Abstract

Introduction

Hepatocellular carcinoma (HCC) is one of the most prevalent cancer and the leading cause of cancer-related death.¹ Despite improved surveillance programs for HCC, around 80% of patients are diagnosed as intermediate or advanced stage disease.^2,3 Transarterial chemoembolization (TACE) has become the standard of care for intermediate HCC globally, while it is also widely used in the advanced HCC.^3–9 Systemic therapies, including molecular targeted therapies (MTT) and immunotherapies, are the standard treatment for advanced HCC in first-line setting.¹⁰

Sorafenib, lenvatinib are the tyrosine kinase inhibitors (TKIs) that once were approved as the first-line treatment for advanced HCC with limited survival benefits.^11–13 Afterward, immunotherapies, including PD-1 and PD-L1 inhibitors, have shown promising efficacy and safety for advanced HCC in phase I and phase II trials.^14–16 However, the phase III trials of CheckMate 459 and KEYNOTE-240 all failed to demonstrate superiority of anti-PD-1 therapy compared with standard of care.^17,18 Recently, combination treatment with an anti-PD-(L)1 agent and anti-VEGF and/or TKIs has been proved to be effective and safe for advanced HCC by several RCTs and has been recommended in the first-line setting.^19–21

Transarterial chemoembolization (TACE) results in necrosis of the tumor tissue and releases tumor antigens which may promote tumor-specific immune responses.²² TACE correlates with lower intra-tumoral exhausted effector cells (CD8⁺/PD-1⁺) and T regulatory cells (CD4⁺/FOXP3⁺) and may transform an immunosuppressive microenvironment into an immunosupportive setting to enhance the response of PD-(L)1 inhibitors.²³ That provides the rationale with potential synergistic anti-tumor effect by combing TACE with PD-(L)1 inhibitors and MTT for both intermediate and advanced HCC.²⁴ Based on such theory and encouraged by the success of RCTs for PD-(L)1 inhibitors combined with targeted agents, many clinical trials on TACE with PD-(L)1 treatment plus MTT are in progress to verify the potential synergetic effect.^25,26 Unfortunately, none of such combination therapies with a large sample size have been reported by now.

Herein, the purpose of the CHANCE001 study was to describe the efficacy and safety in a nationwide, retrospective, propensity score matching (PSM) cohort of HCC patients who received TACE with PD-(L)1 inhibitors plus MTT versus TACE monotherapy in the real-world setting.

Results

Patient characteristics

There were 826 patients screened and included in this study, 376 of whom received TACE with PD-(L)1 blockades plus MTT, and 450 patients treated with TACE alone (Fig. ​(Fig.1).1). Prior to PSM, significantly higher tumor burden, worse liver function, and worse Eastern Cooperative Oncology Group (ECOG) performance status were observed in the combination group (Table ​(Table1).1). After matching in a 1:1 ratio, 456 patients remained (228 patients in each group) in the study cohorts, with a predominantly advanced disease population in both groups (65.8% and 66.2% in combination and monotherapy groups, respectively). There were no significant differences in baseline parameters between two groups (Table ​(Table11).

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Fig. 1

Flowchart of the study. *The criteria of combination timeframe were defined as administration of TACE concurrently with or up to 60 days before anti-PD-(L)1 blockades, and molecular targeted agents were concomitant with TACE or anti-PD-(L)1 blockades. TACE transarterial chemoembolization, anti-PD-(L)1 anti-programmed death-(ligand)1, BCLC Barcelona Clinic Liver Cancer

Table 1

Patient baseline characteristics of combination and monotherapy groups before and after PSM

