- Open Access
Emerging agents and regimens for hepatocellular carcinoma
Journal of Hematology & Oncology volume 12, Article number: 110 (2019)
Liver cancer, mostly hepatocellular carcinoma (HCC), is the second leading cause of cancer mortality globally. Most patients need at least one systemic therapy at different phases of their treatment for HCC. Sorafenib was the first agent shown to improve the survival of patients with advanced HCC. A decade after the approval of sorafenib, most agents failed to improve patient survival more than sorafenib. In recent years, treatment practices have changed, with lenvatinib as another first-line treatment choice and regorafenib, ramucirumab, and cabozantinib as second-line treatment options. Anti-PD-1 antibodies, including nivolumab, pembrolizumab, and camrelizumab, have demonstrated promising anti-tumor effects as monotherapy for advanced HCC in phase II clinical trials. The combination of an anti-PD-1 antibody and an anti-angiogenesis agent has shown more potent anti-tumor effects in early phase clinical trials and is now the hotspot in clinical studies. Furthermore, these agents are investigated in combination treatment with surgery or other loco-regional therapies in patients with early or intermediate-stage HCC.
Primary liver cancer is the second leading cancer-related death globally and ranks second in cancer mortality in China . Although the incidence and mortality of liver cancer in China is declining [2, 3], largely owing to the introduction of vaccination for newborns against the hepatitis B virus , it is increasing in the USA and Europe . More than 90% of primary liver cancers are hepatocellular carcinoma (HCC), and around 5–10% of primary liver cancers are intrahepatic cholangiocarcinoma. Curative treatment to provide long-term survival for patients with early stage HCC includes surgical resection, radiofrequency ablation, or liver transplantation. Transcatheter chemoembolization (TACE) is the standard treatment for patients with intermediate stage HCC . The effect of systemic treatment for advanced stage liver cancer was disappointing until the approval of sorafenib in 2008.
The survival of HCC patients is poorer than many other types of cancer. In China, the 5-year survival of HCC is 12.1%, the second lowest among all types of cancer . In most patients, HCC is associated with chronic liver injuries from hepatitis virus infection, alcohol abuse or non-alcoholic liver steatosis hepatitis, which not only complicates treatment choice, but also competes the effect of tumor progression on patient survival . The treatment toxicities in liver cancer patients usually out-weight that in other cancers.
For patients with early stage HCC, surgical treatment, ablation or liver transplantation, may provide longer survival; however, they are associated with a high risk of tumor recurrence and no adjuvant treatment is accepted as a standard care . In China, most HCC patients are diagnosed at advanced stages , and systemic treatment is the only option to improve survival.
Approved agents for HCC
Sorafenib: the only approved systemic therapy for a decade
Sorafenib has been approved for the treatment of advanced HCC for more than 10 years. Two trials conducted within and outside Asia have shown the efficacy of sorafenib in extending patient survival [11, 12]. Sorafenib became a standard of care recommended by the guidelines from almost all regions, and management of its toxicities, such as hand-foot syndrome, has improved its tolerance . It has been estimated that the survival of patients with advanced stage HCC has been extended from 6.5 months to 8.5–8.9 months in Asian patients and from 10.7 months to 11.8–15.1 months in non-Asian patients, probably because of the improved management of toxicities associated with sorafenib treatment . Attempts to identify a molecular biomarker for the selection of patients sensitive to sorafenib has, however, failed, although several reports demonstrated toxicities associated with better tumor response. Monotherapy with sunitinib , brivanib (BRISK-FL study ), linifanib , or selective internal radiotherapy with yttrium-90 resin microspheres (SARAH and SIRveNIB studies [18, 19]) had been shown not to be superior to sorafenib in head-to-head phase III trials until the REFLECT trial  demonstrated that lenvatinib is not inferior to sorafenib in terms of patient survival, followed by administrative approval.
Sorafenib has also been tested in other scenarios. Combination treatment with TACE has been intensively investigated, although most failed to demonstrate the additional benefit of sorafenib over TACE, while one retrospective analysis showed sorafenib may improve the survival of patients who were concomitantly treated with TACE . Recently, the results from the TACTICS trial demonstrated that TACE plus sorafenib is more effective in prolonging progression-free survival (PFS) than TACE alone in patients with unresectable HCC, but the overall survival (OS) was not reported . A recent randomized control trial (RCT) demonstrated the effect of sorafenib and hepatic arterial infusion using oxaliplatin, 5-fluorouracil, and leucovorin is better than sorafenib alone in patients with tumor invasion to the portal vein in terms of OS and PFS . The combination of sorafenib and erlotinib (SEARCH study ), TACE (STAH study ), doxorubicin (CALGB 80802 study ), or hepatic arterial infusion with low-dose cisplatin and fluorouracil (SILIUS study ) failed to reach the pre-designated objectives.
The STORM trial to evaluate the effect of adjuvant sorafenib treatment after resection or ablation of early stage HCC (BCLC stage 0-A) with a high risk of tumor recurrence did not reach the expected objective . The 1-year and 2-year tumor recurrence rates in the control arm were around 30% and 40%, suggesting more than 60% of patients may be not the target population for receiving adjuvant anti-tumor treatment. “Wrong stage and wrong dose” were the major criticisms for this trial . Several retrospective studies have shown that sorafenib is effective in inhibiting tumor recurrence after resection of HCC with a higher risk of tumor recurrence, where the risk was much higher than in the STORM trial [30, 31]. A small RCT showed that sorafenib improved patient OS and decreased tumor recurrence rate only in those with a higher risk of tumor recurrence . Lately, the surgical samples from the STORM trial were analyzed to establish a link between treatment efficacy and molecular profiling, and the results showed no mutation, gene amplification, or previously proposed gene signatures predicted sorafenib benefit .
