Antiangiogenic treatment in hepatocellular carcinoma: the balance of efficacy and safety

Figures & data

Figure 1 Overall survival in patients with advanced hepatocellular carcinoma treated with sorafenib (all studies, including the pivotal SHARP trial),²¹ sunitinib (SUN1170 trial),²⁸ brivanib (BRISK-FL trial), linifanib, (LIGHT trial),²⁹ and sorafenib plus erlotinib (SEARCH trial),¹³⁵ according to current head-to-head Phase III studies.

Table 1 Efficacy of systemic targeted monotherapy in hepatocellular carcinoma according to current Phase I–III studies

Author	Year	Phase	Investigational drug	n	RR	DCR	PFS/TTP	OS
O’Neil et al^Citation68,a	2009	II	AZD 6244	16	0	37.5	nr	nr
Schwartz et al^Citation69,b	2006	II	Bevacizumab	30	6.7	57	nr/6.4	nr
Siegel et al^Citation70,b	2008	II	Bevacizumab	46	13	65	6.9/nr	12.4
Boige et al^Citation71	2012	II	Bevacizumab	43	14	42	nr	nr
Kim et al^Citation72	2012	II	Bortezomib	35	4	37	nr/1.6	6.0
Park et al^Citation33	2011	II	Brivanib	55	7.2	47.2	2.7	10.0
Finn et al^Citation32	2012	II	Brivanib	46	4.3	45.7	nr/2.7	9.8
Johnson et al^Citation35	2012	III	Brivanib	1,155 (577 brivanib)	12	66	nr/4.2	9.9
Llovet et al^Citation34	2012	III	Brivanib	395 (263 brivanib)	11.5	71.2	nr/4.2	9.4
Gruenwald et al^Citation73	2007	II	Cetuximab	27	0	44	2.0/1.9	nr
Zhu et al^Citation74	2007	II	Cetuximab	30	0	17	1.4/nr	9.6
Philip et al^Citation75	2005	II	Erlotinib	38	9	50	3.2/nr	13.0
Thomas et al^Citation76	2007	II	Erlotinib	40	0	43	3.1/nr	6.25 (10.75)c
Shiah et al^Citation77	2013	I	Everolimus	39	nr	44.4/71.4d	nr	nr
Zhu et al^Citation78	2011	I/II	Everolimus	25	4	44	3.8/nr	8.4
O’Dwyer et al^Citation79	2006	II	Gefitinib	31	3	22.5	2.8/nr	6.5
Lin et al^Citation80	2008	II	Imatinib	15	0	13.3	nr/nr	nr
Bekaii-Saab et al^Citation81	2009	II	lapatinib	26	0	40	1.9/nr	12.6
Ramanathan et al^Citation82	2009	II	lapatinib	40	5	35	2.3/nr	6.2
Toh et al^Citation83	2013	II	linifanib	44	9.1	nr	nr/3.7	9.4
Cainap et al^Citation29	2013	III	linifanib	1,035 (1:1 randomization)	nr	nr	nr/5.4	9.1
Rizell et al^Citation84	2008	II	Sirolimus	21	4.8	23.8	nr/nr	6.5
Furuse et al^Citation23	2008	I	Sorafenib	27	4	83	nr/4.9	15.6
Abou-Alfa et al^Citation22	2006	II	Sorafenib	137	2.2	33.6	nr/4.2	9.2
Yau et al^Citation24	2009	II	Sorafenib	51	8	18	3.0/nr	5.0
Llovet et al^Citation21	2008	III	Sorafenib	602 (299 sorafenib)	2.0	71	nr/5.5	10.7
Cheng et al^Citation85	2009	III	Sorafenib	226 (150 sorafenib)	3.3	54	nr/2.8	6.5
Kudo et al^Citation86	2011	III	Sorafenib	458 (229 sorafenib)	nr	nr	nr/5.4e	29.7
Hoda et al^Citation87	2008	II	Sunitinib	23	6	35	nr/nr	nr
Zhu et al^Citation88	2009	II	Sunitinib	34	2.9	47	3.9/4.1	9.8
Faivre et al^Citation89	2009	II	Sunitinib	37	2.7	35	3.7/5.3	8.0
Koeberle et al^Citation90	2010	II	Sunitinib	45	2	40	2.8/2.8	9.3
Wörns et al^Citation91	2010	II	Sunitinib	11	nr	40	nr/3.2	8.4
Barone et al^Citation92	2013	II	Sunitinib	34	11.8	44.1	nr/2.8	5.8
Cheng et al^Citation28,a	2011	III	Sunitinib	1,073 (529 sunitinib)	nr	nr	3.6/4.1	8.1
Pinter et al^Citation93	2008	I/II	Thalidomide	28	0	7.1	nr	5.1
Santoro et al^Citation94	2013	I	Tivantinib	21	0	45	nr/3.3	nr
Santoro et al^Citation95	2013	II	Tivantinib	107 (71 tivantinib)	3	44	1.5/1.6	6.6
Kanai et al^Citation96	2010	I/II	TSU-68	35	8.6	42.8	nr/2.1	13.1
Hsu et al^Citation97	2012	II	Vandetanib	90 (67 vandetanib)	0	16.0; 5.3f	1.7; 1.1f	5.75;5.95f