Characteristics	Before PSM			After PSM
	Combination group (n=376)	Monotherapy group (n=450)	P-value*	Combination group (n=228)	Monotherapy group (n=228)	P-value*
Median age (years)	55 (49–65)	61 (54–69)	<0.001	57 (50–67)	57 (50–66)	0.874
Sex			0.911			>0.999
Male	317 (84.3)	377 (83.8)		190 (83.3)	191 (83.8)
Female	59 (15.7)	73 (16.2)		38 (16.7)	37 (16.2)
Etiology			0.480			0.834
Hepatitis B virus	288 (76.6)	334 (74.2)		163 (71.5)	166 (72.8)
Others	88 (23.4)	116 (25.8)		65 (28.5)	62 (27.2)
Cirrhosis			<0.001			>0.999
Yes	281 (74.7)	279 (62.0)		166 (72.8)	166 (72.8)
No	95 (25.3)	171 (38.0)		62 (27.2)	62 (27.2)
Child-Pugh class			0.232			0.516
A	312 (83.0)	388 (86.2)		196 (86.0)	190 (83.3)
B	64 (17.0)	62 (13.8)		32 (14.0)	38 (16.7)
ECOG PS			<0.001			0.751
0	248 (66.0)	372 (82.7)		165 (72.4)	169 (74.1)
1	128 (34.0)	78 (17.3)		63 (27.6)	59 (25.9)
BCLC stage			<0.001			>0.999
B	103 (27.4)	226 (50.2)		78 (34.2)	77 (33.8)
C	273 (72.6)	224 (49.8)		150 (65.8)	151 (66.2)
Up-to-seven			0.662			0.913
≤7	91 (24.2)	102 (22.7)		55 (24.1)	57 (25.0)
>7	285 (75.8)	348 (77.3)		173 (75.9)	171 (75.0)
Macroscopic portal vein invasion			<0.001			0.778
Absent	192 (51.1)	293 (65.1)		124 (54.4)	120 (52.6)
Present	184 (48.9)	157 (34.9)		104 (45.6)	108 (47.4)
Extrahepatic spread			<0.001			>0.999
Absent	223 (59.3)	351 (78.0)		152 (66.7)	152 (66.7)
Present	153 (40.7)	99 (22.0)		76 (33.3)	76 (33.3)
TACE type			0.440			0.396
cTACE	279 (74.2)	322 (71.6)		163 (71.5)	172 (75.4)
DEB-TACE	97 (25.8)	128 (28.4)		65 (28.5)	56 (24.6)
HCC-related treatment history			<0.001			0.841
Absent	180 (47.9)	378 (84.0)		154 (67.5)	157 (68.9)
Present	196 (52.1)	72 (16.0)		74 (32.5)	71 (31.1)
Surgery	62 (16.5)	32 (7.1)	<0.001	27 (11.8)	31 (13.6)	0.674
TACE	165 (43.9)	46 (10.2)	<0.001	61 (26.8)	46 (20.2)	0.122
Ablation	35 (9.3)	18 (4.0)	0.002	14 (6.1)	18 (7.9)	0.583
Radiotherapy	38 (10.1)	8 (1.8)	<0.001	15 (6.6)	8 (3.5)	0.198

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Data are median (interquartile range) or n (%)

PSM propensity score matching, ECOG PS Eastern Cooperative Oncology Group performance status, BCLC Barcelona Clinic Liver Cancer, TACE transarterial chemoembolization, cTACE conventional transarterial chemoembolization, DEB-TACE drug-eluting beads transarterial chemoembolization, HCC hepatocellular carcinoma

*Mann–Whitney U and the Student’s t test for continuous variables and Chi-squared test or Fisher exact test for categorical variables were applied

Efficacy

After matching, the median follow-up time was 17.6 months (interquartile range [IQR], 15.0–20.2) in the combination group and 15.9 months (IQR, 15.0–18.6) in the monotherapy group (P=0.200). During the follow-up, the median number of PD-(L)1 inhibitors and TACE in combination group were five cycles (IQR, 3–9 cycles) and two times (IQR, 1–4 times), respectively, and median number of TACE in monotherapy was three times (IQR, 2–6 times). 147 (64.5%) patients in the combination group and 159 (69.7%) in the monotherapy group had disease progression or died (Fig. ​(Fig.2).2). Median PFS was 9.5 months (95% CI, 8.4–11.0) in the combination group, which was significantly longer than that in the monotherapy group (8.0 months [95% CI, 6.6–9.5]; P=0.015) (Fig. ​(Fig.2).2). A total of 98 (43.8%) patients in combination group and 104 (45.6%) in monotherapy group had died. There is a significant difference in terms of OS between combination group (median OS, 19.2 months; 95% CI, 16.1–27.3) and monotherapy group (median OS, 15.7 months; 95% CI, 13.0–20.2; P=0.037). The higher ORR in the combination group was found (60.1% vs. 32.0%; P<0.001). After adjusting the covariates, multivariate Cox proportional hazards models showed that combination therapy (for PFS, adjusted hazard ratio [HR], 0.70; 95% CI, 0.56–0.88; P=0.002; for OS, HR, 0.63; 95% CI 0.47–0.83; P=0.001; Table ​Table2)2) was the independent positive prognostic indicator for PFS and OS in the matched cohorts. The sensitivity analyses supported these findings. Subgroup analyses showed that the combination group had a trend persisted on better PFS and OS benefits compared to the monotherapy group (Fig. ​(Fig.33).