Lenvatinib is a multi-kinase inhibitor targeting vascular endothelial growth factor receptors (VEGFRs) 1–3, fibroblast growth factor receptors (FGFR) 1–4, platelet-derived growth factor receptor (PDGFR) α, RET, and KIT . Lenvatinib was approved for advanced HCC in 2018 based on a non-inferior designed open-labeled control trial . Although there are some doubts concerning the trial design, lenvatinib has been accepted because of its higher objective response rate (ORR), which is 18.8% judged by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or 40.6% by the modified RECIST (mRECIST) by masked independent image review . A real-world study demonstrated that therapeutic response and adverse events after taking lenvatinib were similar with the REFLECT trial, regardless of past tyrosine-kinase inhibitor (TKI) therapies , and its immunomodulatory activity has also been revealed in both experimental study  and clinical study .
Although the trial demonstrated that lenvatinib provided a similar survival benefit with sorafenib, the higher tumor response rate is very important to encourage patients to stay on treatment and tolerate toxicities and for physicians to monitor the effect of treatment. The higher tumor response rate also inspired thought of down-staging treatment for initially unresectable HCC or neoadjuvant therapy for resectable HCC. Furthermore, the REFLECT trial showed lenvatinib may be more effective in hepatitis B virus-infected HCC patients , while sorafenib may be more effective in hepatitis C virus infected-HCC patients , although the mechanism has not been revealed yet.
There are still some concerns regarding lenvatinib, however. In the REFLECT trial , PFS gain in the lenvatinib-treated arm did not translate into OS benefit, and the reason for this is not clear. A post hoc study showed more patients from the sorafenib-treated group received the investigating drug and cabozantinib (9.5% vs 3.1%, 2.3% vs 0%, respectively) . Although the NCCN guideline for the treatment of HCC recommends sorafenib as the second-line treatment for patients who failed lenvatinib, a controlled study is needed to verify efficacy and explore other treatment choices. Finally, a biomarker for the selection of patients who may benefit from lenvatinib has not yet been identified. One study demonstrated that the presence of adverse effect in patients receiving lenvatinib was associated with a better OS .
Regorafenib is also a multi-target TKI, targeting VEGFRs 1–3, Tie-2, PDGFR-β, FGFRs, Kit, and Ret. The RESORCE trial  was conducted in patients who tolerated sorafenib but progressed on sorafenib treatment. The OS in regorafenib-treated patients was 10.6 months compared to 7.8 months in the placebo-treated patients (HR = 0.61, P < 0.0001), and PFS increased from 1.5 months to 3.1 months by regorafenib treatment (HR = 0.46, P < 0.0001). Regorafenib is the first second-line treatment showing an OS benefit, and regorafenib is more potent than sorafenib in terms of tumor response. The incidence of treatment-related grade 3 or 4 adverse event was 50%, including hand-foot syndrome, infection, hypertension, and fatigue.
The introduction of regorafenib has fundamentally changed the clinical management of HCC. Progression on sorafenib treatment became a clear signal to switch to regorafenib treatment. One study showed sequential treatment using sorafenib and regorafenib may result in 28 months of OS in patients with advanced HCC .
Cabozantinib is a multi-kinase inhibitor targeting VEGFR-2, MET, and AXL. A randomized control study demonstrated cabozantinib treatment resulted in a longer OS (10.2 vs 8.0 months, HR = 0.76, P = 0.005) and PFS (5.2 vs 1.9 months, HR = 0.44, P < 0.001) in patients with advanced HCC as a second-line treatment . An interesting finding from this study was that the hazard ratio for death was 0.69 in patients with a disease caused by HBV and 1.11 in patients with HCV, which suggests that cabozantinib may be more potent for HBV-related HCC.
The molecular target of cabozantinib, MET and AXL, have a role in treatment resistance to anti-angiogenesis therapies, which is consistent with the effect of cabozantinib as a second-line treatment for HCC. Compared with regorafenib, cabozantinib resulted in longer PFS (5.2 vs 3.4 months, per RECIST 1.1 [41, 43]), while grade 3 and 4 adverse events were more common in cabozantinib-treated patients, including hypertension, diarrhea, and hand-foot syndrome.
Ramucirumab is an antibody targeting VEGFR-2. VEGFR-2 is the receptor on endothelial cells, whose ligands are VEGF-A, C, and D. Ramucirumab has been approved for the treatment of several other cancers, such as advanced gastric cancer, colorectal cancer, and non-small cell lung cancer. In the REACH trial in patients with advanced HCC (BCLC-B/C) who have been treated with sorafenib without success, prespecified subgroup analysis revealed that patients with AFP ≥ 400 ng/mL may benefit from ramucirumab treatment . The REACH-2 trial was therefore conducted specifically in patients with AFP ≥ 400 ng/mL, and the results demonstrated that OS and PFS were significantly better than in the control arm .
The grade 3 or 4 adverse events associated with ramucirumab were very low. The median treatment intensity was 98% in the ramucirumab-treated group, suggesting that most patients received a full dose of ramucirumab, and adverse events leading to treatment discontinuation occurred in 11% of patients. Hypertension and hyponatremia were the only grade 3 or worse treatment-emergent adverse events that were noted in 5% or more of patients .
Both nivolumab and pembrolizumab have been approved for the second-line treatment of advanced HCC by the USFDA, based on the results from two single-arm studies CheckMate 040  and KEYNOTE-224 trials . In the CheckMate 040 trial, nivolumab demonstrated an ORR for HCC of 20% as a first-line treatment or 14% as a second-line treatment (RECIST v1.1), and median OS (mOS) was 28.6 (95% CI, 16.6—not reached at data cutoff) months as a first-line treatment or 15.6 (95% CI, 13.0–18.9) months as a second-line treatment . Similarly, the KEYNOTE-224 trial using pembrolizumab demonstrated an ORR of 17% (RECIST 1.1), and mOS was 12.9 months as a second-line treatment. Notably, the grade 3 or 4 treatment-related adverse effects were much lower than for TKIs, which were 19% in nivolumab-treated patients and 26% in pembrolizumab-treated patients as a second-line treatment, compared with 50% in regorafenib-treated patients and 68% in cabozantinib-treated patients [41, 43].
