
Stable disease, n (%)	144 (44.2)	69 (43.4)
Confirmed ORR per mRECIST, % (95% CI)	35.4 (30.2–40.9)	13.9 (8.9–20.3)	-	-
Complete response, n (%)	39 (12)	4 (2.5)
Partial response, n (%)	76 (23.4)	18 (11.4)
Stable disease, n (%)	121 (37.2)	65 (41.1)
Disease control rate per RECIST 1.1, n (%)	241 (74)	87 (50.7)	-	-
per mRECIST, n (%)	236 (72.6)	87 (55)	-	-
Median duration of response (months)
per RECIST 1.1 (95% CI)	18.1 (14.6–NE)	14.9 (4.9–17.0)	-	-
per mRECIST (95% CI)	16.3 (13.1–21.4)	12.6 (6.1–17.7)	-	-

Abbreviations: ORR, Objective response rate; 95% CI, 95% confidence interval; -, not available; NE, not estimable.

Table 4 Safety Profile of the Combination of Atezolizumab Plus Bevacizumab Reported in the Phase III IMbrave150 Trial (Updated Analysis)¹¹

	Atezolizumab + Bevacizumab (n=329)	Sorafenib (n=156)
Any grade AEs, n (%)	322 (98)	154 (99)
Grade 3–4 AEs, n (%)	207 (63)	89 (57)
Serious AEs, n (%)	160 (49)	51 (33)
Grade 5 AEs, n (%)	23 (7)	9 (6)
Any grade TRAEs, n (%)	284 (86)	148 (95)
Grade 3–4 TRAEs, n (%)	143 (43)	72 (46)
Serious TRAEs, n (%)	76 (23)	25 (16)
Grade 5 TRAEs, n (%)	6 (2)	1 (<1)
Most common TRAEs of any grade	Proteinuria	PPE
	Hypertension	Diarrhea
	AST increase	Hypertension
Most common G≥3 TRAEs	Hypertension	Hypertension
	AST increase	PPE
	Proteinuria	Diarrhea

Notes: Adapted from Cheng AL, Qin S, Ikeda et al Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76(4):862–873. Creative Commons.¹¹

Abbreviations: AEs, adverse events; TRAEs, treatment-related adverse events; G≥3, grade ≥3; AST, aspartate aminotransferase; PPE, palmar-plantar erythrodysesthesia.

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