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Fig. 2

Kaplan–Meier analysis of progression-free survival (a) and overall survival (b)

Table 2

Predictors of progression-free survival and overall survival after matching

	Univariable analysis			Multivariable analysis
	HR	95% CI	P-value	HR	95% CI	P-value
PFS analyses
ECOG PS (1 vs. 0)	1.10	0.85–1.41	0.466
Etiology (HBV vs. others)	0.92	0.72–1.18	0.532
Cirrhosis (present vs. absent)	1.05	0.81–1.36	0.706
Child-Pugh class (B vs. A)	1.27	0.94–1.72	0.123
BCLC stage (C vs. B)	1.75	1.37–2.23	<0.001	1.50	0.96–2.34	0.073
Up-to-seven criteria (>7 vs. ≤7)	1.42	1.09–1.86	0.010	1.27	0.95–1.69	0.103
Macroscopic portal vein invasion (present vs. absent)	1.47	1.17–1.85	0.001	1.01	0.71–1.45	0.939
Extrahepatic spread (present vs. absent)	1.46	1.15–1.85	0.002	1.16	0.84–1.61	0.360
TACE type (DEB-TACE vs. cTACE)	1.06	0.82–1.36	0.677
HCC-related treatment history (present vs. absent)	0.63	0.49–0.81	<0.001	0.76	0.48–1.19	0.224
Previous TACE history (present vs. absent)	0.66	0.50–0.87	0.004	0.95	0.59–1.54	0.837
Treatment (combination therapy vs. monotherapy)	0.76	0.60–0.95	0.016	0.70	0.56–0.88	0.002
OS analyses
ECOG PS (1 vs. 0)	1.12	0.83–1.52	0.461
Etiology (HBV vs. others)	0.87	0.64–1.17	0.345
Cirrhosis (present vs. absent)	1.05	0.76–1.44	0.765
Child-Pugh class (B vs. A)	1.56	1.10–2.21	0.013	1.21	0.84–1.74	0.307
BCLC stage (C vs. B)	1.84	1.36–2.49	<0.001	1.14	0.66–1.98	0.631
Up-to-seven criteria (>7 vs. ≤7)	1.81	1.27–2.59	0.001	1.49	1.03–2.17	0.034
Macroscopic portal vein invasion (present vs. absent)	1.75	1.33–2.31	<0.001	1.32	0.84–2.05	0.225
Extrahepatic spread (present vs. absent)	1.49	1.12–1.98	0.007	1.29	0.88–1.89	0.200
TACE type (DEB-TACE vs. cTACE)	1.08	0.79–1.49	0.621
HCC-related treatment history (present vs. absent)	0.46	0.34–0.63	<0.001	0.54	0.30–0.96	0.037
Previous TACE history (present vs. absent)	0.54	0.38–0.77	0.001	1.05	0.56–1.96	0.881
Treatment (combination therapy vs. monotherapy)	0.75	0.57–0.98	0.037	0.63	0.47–0.83	0.001

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The multivariable analysis includes the variables with P-value ≤0.1 from the univariable analysis

HR hazard ratio, CI confidence intervals, ECOG PS Eastern Cooperative Oncology Group performance status, HBV hepatitis B virus, BCLC Barcelona Clinic Liver Cancer, TACE transarterial chemoembolization, cTACE conventional TACE, DEB-TACE drug-eluting beads TACE, HCC hepatocellular carcinoma

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Fig. 3

Subgroup analysis of progression-free survival (a) and overall survival (b). HR hazard ratio, CI confidence interval, ECOG Eastern Cooperative Oncology Group, BCLC Barcelona Clinic Liver Cancer, TACE transarterial chemoembolization, cTACE conventional transarterial chemoembolization, DEB-TACE drug-eluting beads transarterial chemoembolization, HCC hepatocellular carcinoma

Safety

After matching, the AEs were reported by 134 of 228 patients (58.8%) in the combination group and 101 (44.3%) in the monotherapy group (Table ​(Table33 & Supplementary Table 1). Grade 3 or 4 AEs occurred in 36 patients (15.8%) in the combination group and 17 (7.5%) in the monotherapy group. No grade 5 AEs were observed in either matching group. In the combination group, PD-(L)1 inhibitors were discontinued due to AEs in 13 (5.7%) patients. Molecular targeted agents were discontinued in 27 (11.8%) patients because of AEs. There were 9 patients (3.9%) who experienced dose interruption of anti-PD-(L)1 agents in consequence of AEs. AEs resulting in dose reduction or interruption of TKIs and/or anti-VEGF agents were reported by 22 (9.6%) patients.