The KEYNOTE-240, a RCT to evaluate the efficacy of pembrolizumab as a second-line treatment, failed . In this study, pembrolizumab did show a trend of better OS (HR = 0.78, 95% CI, 0.611–0.998, P = 0.0238) and PFS (HR = 0.78, 95% CI, 0.61–0.99, P = 0.0209) without statistical significance per the prespecified statistical plan. However, the magnitude of benefit as captured by HR for both primary endpoints and duration of response is consistent with the findings of KEYNOTE-224. It is noteworthy that more patients in the placebo arm received post-study anti-cancer therapy than those in the pembrolizumab-treated arm. The KEYNOTE-394, designed like KEYNOTE-240, is an ongoing trial in Asian patients with advanced HCC. Recently, Bristol-Myers Squibb announced the results of CheckMate-459, comparing nivolumab and sorafenib as first-line therapy for advanced HCC . Although nivolumab monotherapy did show anti-tumor effects, the study did not achieve statistical significance for its primary endpoint of OS (HR = 0.85, 95% CI, 0.72–1.02, P = 0.0752).
The third PD-1 antibody agent that has been intensively evaluated in HCC is camrelizumab (SHR-1210, Hengrui Pharmaceutical, China). A phase II study demonstrated ORR as a second-line treatment was 13.8% (RECIST v1.1), and the mOS was estimated at 14.4 months (95% CI, 13.8—not reached at data cutoff). The grade 3 or 4 treatment-related adverse effect was 19.4% . A unique adverse effect related with camrelizumab treatment is reactive capillary hemangioma , and a total of 66.8% of HCC patients who received camrelizumab monotherapy developed reactive capillary hemangioma . The exact mechanism and its association with tumor response are not clear. However, the incidence of reactive capillary hemangioma was 20% when those patients were treated with a combination of camrelizumab and gemcitabine plus cisplatin , and 12.1% in patients treated by a combination of apatinib (a VEGFR-2 inhibitor) at a dose of 250 mg per day and camrelizumab .
Although the treatment-related adverse events of grade 3 or greater were relatively low for PD-1 antibodies compared with TKIs, early detection and management of these adverse events are even more important as some of them (e.g., myocarditis, pneumonitis, hepatitis, adrenal insufficiency, and myositis) may be fatal . For patients with a large tumor burden in the liver and comorbidity of liver cirrhosis or chronic virus hepatitis, the diagnosis and treatment of liver immune-related adverse effects are more difficult. The incidence of immune checkpoint inhibitor (ICI)-related hepatotoxicity is about 2–30% and severe cases are very rare ; however, hepatitis accounts for 16–22% of all fatal immune-related adverse events . The accumulation of personal experiences in the management of these cases will be very slow, while collaborations between oncologists and hepatologists may refine the management of ICI-related hepatotoxicity.
Other emerging targets and agents
Much effort has been made to identify the driver mutation in HCC, but most of the identified somatic mutations were not actionable . All approved targeted drugs for advanced HCC were not specifically developed for HCC. Specific targeting agents for HCC may be not feasible in the near future, but there are some promising molecular targets in drug development for HCC.
Colony-stimulating factor-1/CSF-1 receptor
Macrophages play a critical role in the progression of HCC, and colony-stimulating factor-1 (CSF-1) is the major chemokine for the recruitment of macrophages . A preclinical study found that PLX3397, a CSF-1 receptor (CSF-1R) inhibitor, showed robust anti-tumor effects in xenograft HCC models , and the effects of sorafenib were enhanced when combined with macrophage-depleting drugs . Several agents targeting CSF-1/CSF-1R axis (e.g., PLX3397, JNJ-40346527, and BLZ945) are currently being investigated in clinical trials for solid tumors including HCC.
CD47 is expressed on cancer cells, which can bind to SIRPα on macrophages and serve as a “do not eat me” signal usually presented by normal blood cells; it enables cancer cells to evade immunosurveillance by macrophages or other phagocytes . When administered to patients with lymphoma together with rituximab, 5F9, which occupies the CD47 receptor, showed promising anti-tumor efficacy in a phase Ib study . Preclinical studies also found that CD47 blockage inhibited tumor growth  and showed synergic effects with sorafenib  in HCC mouse models.
CTLA-4 is another extensively studied co-inhibitory receptor. CTLA-4 is a CD28 (T cell co-stimulatory protein) homolog and outcompetes CD28 binding affinity for B7 on antigen-presenting cells. CTLA-4 is also found constitutively expressed in regulatory T cells. Ipilimumab, an anti-CTLA-4 antibody, was approved as monotherapy for melanoma and in combination with nivolumab for renal cell carcinoma by USFDA. In the CheckMate 040 study, the combinational use of ipilimumab and nivolumab was also studied in sorafenib-treated patients with advanced HCC . A total of 148 patients were randomized to three arms with different dosages of ipilimumab and nivolumab. Overall, the combination showed a more potent anti-tumor effect than nivolumab monotherapy with a higher ORR (31% vs 14%) [48, 65], the median DOR was 17 months, and the 24-month OS rate was 40%. Although the combination was well tolerated, the rate of grades 3–4 treatment-related adverse events were also much higher than nivolumab monotherapy (37% vs 18%).
Besides anti-PD-L1/PD-1 antibodies and anti-CTLA-4 antibodies which have already shown clinical efficacy and had led to FDA approval in the treatment of various solid tumors including HCC , other co-inhibitory receptors, such as Lag-3, T cell immunoglobulin mucin-3 (Tim-3), and TIGHT were promising targets to be translated to the clinical development . Preclinical studies established the anti-tumor effects of targeting Tim-3 as monotherapy or in combination with other agents in various types of malignancies (summarized in Ref. ). Patients with advanced HCC will also benefit from the clinical development of the next generation of ICIs targeting Tim-3, Lag-3, and TIGHT in solid tumors .
