Angiogenesis and immune checkpoint dual blockade: Opportunities and challenges for hepatocellular carcinoma therapy

Table 1 Currently approved anti-angiogenic therapy for advanced hepatocellular carcinoma

Therapy	Type	Line of therapy	Target	Study name	Primary outcome in the study (mo) (95%CI)	Adverse events in the study [affected/at risk (%)]
Anti-VEGFA
Bevacizumab (combination with atezolizumab)	mAb	First line (plus atezolizumab)	VEGF-A	IMBrave150	OS at CCOD 30 mo: 19.2 (17.0-23.7); PFS: 6.8 (5.6-8.3)	Gastrointestinal perforation [1/329 (0.30%)], haemorrhage [40/329 (12.15%)], hypertension [2/329 (0.61%)] and proteinuria [100/329 (30.40%)], etc.
Anti-VEGFR
Sorafenib	TKIs	First line	VEGFR1-3, c-Kit, PDGFR-b, and FLT-3	SHARP	OS: 10.8 (9.5-13.5); TTSP: 4.2 (3.5-4.2)	Diarrhea [166/297 (55.89%)], hand-foot skin reactions [2/297 (0.67%)], fatigue [145/297 (48.82%)], etc.
Lenvatinib	TKIs	First line	VEGFR1-3, FGFR1-4, PDGFRa, RET and c-Kit	REFLECT	OS: 13.6 (12.1–14.9); PFS: 7.4 (6.9–8.8)	Diarrhea [154/468 (33%)], decreased appetite [204/468 (44%)], etc.
Regorafenib	TKIs	Second line	VEGFR, RET, c-Kit, B-Raf, FGFR1 and PDGFR	RESORCE	OS: 10.7 (9.2-12.3); TTP:3.9 (2.9-4.26)	Toxicities were manageable this sorafenib- tolerant population and were similar to those observed with sorafenib, including diarrhea [163/374 (43.58%)], etc.
Cabozantinib	TKIs	Second and third line	VEGFR2, c-Kit, RET, FLT-3, Tie2, and Axl	CELESTIAL	OS: 10.2 (9.1-12.0)	Hypertension [137/467 (29.34%)]. Pneumonia [16/467 (3.43%)], etc.
Ramucirumab	mAb	Second line and AFP ≥ 400 ng/mL	VEGFR2	REACH-2	OS: 8.5 (7.0-10.6)	Hypertension [48/197 (24.37%)], hyponatremia [11/197 (5.58%)], etc.

TKIs: Tyrosine kinase inhibitor; CCOD: Clinical cut off date; OS: Overall survival; PFS: Progression free survival; TTSP: Time to symptomatic progression; TTP: Time to progression; CI: Confidence interval; AFP: Alpha fetoprotein; VEGFR: Vascular endothelial growth factor receptor; FLT: FMS related tyrosine kinase 1; FGFR: Fibroblast growth factor receptor; PDGFR: Platelet-derived growth factor receptor.

Table 2 Phase III clinical trials of combinations of anti-angiogenic inhibitors and immune checkpoint inhibitors in hepatocellular carcinoma

Trial name	Treatment	Setting	Primary endpoints	Current status	Enrollment, n
NCT03434379	Atezolizumab + bevacizumab	Advanced HCC; first line	OS, PFS	Active, not recruiting	558
NCT04770896	Atezolizumab + lenvatinib/sorafenib versus lenvatinib/sorafenib	Unresectable HCC; second line	OS	Recruiting	554
NCT03713593	Pembrolizumab + lenvatinib versus lenvatinib	Advanced HCC; first line	OS, PFS	Active, not recruiting	794
NCT03755791	Atezolizumab + cabozantinib versus sorafenib	Advanced HCC; first line	OS, PFS	Recruiting	740

OS: Overall survival; PFS: Progression free survival; HCC: Hepatocellular carcinoma.