Table 3

Adverse events from any cause after PSM

Variable	Combination group (n=228)	Monotherapy group (n=228)
Patients with an adverse event from any cause	134 (58.8)	101 (44.3)
Grade 1 or 2 eventa	98 (43.0)	84 (36.8)
Grade 3 eventa	33 (14.5)	17 (7.5)
Grade 4 eventa	3 (1.3)	0
Grade 5 eventa	0	0
Discontinuation of anti-PD-(L)1 therapies	13 (5.7)	N/A
Discontinuation of molecular targeted therapies	27 (11.8)	N/A
Dose interruption of anti-PD-(L)1 therapies	9 (3.9)	N/A
Dose reduction or interruption of molecular targeted therapies	22 (9.6)	N/A

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PSM propensity score matching, PD-1 programmed death 1, PD-L1 programmed death ligand 1, N/A not applicable

Data are n (%)

^aNumbers represent the highest grades assigned

In the monotherapy group, AEs of any grade (>10%) were abdominal pain (30.3%), elevated aspartate aminotransferase (18.0%), nausea (16.7%), elevated alanine aminotransferase (14.9%), and vomiting (12.3%) (Supplementary Table 2). In the combination group, AEs of any grade (>10%) were elevated aspartate aminotransferase (47.8%), abdominal pain (39.0%), elevated alanine transaminase (36.8%), pyrexia (25.4%), elevated bilirubin (22.4%), hypertension (13.6%), hand-foot skin reaction (13.2%), and proteinuria (10.5%) (Supplementary Table 3).

Discussion

The present multicenter, retrospective, matched cohort study (CHANCE001) based on the nationwide data showed that TACE with PD-(L)1 inhibitors plus MTT significantly improved PFS, OS, and ORR in predominantly advanced HCC patients when compared to TACE alone. Subgroup analyses showed generally consistent survival benefits across clinical subgroups. The incidence of AEs in combination group appears to be slightly higher than that reported in monotherapy, and most AEs were easily managed with mild-to-moderate severity.

Worse liver function and performance status were observed in the present study compared with previously reported IMbrave 150 and ORIENT-32 trials.^20,21 Longer PFS (9.5 [95% CI 8.4–11.0] vs. 6.9 [95% CI 5.7–8.6] vs. 4.6 [95% CI 4.1–5.7] months) with higher ORR (60.1% vs. 33.2% vs. 24.3%, according to modified Response Evaluation Criteria in Solid Tumors [mRECIST]) were achieved in our study than those in the IMbrave 150 and ORIENT-32 trials, respectively. Median OS was 19.2 months [95% CI 16.1–27.3] in the CHANCE001 combination group with poorer clinical characteristics, which was similar to updated IMbrave 150 trial data (19.2 months [95% CI 17.0–23.7]).²⁷

The efficacy benefits of TACE with PD-(L)1 inhibitors plus MTT were generally consistent across clinical subgroups, including those of relevance to HCC (ECOG performance status, HBV etiology, baseline tumor burden, and the with or without macrovascular invasion and/or extrahepatic spread). Besides, early combination therapy is expected to lead to greater potential gain than those who had previous treatment history. As these were subgroup analyses, these findings should be interpreted with caution. All AEs from any cause were reported in 98.2% and 99% of patients receiving PD-(L)1 inhibitors plus MTT, while grade ≥3 AEs were 61.6% and 56% in the IMbrave 150 and ORIENT-32 trials, respectively.^20,21 Most AEs were mild-to-moderate severity and readily managed or reversible in our study, with a small percentage of patients discontinuing PD-(L)1 inhibitors (5.7%) or molecular targeted agents (11.8%) due to AEs.