Fibroblast growth factor receptor 4
FGF19 was identified as an oncogenic driver via its receptor, fibroblast growth factor receptor 4 (FGFR4). The aberrantly activated FGF19/FGFR4 signaling pathway was identified as driving hepatocarcinogenesis  and was associated with poor prognosis in patients with HCC . BLU-554 is a potent and highly selective FGFR4 inhibitor. In a phase I study of BLU-554 in HCC patients, the ORR was 26% (5/19, including 1 CR and 4 PR) in the subgroup with high FGF19 expression, accounting for 27% of the study participants . FGF401, another FGFR4 inhibitor, was investigated as a monotherapy or in combination with PDR001 in HCC patients with positive FGFR4 and KLB (a FGF19 co-receptor) expression (NCT02325739).
A previous study found that CD105 (endoglin)-positive HCC endothelial cells showed increased apoptosis resistance, motility, and proangiogenic properties. These cells acquired more resistance to adriamycin, 5-fluorouracil, and sorafenib than their counterparts without CD105 expression in normal liver tissue . The combination of TRC105 (an anti-endoglin antibody) and sorafenib demonstrated encouraging evidence of efficacy, including a 25% partial response rate and a durable PR in HCC patients with measurable disease in an early stage clinical trial [74, 75].
Other small molecular agents, donafenib (kinase inhibitor of Raf and VEGFRs) (NCT02645981) and apatinib (kinase inhibitor of VEGFR2) (NCT02329860), have been investigated in phase III studies. Both studies were closed, and the results will be released shortly.
Novel approaches to improve the effect of systemic treatments
Two approaches may improve treatment efficacy using currently approved agents. The first strategy is to enrich patients with biomarkers. Several biomarkers have been found to be associated with sorafenib efficacy , but none of them were prospectively validated. The only proved biomarker is AFP for ramucirumab treatment. Although some studies showed PD-L1 expression on tumor tissue and tumor mutation burden was associated with the effect of PD-L1/PD-1 antibody treatment , there is no biomarker approved for predicting the efficacy of ICI in HCC [47, 54].
The second approach is the combination of therapies targeting various pathways.
Combination therapy of anti-angiogenesis and PD-L1/PD-1 antibodies
Anti-angiogenic drugs targeting the VEGF-VEGFRs signaling pathway are the first-line and second-line therapies approved for HCC. In all phase III studies that led to the approval of molecular targeting therapies, the mOS for patients with advanced or unresectable HCC was about 1 year [11, 12, 20], and there may be a ceiling of effects for these TKIs . However, all combinational therapies with sorafenib, including systemic chemotherapy (doxorubicin) , hepatic arterial infusion chemotherapy , tigatuzumab (a death receptor-5 agonist) , erlotinib (an EGFR inhibitor) , and TACE , have failed to improve mOS compared with sorafenib monotherapy.
ICIs may be promising for combination therapy with sorafenib and other anti-angiogenic drugs because the major toxicity profiles of TKIs and ICIs are not overlapped. Early stage clinical studies in HCC and late-stage studies in other solid tumors have shown that the toxicity of these two categories’ combination is manageable (Table 1).
In a phase Ib study evaluating the safety of lenvatinib in combination with pembrolizumab in 13 evaluable patients with unresectable HCC (NCT03006926) , no new adverse event was identified, with a PR rate of 46% (6/13). Another phase I study investigating the combinational use of camrelizumab and apatinib in patients with advanced solid tumors showed manageable toxicity, with a PR of 50% (8/16) in the evaluable HCC patients . The combination of lenvatinib and pembrolizumab showed promising anti-cancer activity in a phase II study in renal cell carcinoma, with the ORR as high as 66.7%, and the mPFS as 17.7 months . The successful experience in renal cell carcinoma has shed light on drug development for HCC, and the combination of TKI and ICI can be anticipated to further improve HCC outcomes based on multiple mechanisms (reviewed in Ref ). For example, anti-angiogenesis treatment may increase the efficacy of immunotherapies by targeting angiopoietin 2 and hepatocyte growth factor pathways, while immunotherapies, especially checkpoint inhibitors, may increase the efficacy of anti-angiogenesis treatment, reportedly by eliciting antibody-dependent cytotoxicity on endothelial cells followed by destructing tumor vasculature . The highest ORR was reported in several small trials testing combination treatment of anti-angiogenesis agents with PD-1 antibodies, which are summarized in Table 1. Further evaluation of the safety and efficacy in phase III clinical trials is warranted as a top priority in drug development for advanced HCC by the pharmaceutical industry. The ongoing large phase III clinical trials, which most concerned the combination therapy with anti-angiogenesis and ICI in HCC patients, are listed in Table 2.
Anti-angiogenic drugs that failed to show efficacy in HCC due to intolerability and consequently insufficient exposure may be rescued by the combination with an ICI. In a phase II study, bevacizumab at 5–10 mg/kg every 2 weeks did show anti-tumor activity in HCC patients with an ORR of 13%, and 65% were progression-free at 6 months . However, serious bleeding occurred in 11% of the HCC patients and held back further phase III studies. However, in more carefully selected HCC patients, when combined with atezolizumab, an anti-PD-L1 antibody, bevacizumab at a dose of 15 mg/kg every 3 weeks showed acceptable tolerability with promising results; ORR was 34% and 6-month PFS was 71% in a phase Ib clinical trial in 68 HCC patients . The combination was further investigated as first-line treatment compared with sorafenib in a phase III study (IMbrave150 study) and the results are to be released at the end of 2019. Tivantinib, a non-anti-angiogenic TKI targeting MET, failed to improve patient OS in a phase III study, probably due to dose-limited toxicity and inadequate dosage [90, 91]. There are ongoing early phase clinical trials evaluating the safety and tolerability of combination therapy of MET inhibitors and ICIs (NCT02795429).
Reformative loco-regional therapies
Chemotherapy agents, whether used alone  or in combination with sorafenib , or in modified formulation , failed to show benefits in RCT settings. However, the intratumoral drug concentration enrichment strategy seems to be promising. In a phase I trial , 10 patients with primary or secondary liver tumors received a single intravenous infusion of lyso-thermosensitive liposomal doxorubicin, followed by extracorporeal focused ultrasound exposure at a single liver tumor site. This treatment resulted in an average 3.7 times increase of intratumoral doxorubicin concentrations.