Notes:

a Trial stopped

b overlap of patient cohorts cannot be excluded from information provided

c recorded from therapy start (recorded from diagnosis)

d for weekly and daily treated cohorts, respectively

e only patients with advanced HCC and response to TACE were included, and TTP did not differ significantly between sorafenib and placebo

f for vandetanib 100 or 300 mg, respectively. For a better comparison of study results, efficacy according to RECIST criteria is given, as some studies used RECIST and some RECIST and modified RECIST criteria.

Adapted from Welker and Trojan.⁶⁷

Abbreviations: DCR, disease-control rate (complete response + partial response + stable disease [%]); OS, overall survival (months) – may differ between studies with respect to start point (start of therapy/diagnosis); PFS/TTP, progression-free survival/time to progression (months); RR, response rate (complete + partial response [%]); nr, not reported; TACE, transcatheter arterial chemoembolization; RECIST, Response Evaluation Criteria in Solid Tumors trial; HCC, hepatocellular carcinoma.

Table 2 Efficacy of sorafenib and TACE or SIRT in hepatocellular carcinoma (sequential therapy not included), according to current Phase I and II studies

Author	Year	Phase	Investigational drug	n	RR	DCR	OS
Britten et al^Citation98	2012	I	Bevacizumab + TACE	30 (15 bevacicumab)	nr	nr	49
Buijs et al^Citation99	2013	II	Bevacizumab + TACE	25	60	100	10.8
Pawlik et al^Citation100	2011	II	Sorafenib + DEB-TACE	35	58	100	nr
Cabrera et al^Citation101	2011	II	Sorafenib + DEB-TACE or SIRT	47	56.1	68.2	18.5
Lencioni et al^Citation57	2012	II	Sorafenib + DEB-TACE	307 (154 sorafenib)	nr	nr	nt
Chow et al^Citation102	2010	II	Sorafenib + SIRT	35	31.4	77.1	10.8
Dufour et al^Citation54	2010	I	Sorafenib + TACE	14	nra	nra	nra
Erhardt et al^Citation103	2011	II	Sorafenib + TACE	45	2	77.8	18.5
Wu et al^Citation104	2012	II	Sorafenib + TACE	35	45.7	81.8	nr
Qu et al^Citation49	2012	II	Sorafenib + TACE	45	nr	nr	27
Park et al^Citation46	2012	II	Sorafenib + TACE	50	44	84	20.8
Sieghart et al^Citation105,b	2012	I	Sorafenib + TACE	15	46.7	53.3	10.6
Bai et al^Citation51	2013	II	Sorafenib + TACE	164	9.7	58.5	7.5
Chung et al^Citation50	2013	II	Sorafenib + TACE	147	52.4	91.2	nr
Duan et al^Citation47	2012	II	Sorafenib + TACE/TAEc	52	nr	nr	12.0

Notes:

a The primary objective of this prospective trial was evaluation of safety and tolerability of a continuous regimen of sorafenib combined with TACE

b trial stopped prematurely due to safety reasons

c transarterial chemoperfusion in patients with pulmonary metastasis. For a better comparison of study results, efficacy according to RECIST criteria is given, as some studies used RECIST and some RECIST and modified RECIST criteria.

Adapted from Welker and Trojan.⁶⁷

Abbreviations: DEB-TACE, drug eluting beads–transarterial chemoembolization; DCR, disease-control rate (complete response + partial response + stable disease [%]); OS, overall survival (months) – may differ between studies with respect to start point (start of therapy/diagnosis); RR, response rate (complete + partial response [%]); SIRT, selective internal radio therapy; nr, not reported; TAE, transarterial embolization; RECIST, Response Evaluation Criteria in Solid Tumors trial.

Table 3 Efficacy of combination therapy with systemic acting agents and targeted therapy in hepatocellular carcinoma, according to current Phase I–II studies.