There are rationales for the combination of TACE with PD-(L)1 inhibitors plus MTT.^28,29 First, TACE induces hypoxia microenvironment and VEGF elevation expression in the residual surviving cancerous tissue.³⁰ Antiangiogenic therapy (antibodies targeting VEGF or TKIs) might delay the revascularization and recurrence of tumor after TACE.²⁸ Unfortunately, several RCTs, including SPACE, Post-TACE, and TACE-2 trials, failed to demonstrate the expected results in HCC patients who received TACE plus sorafenib.³¹ The possible causes of the failures of these reported trials mainly involved population selection, endpoint selection, combination strategies, and timing and duration of drug administration.^32,33 Second, the liver contains immunosuppressive cells and has an intrinsic immune tolerance, which may decrease the immune response to tumor.³⁴ TACE can induce the release of tumor antigens and proinflammatory cytokines and is associated with reduced intra-tumoral exhausted effector cells and T regulatory cells.^22,28 Thus, it can locoregionally induce immunogenic cell death in HCC and turn the immunosuppressive “cold tumor” into an immunogenic “hot tumor” by restoring the immune microenvironment to further improve immune response.^23,35,36 Third, there is a close relationship between angiogenesis and suppression of anti-tumor immunity. The VEGF, a key regulator factor of tumor angiogenesis, can directly influence immune cells and facilitate immune evasion, and indirectly influence immunity by increasing vessel permeability.³⁷ For example, VEGF can result in an immunosuppressive tumor microenvironment by hindering the maturation and function of dendritic cells and increasing T regulatory cells and myeloid-derived suppressor cells recruitments.³⁸ Targeting VEGF can restore anti-tumor activity and enhance the efficacy of immune checkpoint inhibitors.^37,38

There are several limitations in the present study. The retrospective nature may introduce the risk of selection bias, as demonstrated by the difference in baseline characteristics. To minimize the effects of this limitation, we performed the PSM and several sensitivity analyses which are frequently used in real-world studies. Second, various kinds of PD-(L)1 inhibitors and MTT were provided by several esteemed or new pharmaceutical companies in the study. Notably, all the PD-(L)1 inhibitors and MTT applied in the present study are recommended for HCC either in the west or in Chinese guidelines. We pool all drugs together because they have similar targets inspired by the notion of “umbrella” trials to identify the efficacy of different drugs, based on different mutations in one cancer.³⁹ This design can validate a treatment strategy involving a mixture of agents and has been successfully conducted in several trials.^40,41 Along with increasing sample size in the database, stratified analyses could identify better combination protocols in the future. Third, bias due to allocation constraints of immunotherapy caused by financial resources and routine follow-up examinations disrupted by COVID-19 could influence the results of the study.

In conclusion, compare to TACE monotherapy, TACE with anti-PD-(L)1 plus MTT shows significantly better PFS, OS, and ORR for chinese patients with predominantly advanced HCC in a real-world setting, with an acceptable safety profile. Before the outcomes of ongoing RCTs are reported, the present study provides proper evidence for this combination therapy strategy in HCC.

Materials and methods

Supplementary information

Acknowledgements

Author contributions

Study concept and design: G.J.T., L.G.L., and X.L.Z. Acquisition of data: H.L.L., M.S.H., W.Z.Y., G.W.Y., B.Y.Z., J.H.S., Z.C.J., J.J.C., N.J.G., W.B.D., W.H.L., J.H.H., W.M., S.Z.G., J.P.L., H.Z., S.W.W., Y.M.L., Y.S.S., C.W.Y., W.D.W., M.H., W.Z., J.B.W., S.W., X.Z., J.J.H., W.X.R., Z.M.L., W.G.X., Y.F., H.L.L., Z.S.Z., G.H.X., W.H.H., Q.T., H.Y.S., C.S.Z., Y.C., X.Y.Z., Z.T.F., Q.W., J.W.Z., A.B.X., J.X., Q.H.W., H.Z.N., J.W., F.D., D.P.F., Q.D.L., R.S.S., J.R.L., G.Y., H.B.S., J.S.J., Y.E.L., Z.C., and P.Y. Analysis and interpretation of data: Y.Z., H.Z.D., B.Y.Z., Z.C.J., and J.J.C. Drafting of the manuscript: H.Z.D. Critical revision of the manuscript for important intellectual content: G.J.T. Statistical analysis: Y.Z., H.Z.D., B.Y.Z., Z.C.J., and J.J.C. Obtained funding: G.J.T. Administrative, technical, or material support: none. Study supervision: G.J.T. All authors have read and approved the article.

Data availability

Correspondence and reasonable requests for original dataset should be addressed to Dr. Gao-Jun Teng ([email protected]).

Competing interests

The authors declare no competing interests.

Footnotes

Contributor Information

Xiao-Li Zhu, Email: moc.361@09iloaixuhz.

Li-Gong Lu, Email: moc.621@9691gnogilul.

Gao-Jun Teng, Email: nc.ude.ues@gnetjg.

References