Local administration of an oncolytic and immunotherapeutic vaccinia virus JX-594 (Pexa-Vec) showed promising anti-tumor effects in a phase II dose-finding trial . The response rates were 15% (mRECIST criteria) and 62% (Choi criteria). The intrahepatic disease control (50%) was equivalent in injected and distant non-injected tumors. The mOS was 14.1 months and 6.7 months in patients with high and low infused dose, respectively. An ongoing phase III study (PHOCUS study, NCT02562755) is evaluating Pexa-Vec followed by sorafenib vs sorafenib monotherapy in first-line therapy for advanced HCC .
The future of liver cancer treatment
A molecule-based enrichment system to guide targeting therapies in HCC is not yet available. Although the phase III study REACH-2 showed improved survival in the biomarker AFP-enriched population with advanced HCC  and led to the approval of ramucirumab for second-line therapy for advanced HCC, AFP was not the molecular target of ramucirumab. There are also no biomarkers guiding patient selection for ICI treatment in advanced HCC. Further efforts to identify enrichment biomarkers are merited.
No agent has been proved effective as an adjuvant therapy for HCC yet. A potent adjuvant therapy for HCC patients with high risk of recurrence is more valuable. The ongoing studies, such as Checkmate-9DX (NCT03383458) and KENOTE-937 (NCT03867084), evaluate the effect of nivolumab or pembrolizumab in adjuvant settings for HCC patients with a high risk of recurrence after resection or ablation. Other ICIs are also being evaluated as adjuvant therapies (Table 3). Adjuvant therapies for Chinese patients are of greater value. According to Chinese guidelines for the diagnosis and treatment of liver cancer , indications of liver resection can be expanded to patients at BCLC B stage (Chinese stages IIa and IIb) or partly BCLC C stage (Chinese stage IIIa). These patients are at high risk of disease recurrence, and an effective adjuvant therapy with high efficacy and acceptable toxicity will improve the long-term survival in these patients.
Nivolumab, pembrolizumab, and three PD-1 antibodies manufactured in China (toripalimab, sintilimab, and camrelizumab) have been approved by the NMPA in China, but HCC is not an approved indication. Off-label use of anti-cancer drugs is common in China. The price of the three PD-1 antibodies manufactured by local pharmaceutical companies is about one third that of nivolumab or pembrolizumab (less than 2000 US dollars per month). Drug development by local pharmaceuticals will provide Chinese patients with more affordable medications.
As for patients with intermediate stage HCC, all the studies evaluated the combination of sorafenib and TACE failed to show an improved mOS as compared with sorafenib or TACE monotherapy [25, 98, 99]. The ongoing TACTICS study comparing TACE plus sorafenib vs TACE alone in unresectable HCC showed an improved PFS (25.2 vs 13.5 months, P = 0.006), but the OS data were immature at the data cutoff . Combining ICI may improve the efficacy of TACE monotherapy based on several potential synergic effects between loco-regional therapies and ICI (reviewed in Ref. ). For example, the ongoing EMERALD-1 study (NCT03778957) compares TACE plus durvalumab (an anti-PD-L1 antibody), with or without bevacizumab, with TACE plus placebo. In the near future, the efficacy of TACE may be improved by an ICI; therefore, patients with intermediate HCC may also benefit from systemic therapy.
The systemic therapy for the patients with advanced HCC will be changed by the novel molecular targeted therapy and immunotherapy. Treatment algorithm for early stage and intermediate stage HCC is also evolving with the emerging agents or novel strategies combined with the existing treatment modalities, all of which may improve patients’ survival in general.
Availability of data and materials
Immune checkpoint inhibitor
Objective response rate
Program death-1 ligand
Response Evaluation Criteria in Solid Tumors
Tyrosine kinase inhibitor
Zhou M, Wang H, Zeng X, Yin P, Zhu J, Chen W, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990–2017: a systematic analysis for the global burden of disease study 2017. Lancet. 2019;394(10204):1145–58.
Zhou M, Wang H, Zhu J, Chen W, Wang L, Liu S, et al. Cause-specific mortality for 240 causes in China during 1990–2013: a systematic subnational analysis for the Global Burden of Disease Study 2013. Lancet. 2016;387(10015):251–72.
Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.
Liang X, Bi S, Yang W, Wang L, Cui G, Cui F, et al. Evaluation of the impact of hepatitis B vaccination among children born during 1992-2005 in China. J Infect Dis. 2009;200(1):39–47.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.
Lencioni R, de Baere T, Soulen MC, Rilling WS, Geschwind JF. Lipiodol transarterial chemoembolization for hepatocellular carcinoma: a systematic review of efficacy and safety data. Hepatology. 2016;64(1):106–16.
Zeng H, Chen W, Zheng R, Zhang S, Ji JS, Zou X, et al. Changing cancer survival in China during 2003–15: a pooled analysis of 17 population-based cancer registries. Lancet Glob Health. 2018;6(5):e555–67.
Medavaram S, Zhang Y. Emerging therapies in advanced hepatocellular carcinoma. Exp Hematol Oncol. 2018;7:17.
Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019;380(15):1450–62.
Park JW, Chen M, Colombo M, Roberts LR, Schwartz M, Chen PJ, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE study. Liver Int. 2015;35(9):2155–66.
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.
Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34.
Ren Z, Zhu K, Kang H, Lu M, Qu Z, Lu L, et al. Randomized controlled trial of the prophylactic effect of urea-based cream on sorafenib-associated hand-foot skin reactions in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2015;33(8):894–900.
Faivre S, de Gramont A, Raymond E. Learning from 7 years of experience with sorafenib in advanced HCC: sorafenib better than sorafenib? Target Oncol. 2016;11(4):565–7.
Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013;31(32):4067–75.
Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol. 2013;31(28):3517–24.
Cainap C, Qin S, Huang WT, Chung IJ, Pan H, Cheng Y, et al. Linifanib versus sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol. 2015;33(2):172–9.
Vilgrain V, Pereira H, Assenat E, Guiu B, Ilonca AD, Pageaux GP, et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2017;18(12):1624–36.
