Atezolizumab and bevacizumab as first line therapy in advanced hepatocellular carcinoma: Practical considerations in routine clinical practice

Table 1 Results of phase Ib GO30140 study

	Arm A	Arm F
	Atezolizumab and bevacizumab combination (n = 104), median follow up 12.4 mo	Atezolizumab and bevacizumab combination (n = 60), median follow up 6.6 mo	Atezolizumab monotherapy (n = 59), median follow up 6.7 mo
ORR, n (%)	37 (36)	12 (20)	10 (17)
CR, n (%)	12 (12)	1 (2)	3 (5)
DCR, n (%)	78 (75)	40 (67)	29 (49)
Median PFS, mo	7.4 (5.6-10.7)	5.6 (3.6-2.4)	3.4 (1.9-5.2)
HR (80%CI)	-	0.55 (0.40-0.74), P value (0.0108)
12 mo PFS (%)	38
12 mo OS (%)	63

ORR: Over all response rates; CR: Complete response; DCR: Disease control rate; PFS: Progression free survival; HR: Hazard ratio; OS: Overall survival.

Table 2 Results of IMBrave 150 trial

Results	Atezolizumab and bevacizumab arm	Sorafenib arm	Statistically significant
Estimated OS at 6 mo (%)	84.8	72.2
Estimated OS at 12 mo (%)	67.2	54.6
PFS (mo)	6.8	4.3	HR for progression or death was 0.59 (0.47-0.76) P < 0.0001
Confirmed ORR as per independent mRECIST assessment (%)	27.3	11.9
As per HCC specific mRECIST CR (%)	5.5	-
Disease Control Rate (ORR + SD) (%)	73.6	55.3

HCC: Hepatocellular carcinoma; OS: Overall survival; PFS: Progression free survival; ORR: Objective response rate; mRECIST: Modified response evaluation criteria in solid tumours.

Table 3 Grade 5 events in both the arms IMBrave 150 trial

Atezolizumab and bevacizumab (n = 15), grade 5 adverse events	Sorafenib (n = 9), grade 5 adverse events
Gastrointestinal Haemorrhage (3)	Death (2)
Pneumonia (2)	Hepatic cirrhosis (2)
Empyema, gastric ulcer perforation, abnormal hepatic function, liver injury, multi-organ dysfunction syndrome, esophageal varices haemorrhage, subarachnoid haemorrhage, respiratory distress, sepsis and cardiac arrest (1 in each patient)	Cardiac arrest, cardiac failure, general physical health deterioration, hepatitis E, peritoneal haemorrhage (1 in each patient)

Table 4 Advanced hepatocellular carcinoma in special subset of population with absolute and relative contraindication for atezolizumab and bevacizumab combination

Special population	Absolute contraindication for atezolizumab and bevacizumab combination	Relative contraindication for atezolizumab and bevacizumab combination	Comments
Solid organ transplantation	Yes	N/A	If HCC in patients with liver transplant, transplant rejection can be potentially lethal. Sorafenib or lenvatinib are preferred first line options
HIV patients	N/A	No data	This was an exclusion criteria in IMBrave150 trial. The NCT04487067 AMETHISTA study of atezolizumab and bevacizumab in HCC is including patients with HIV disease who are stable on HAART, with CD4+T cell count ≥ 200/µL, and an undetectable viral load
Prior or active autoimmune disease (AID)	Yes, in patients when AID including autoimmune hepatitis, reactivation can be life threatening, neurological or neuromuscular disorders, poorly controlled AID on high dose immunosuppression	Can be used after discussion with patients and care givers about risk and benefit if do not fall in subgroups described in absolute contraindications	Patients with symptomatic AID are at higher risk for flare. Sorafenib or lenvatinib are preferred first line options in such patients
Inflammatory bowel disease	Bevacizumab can increase complication risk in patients with Crohn’s disease with fistula	Can be used after discussion with patients and care givers about risk and benefit in patients with quiescent disease	Selective immunosuppressants like vedolizumab may be better before considering the ICP therapy
Significant cardiovascular/thromboembolic disease	N/A	Bevacizumab increases risk of HTN, thromboembolic and cardiovascular events	Can be used after discussion with patients and care givers and treating hypertension
Haemodialysis	N/A	No data available, can be considered after discussing risk and benefit and limited evidence	A recent study of 55 patients with metastatic RCC on haemodialysis showed relative safety of sorafenib, nivolumab and atezolizumab in small subgroup of patients[33]

N/A: Not applicable; HTN: Hypertension; RCC: Renal cell carcinoma; HCC: Hepatocellular carcinoma; HIV: Human immunodeficiency virus; ICP: Individualized care plan.