Author	Year	Phase	Investigational drug	n	RR	DCR	PFS/TTP	OS
Hsu et al^Citation106	2010	II	Bevacizumab/capecitabine	45	9	51	2.7/nr	5.9
Sun et al^Citation107	2011	II	Bevacizumab/CapOx	40	20	78	6.8/nr	9.8
Thomas et al^Citation108	2009	II	Bevacizumab/erlotinib	40	25	67.5	9.0/nr	15.7
Kaseb et al^Citation109	2012	II	Bevacizumab/erlotinib	59	24	80	7.2/nr	13.7
Yau et al^Citation110	2012	II	Bevacizumab/erlotinib	10	0	0	1.5/1.8	4.4
Philip et al^Citation111	2012	II	Bevacizumab/erlotinib	27	2.1	44.4	nr/3.0	9.5
Govindarajan et al^Citation112	2012	II	Bevacizumab/erlotinib	21	nr	nr	nr/2.6	8.3
Treiber et al^Citation113	2012	II	Bevacizumab/everolimus	31	nr	nr	nr/5.8	13.3
Zhu et al^Citation114	2006	II	Bevacizumab/GemOx	33	18	42	5.3/nr	9.6
Berlin et al^Citation115	2008	II	Bortezomib/doxorubicin	39	2.3	25.6	2.4/nr	5.7
Sanoff et al^Citation116	2011	II	Cetuximab/CapOx	24	12.5	83	nr/4.5	4.4
Louafi et al^Citation117,a	2007	II	Cetuximab/GemOx	35	24	4.5	nr/nr	9.2
Asnacios et ^Citation118,a	2008	II	Cetuximab/GemOx	45	20	40	4.7/nr	9.5
Chiorean et al^Citation119	2012	II	Erlotinib/docetaxel	14	0	46	3.5/nr	6.7
Luelmo et al^Citation120	2012	II	Everolimus/capcitabine	10	0	40	3.4/nr	Nr
Knox et al^Citation121,b	2008	II	G3139/doxorubicin	17	0	35	nr/1.8	5.4
Yau et al^Citation122	2010	I/II	PTK787/doxorubicin	27	26	46	5.4/nr	7.3
Petrini et al^Citation123	2012	II	Sorafenib/5-fluorouracil	38	3	48	nr/7.6	12.2
Richly et al^Citation124	2009	I	Sorafenib/doxorubicin	18	6.3	69	4.0/nr	Nr
Abou-Alfa et al^Citation125,c	2010	II	Sorafenib/doxorubicin	96	4	77	6.9/8.6	13.7
Dima et al^Citation126	2009	II	Sorafenib/mitomycin C	22	27	77	nr	Nr
Prete et al^Citation127	2010	II	Sorafenib/octreotide	50	10	71	nr/7.0	12.0
Abou-Alfa et al^Citation128	2011	I	Sorafenib/PR-104	14	7	50	nr	Nr
Bitzer et al^Citation129	2012	I/II	Sorafenib/resminostat	25	d	d	d	d
Shen et al^Citation130,a	2008	II	Sorafenib/tegafur-uracil	40	13	58.3	3.7/nr	nr
Hsu et^Citation131,a	2010	II	Sorafenib/tegafur-uracil	53	8	57	3.7/nr	7.4
Hsu et al^Citation132	2009	II	Thalidomide/tegafur-uracil	43	9.3	32.6	1.9/nr	4.6
Zhu et al^Citation133	2005	II	Thalidomide/epirubicin	19	0	41	6.0/nr	6.4

Notes:

a Overlap of patient cohorts cannot be excluded from information provided in the abstracts

b trial stopped due to lack of efficacy

c trial stopped due to superiority of sorafenib

d not reported for combination subgroup. For a better comparison of study results, efficacy according to RECIST criteria is given, as some studies used RECIST and some RECIST and modified RECIST criteria. © 1995–2013 Baishideng Publishing Group Co., Limited. Adapted with permission from Welker MW, Trojan J. Anti-angiogenesis in hepatocellular carci noma treatment: current evidence and future perspectives. Word J Gastroenterol. 2011;17:3075–3081.⁶⁷

Abbreviations: DCR, disease-control rate (complete response + partial response + stable disease [%]); GemOx, gemcitabine and oxaliplatin; nr, not reported; OS, overall survival (months) – may differ between studies with respect to start point (start of therapy/diagnosis); PFS/TTP, progression-free survival/time to progression (months); RR, response rate (complete + partial response [%]); CapOx, capecitabine and oxaliplatin; RECIST, Response Evaluation Criteria in Solid Tumors trial; nr, not reported; HCC, hepatocellular carci noma; nr, not reported.

Figure 2 Molecular targets in hepatocellular carcinoma and antiangiogenic drugs according to current Phase II and Phase III studies in advanced hepatocellular carcinoma. Most agents in clinical development are antiangiogenic agents targeting angiogenesis and include different tyrosine-kinase inhibitors as well as antibodies to different cell-growth receptors. *press release (http://www.novartis.com/newsroom/media-releases/en/2013/1721562.shtml)

Abbreviations: Ang-1/2, angiopoietin-1/2; EGF(R), epidermal growth factor (receptor); ERK, extracellular-signal-regulated kinase; FGF(R), fibroblast growth factor (receptor); HGF, hepatocyte growth factor; JNK, c-Jun N-terminal kinases; mTOR, mammalian target of rapamycin; NFkB, nuclear factor kappa-light-chain-enhancer of activated B cells; PDGF(R), platelet-derived growth factor (receptor); PI3K, phosphatidylinositide 3-kinases; RPS6, ribosomal protein S6; TRAIL, TNF-related apoptosis-inducing ligand; VEGF(R), vascular endothelial growth factor (receptor).

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