Chow PKH, Gandhi M, Tan SB, Khin MW, Khasbazar A, Ong J, et al. SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol. 2018;36(19):1913–21.
Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163–73.
Zhao Y, Wang WJ, Guan S, Li HL, Xu RC, Wu JB, et al. Sorafenib combined with transarterial chemoembolization for the treatment of advanced hepatocellular carcinoma: a large-scale multicenter study of 222 patients. Ann Oncol. 2013;24(7):1786–92.
Kudo M, Ueshima K, Ikeda M, Torimura T, Tanabe N, Aikata H, et al. Randomized, open label, multicenter, phase II trial comparing transarterial chemoembolization (TACE) plus sorafenib with TACE alone in patients with hepatocellular carcinoma (HCC): TACTICS trial. J Clin Oncol. 2018;36(4_suppl):206.
He M, Li Q, Zou R, Shen J, Fang W, Tan G, et al. Sorafenib plus hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin vs sorafenib alone for hepatocellular carcinoma with portal vein invasion: a randomized clinical trial. JAMA Oncol. 2019. https://doi.org/10.1001/jamaoncol.2019.0250.
Zhu AX, Rosmorduc O, Evans TR, Ross PJ, Santoro A, Carrilho FJ, et al. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of Sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2015;33(6):559–66.
Park J-W, Kim YJ, Kim DY, Bae S-H, Paik SW, Lee Y-J, et al. Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: the phase III STAH trial. J Hepatol. 2019;70(4):684–91.
Abou-Alfa GK, Niedzwieski D, Knox JJ, Kaubisch A, Posey J, Tan BR, et al. Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC): CALGB 80802 (Alliance). J Clin Oncol. 2016;34(4_suppl):192.
Kudo M, Ueshima K, Yokosuka O, Ogasawara S, Obi S, Izumi N, et al. Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial. Lancet Gastroenterol Hepatol. 2018;3(6):424–32.
Bruix J, Takayama T, Mazzaferro V, Chau GY, Yang J, Kudo M, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2015;16(13):1344–54.
Kelley RK. Adjuvant sorafenib for liver cancer: wrong stage, wrong dose. Lancet Oncol. 2015;16(13):1279–81.
Zhang XP, Chai ZT, Gao YZ, Chen ZH, Wang K, Shi J, et al. Postoperative adjuvant sorafenib improves survival outcomes in hepatocellular carcinoma patients with microvascular invasion after R0 liver resection: a propensity score matching analysis. HPB (Oxford). 2019. https://doi.org/10.1016/j.hpb.2019.04.014.
Xia F, Wu LL, Lau WY, Huan HB, Wen XD, Ma KS, et al. Adjuvant sorafenib after heptectomy for Barcelona Clinic Liver Cancer-stage C hepatocellular carcinoma patients. World J Gastroenterol. 2016;22(23):5384–92.
Wang SN, Chuang SC, Lee KT. Efficacy of sorafenib as adjuvant therapy to prevent early recurrence of hepatocellular carcinoma after curative surgery: a pilot study. Hepatol Res. 2014;44(5):523–31.
Pinyol R, Montal R, Bassaganyas L, Sia D, Takayama T, Chau GY, et al. Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial. Gut. 2019;68(6):1065–75.
Yamamoto Y, Matsui J, Matsushima T, Obaishi H, Miyazaki K, Nakamura K, et al. Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc Cell. 2014;6:18.
Hiraoka A, Kumada T, Kariyama K, Takaguchi K, Atsukawa M, Itobayashi E, et al. Clinical features of lenvatinib for unresectable hepatocellular carcinoma in real-world conditions: multicenter analysis. Cancer Med. 2019;8(1):137–46.
Kimura T, Kato Y, Ozawa Y, Kodama K, Ito J, Ichikawa K, et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci. 2018;109(12):3993–4002.
Lin YY, Tan CT, Chen CW, Ou DL, Cheng AL, Hsu C. Immunomodulatory effects of current targeted therapies on hepatocellular carcinoma: implication for the future of immunotherapy. Semin Liver Dis. 2018;38(4):379–88.
Jackson R, Psarelli EE, Berhane S, Khan H, Johnson P. Impact of viral status on survival in patients receiving sorafenib for advanced hepatocellular cancer: a meta-analysis of randomized phase III trials. J Clin Oncol. 2017;35(6):622–8.
Alsina A, Kudo M, Vogel A, Cheng A-L, Tak WY, Ryoo B-Y, et al. Subsequent anticancer medication following first-line lenvatinib: a posthoc responder analysis from the phase 3 REFLECT study in unresectable hepatocellular carcinoma. J Clin Oncol. 2019;37(4_suppl):371.
Sung MW, Finn RS, Qin S, Han K-H, Ikeda K, Cheng A-L, et al. Association between overall survival and adverse events with lenvatinib treatment in patients with hepatocellular carcinoma (REFLECT). J Clin Oncol. 2019;37(4_suppl):317.
Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56–66.
Finn RS, Merle P, Granito A, Huang Y-H, Bodoky G, Pracht M, et al. Outcomes with sorafenib (SOR) followed by regorafenib (REG) or placebo (PBO) for hepatocellular carcinoma (HCC): results of the international, randomized phase 3 RESORCE trial. J Clin Oncol. 2017;35(4_suppl):344.
Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54–63.
Zhu AX, Park JO, Ryoo B-Y, Yen C-J, Poon R, Pastorelli D, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015;16(7):859–70.
Zhu AX, Kang Y-K, Yen C-J, Finn RS, Galle PR, Llovet JM, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282–96.
El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492–502.
Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940–52.
Crocenzi TS, El-Khoueiry AB, Yau TC, Melero I, Sangro B, Kudo M, et al. Nivolumab (nivo) in sorafenib (sor)-naive and -experienced pts with advanced hepatocellular carcinoma (HCC): CheckMate 040 study. J Clin Oncol. 2017;35(15_suppl):4013.
Finn RS, Ryoo B-Y, Merle P, Kudo M, Bouattour M, Lim H-Y, et al. Results of KEYNOTE-240: phase 3 study of pembrolizumab (Pembro) vs best supportive care (BSC) for second line therapy in advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2019;37(15_suppl):4004.
Bristol-Myers Squibb Announces Results from CheckMate −459 Study Evaluating Opdivo (nivolumab) as a First-Line Treatment for Patients with Unresectable Hepatocellular Carcinoma. https://news.bms.com/press-release/bmy/bristol-myers-squibb-announces-results-checkmate-459-study-evaluating-opdivo-nivol. Accessed 24 June 2019.
Qin S-K, Ren Z-G, Meng Z-Q, Chen Z-D, Chai X-L, Xiong J-P, et al. LBA27 a randomized multicentered phase II study to evaluate SHR-1210 (PD-1 antibody) in subjects with advanced hepatocellular carcinoma (HCC) who failed or intolerable to prior systemic treatment. Ann Oncol. 2018;29(suppl_8):mdy424.029.
Teng Y, Guo R, Sun J, Jiang Y, Liu Y. Reactive capillary hemangiomas induced by camrelizumab (SHR-1210), an anti-PD-1 agent. Acta Oncol. 2019;58(3):388–9.
Fang W, Yang Y, Ma Y, Hong S, Lin L, He X, et al. Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials. Lancet Oncol. 2018;19(10):1338–50.
Xu J, Zhang Y, Jia R, Yue C, Chang L, Liu R, et al. Anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: an open-label, dose escalation and expansion study. Clin Cancer Res. 2019;25(2):515–23.
Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 2018;4(12):1721–8.
Jennings JJ, Mandaliya R, Nakshabandi A, Lewis JH. Hepatotoxicity induced by immune checkpoint inhibitors: a comprehensive review including current and alternative management strategies. Expert Opin Drug Metab Toxicol. 2019;15(3):231–44.
Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23(6):703–13.
Zhu XD, Zhang JB, Zhuang PY, Zhu HG, Zhang W, Xiong YQ, et al. High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol. 2008;26(16):2707–16.
Ao JY, Zhu XD, Chai ZT, Cai H, Zhang YY, Zhang KZ, et al. Colony-stimulating factor 1 receptor blockade inhibits tumor growth by altering the polarization of tumor-associated macrophages in hepatocellular carcinoma. Mol Cancer Ther. 2017;16(8):1544–54.
Zhang W, Zhu XD, Sun HC, Xiong YQ, Zhuang PY, Xu HX, et al. Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects. Clin Cancer Res. 2010;16(13):3420–30.
Liu X, Kwon H, Li Z, Fu YX. Is CD47 an innate immune checkpoint for tumor evasion? J Hematol Oncol. 2017;10(1):12.
Advani R, Flinn I, Popplewell L, Forero A, Bartlett NL, Ghosh N, et al. CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin's lymphoma. N Engl J Med. 2018;379(18):1711–21.
Xiao Z, Chung H, Banan B, Manning PT, Ott KC, Lin S, et al. Antibody mediated therapy targeting CD47 inhibits tumor progression of hepatocellular carcinoma. Cancer Lett. 2015;360(2):302–9.
Lo J, Lau EY, Ching RH, Cheng BY, Ma MK, Ng IO, et al. Nuclear factor kappa B-mediated CD47 up-regulation promotes sorafenib resistance and its blockade synergizes the effect of sorafenib in hepatocellular carcinoma in mice. Hepatology. 2015;62(2):534–45.
Yau T, Kang Y-K, Kim T-Y, El-Khoueiry AB, Santoro A, Sangro B, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040. J Clin Oncol. 2019;37(15_suppl):4012.
Myint ZW, Goel G. Role of modern immunotherapy in gastrointestinal malignancies: a review of current clinical progress. J Hematol Oncol. 2017;10(1):86.
Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity. 2016;44(5):989–1004.
Liu F, Liu Y, Chen Z. Tim-3 expression and its role in hepatocellular carcinoma. J Hematol Oncol. 2018;11(1):126.
Marin-Acevedo JA, Dholaria B, Soyano AE, Knutson KL, Chumsri S, Lou Y. Next generation of immune checkpoint therapy in cancer: new developments and challenges. J Hematol Oncol. 2018;11(1):39.
Sawey ET, Chanrion M, Cai C, Wu G, Zhang J, Zender L, et al. Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by Oncogenomic screening. Cancer Cell. 2011;19(3):347–58.
Kang HJ, Haq F, Sung CO, Choi J, Hong SM, Eo SH, et al. Characterization of hepatocellular carcinoma patients with FGF19 amplification assessed by fluorescence in situ hybridization: a large cohort study. Liver Cancer. 2019;8(1):12–23.
Kim R, Yoon J-H, Lim HY, Zhu A, Park J-W, Faivre S, et al. 365O phase 1 safety and clinical activity of BLU-554 in advanced hepatocellular carcinoma (HCC). Ann Oncol. 2017;28(suppl_5). https://doi.org/10.1093/annonc/mdx367.
Xiong YQ, Sun HC, Zhang W, Zhu XD, Zhuang PY, Zhang JB, et al. Human hepatocellular carcinoma tumor-derived endothelial cells manifest increased angiogenesis capability and drug resistance compared with normal endothelial cells. Clin Cancer Res. 2009;15(15):4838–46.
Duffy AG, Ma C, Ulahannan SV, Rahma OE, Makarova-Rusher O, Cao L, et al. Phase I and preliminary phase II study of TRC105 in combination with sorafenib in hepatocellular carcinoma. Clin Cancer Res. 2017;23(16):4633–41.
Raghav KPS, Lee RT, Paluri RK, Mody K, Simpson B, Adams BJ, et al. An open-label phase Ib/2 trial of TRC105 plus sorafenib in patients with advanced/metastatic hepatocellular carcinoma (HCC) (NCT01806064). J Clin Oncol. 2019;37(4_suppl):268.
Bruix J, Cheng AL, Meinhardt G, Nakajima K, De Sanctis Y, Llovet J. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies. J Hepatol. 2017;67(5):999–1008.
Diggs LP, Hsueh EC. Utility of PD-L1 immunohistochemistry assays for predicting PD-1/PD-L1 inhibitor response. Biomark Res. 2017;5:12.
Abou-Alfa GK, Venook AP. The antiangiogenic ceiling in hepatocellular carcinoma: does it exist and has it been reached? Lancet Oncol. 2013;14(7):e283–8.
Abou-Alfa GK, Niedzwieski D, Knox JJ, Kaubisch A, Posey J, Tan BR, et al. Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC): CALGB 80802 (Alliance). 2016 ASCO Ann Meeting. 2016;suppl 4S:abstr 192.
Cheng A-L, Kang Y-K, He AR, Lim HY, Ryoo B-Y, Hung C-H, et al. Safety and efficacy of tigatuzumab plus sorafenib as first-line therapy in subjects with advanced hepatocellular carcinoma: a phase 2 randomized study. J Hepatol. 2015;63(4):896–904.
Kudo M. Pembrolizumab for the treatment of hepatocellular carcinoma. Liver Cancer. 2019;8(3):143–54.
Pishvaian MJ, Lee MS, Ryoo B-Y, Stein S, Lee K-H, Liu B, et al. LBA26 updated safety and clinical activity results from a phase Ib study of atezolizumab + bevacizumab in hepatocellular carcinoma (HCC). Ann Oncol. 2018;29(suppl_8). https://doi.org/10.1093/annonc/mdy424.028.
Kelley RK, Abou-Alfa GK, Bendell JC, Kim T-Y, Borad MJ, Yong W-P, et al. Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): phase I safety and efficacy analyses. J Clin Oncol. 2017;35(15_suppl):4073.
Kudo M, Motomura K, Wada Y, Inaba Y, Sakamoto Y, Kurosaki M, et al. First-line avelumab + axitinib in patients with advanced hepatocellular carcinoma: results from a phase 1b trial (VEGF Liver 100). J Clin Oncol. 2019;37(15_suppl):4072.
Qin S, Chen Z, Liu Y, Xiong J, Ren Z, Meng Z, et al. A phase II study of anti-PD-1 antibody camrelizumab plus FOLFOX4 or GEMOX systemic chemotherapy as first-line therapy for advanced hepatocellular carcinoma or biliary tract cancer. J Clin Oncol. 2019;37(15_suppl):4074.
Ikeda M, Sung MW, Kudo M, Kobayashi M, Baron AD, Finn RS, et al. A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2018;36(15_suppl):4076.
Lee C-H, Motzer RJ, Makker V, Rasco D, Taylor M, Dutcus C, et al. 847O a phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with renal cell carcinoma. Ann Oncol. 2017;28(suppl_5). https://doi.org/10.1093/annonc/mdx371.002.
Khan KA, Kerbel RS. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol. 2018;15(5):310–24.
Siegel AB, Cohen EI, Ocean A, Lehrer D, Goldenberg A, Knox JJ, et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol. 2008;26(18):2992–8.
Weekes CD, Clark JW, Zhu AX. Tivantinib for advanced hepatocellular carcinoma: is MET still a viable target? Lancet Oncol. 2018;19(5):591–2.
Rimassa L, Assenat E, Peck-Radosavljevic M, Pracht M, Zagonel V, Mathurin P, et al. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol. 2018;19(5):682–93.
Kudo M, Moriguchi M, Numata K, Hidaka H, Tanaka H, Ikeda M, et al. S-1 versus placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): a randomised, double-blind, multicentre, phase 3 trial. Lancet Gastroenterol Hepatol. 2017;2(6):407–17.
Merle P, Blanc JF, Phelip JM, Pelletier G, Bronowicki JP, Touchefeu Y, et al. Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial. Lancet Gastroenterol Hepatol. 2019;4(6):454–65.
Lyon PC, Gray MD, Mannaris C, Folkes LK, Stratford M, Campo L, et al. Safety and feasibility of ultrasound-triggered targeted drug delivery of doxorubicin from thermosensitive liposomes in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial. Lancet Oncol. 2018;19(8):1027–39.
Heo J, Reid T, Ruo L, Breitbach CJ, Rose S, Bloomston M, et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med. 2013;19(3):329–36.
Abou-Alfa GK, Galle PR, Chao Y, Brown KT, Heo J, Borad MJ, et al. PHOCUS: a phase 3 randomized, open-label study comparing the oncolytic immunotherapy Pexa-Vec followed by sorafenib (SOR) vs SOR in patients with advanced hepatocellular carcinoma (HCC) without prior systemic therapy. J Clin Oncol. 2016;34(15_suppl):TPS4146–6.
Zhou J, Sun HC, Wang Z, Cong WM, Wang JH, Zeng MS, et al. Guidelines for diagnosis and treatment of primary liver cancer in China (2017 edition). Liver Cancer. 2018;7(3):235–60.
Meyer T, Fox R, Ma YT, Ross PJ, James MW, Sturgess R, et al. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2017;2(8):565–75.
Lencioni R, Llovet JM, Han G, Tak WY, Yang J, Guglielmi A, et al. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial. J Hepatol. 2016;64(5):1090–8.
Greten TF, Mauda-Havakuk M, Heinrich B, Korangy F, Wood BJ. Combined locoregional-immunotherapy for liver cancer. J Hepatol. 2019;70(5):999–1007.
The authors thank Dr. Joan Zhang for the critical review of part of the manuscript.
This work was supported by the Leading Investigator Program of Shanghai municipal government (17XD1401100), the National Key Basic Research Program (973 Program; 2015CB554005) from the Ministry of Science and Technology of China, and the National Natural Science Foundation of China (81372655, 81472224, and 81672326) to HCS.
Ethics approval and consent to participate
Consent for publication
HCS received a lecture fee from Bayer, Eisai, and MSD. The other author declares no conflict of interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Zhu, X., Sun, H. Emerging agents and regimens for hepatocellular carcinoma. J Hematol Oncol 12, 110 (2019) doi:10.1186/s13045-019-0794-6
- Hepatocellular carcinoma
- Systemic therapy
- Molecular targeted therapy
- Anti-PD-1 antibody