Systemic therapy for intermediate and advanced hepatocellular carcinoma: Sorafenib and beyond

Open AccessPublished:May 14, 2018DOI:https://doi.org/10.1016/j.ctrv.2018.05.006

      Highlights

      • Sorafenib is indicated for advanced and intermediate (post-TACE failure) HCC.
      • Sorafenib should be given early to ensure patients can benefit from all therapies.
      • Sorafenib toxicities can be effectively prevented and managed for treatment benefit.
      • Sorafenib, lenvatinib, regorafenib, cabozantinib, and ramucirumab improve survival.
      • New systemic agents are emerging for the treatment of patients with advanced HCC.

      Abstract

      The hepatocellular carcinoma (HCC) treatment landscape changed a decade ago, with sorafenib demonstrating survival benefit in the first-line setting and becoming the first systemic therapy to be approved for HCC. More recently, regorafenib and nivolumab have received approval in the second-line setting after sorafenib, with further positive phase 3 studies emerging in the first line (lenvatinib non-inferior to sorafenib) and second line versus placebo (cabozantinib and ramucirumab). A key recommendation in the management of patients receiving sorafenib is to promote close communication between the patient and the physician so that adverse events (AEs) are detected early and severe AEs can be prevented. Sorafenib-related AEs have been identified as clinical biomarkers for sorafenib efficacy. Healthcare professionals have become more efficient in managing AEs, identifying patients who are likely to benefit from treatment, and assessing response to treatment, resulting in a trend towards increased overall survival in the sorafenib arms of clinical studies. The rapidly changing treatment landscape due to the emergence of new treatment options (sorafenib and lenvatinib equally effective in first line; regorafenib, cabozantinib, and ramucirumab showing OS benefit in second line with nivolumab approved by the FDA based on response rate) underscores the importance of re-assessing the role of the first approved systemic agent in HCC, sorafenib.

      Keywords

      Introduction

      Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the second leading cause of cancer-related mortality worldwide [

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      ]. Similarly, a number of trials have failed in the second-line setting [
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      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.
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      Phase III randomized study of second-line ADI-peg 20 (A) plus best supportive care versus placebo (P) plus best supportive care in patients (pts) with advanced hepatocellular carcinoma (HCC).
      ], with two agents recently approved in patients who have received prior sorafenib: regorafenib, which has demonstrated a survival benefit after progression on sorafenib in sorafenib-tolerant patients [
      • Bruix J.
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      • Merle P.
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      Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.
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      Food and Drug Administration. Regorafenib (Stivarga) prescribing information [accessed 4 April 2018].

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      European Medicines Agency. Regorafenib (Stivarga). Summary of Product Characteristics [accessed 4 April 2018].

      ]; and nivolumab, which received an accelerated FDA approval based on tumor response rate and durability of response in an uncontrolled, single-arm study [

      Food and Drug Administration. Nivolumab (Opdivo) prescribing information [accessed 4 April 2018].

      ]. More recently, results from two phase 3 trials reported improved survival with cabozantinib versus placebo and ramucirumab versus placebo in the second line following sorafenib [
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      Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: results from the randomized phase III CELESTIAL trial.
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      Lilly Press Release. Lilly announces CYRAMZA® (ramucirumab) phase 3 REACH-2 study in second-line hepatocellular carcinoma patients met overall survival endpoint <https://investor.lilly.com/news-releases/news-release-details/lilly-announces-cyramzar-ramucirumab-phase-3-reach-2-study> [accessed 4 April 2018].

      ]. With the advent of new agents, it appears timely to reflect on the role of sorafenib as the gold standard in the first-line setting, its efficacy, and on the progress achieved in managing its side effects as new drugs are emerging in the first line (none of which have demonstrated superiority to sorafenib), and in second line after sorafenib failure. This review will provide an overview of established and novel systemic therapies in development for unresectable HCC and will discuss ways to improve their use to benefit patients.

      Sorafenib history: Efficacy and safety

      Sorafenib is an oral multikinase inhibitor that inhibits a number of receptor tyrosine kinases (VEGFR1-3, PDGFR, KIT, and RET) and downstream Raf signaling molecules (Raf-1 and B-Raf), affecting multiple tumor-signaling pathways including those involved in angiogenesis, tumor proliferation, and apoptosis [
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      ].

       Clinical trials

      Four phase 1 trials evaluated a range of oral doses of sorafenib in patients with advanced recurrent or refractory solid tumors [
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      ]. The optimal regimen was continuous oral administration of 400 mg sorafenib twice daily (bid) [
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      ]. The most common drug-related toxicities were gastrointestinal or dermatologic [
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      ].
      A subsequent single-arm, phase 2 trial was carried out in patients with unresectable HCC (N = 137) who had not received prior systemic treatment and had a Child–Pugh score of A (72%) or B (28%) [
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      ]. Treatment with continuous oral sorafenib 400 mg bid was associated with manageable toxicity – grade 3/4 drug-related toxicities included fatigue (9.5%), diarrhea (8.0%), and hand–foot skin reaction (HFSR; 5.1%). Tumor response rate was low, with 2.2% of patients showing a partial response (PR) based on independent assessment. Investigator-assessed median time to progression (TTP) was 4.2 months and median overall survival (OS) was 9.2 months. Independent review reported an interesting median TTP of 5.5 months, which provided the rationale for the continued development of sorafenib as an HCC treatment.
      Subsequently, two phase 3 clinical trials were initiated, the results of which led to the approval of sorafenib for the treatment of HCC [

      Food and Drug Administration. Sorafenib (Nexavar) prescribing information [accessed 4 April 2018].

      ,

      European Medicines Agency. Sorafenib (NEXAVAR). Summary of Product Characteristics [accessed 4 April 2018].

      ] – the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial (N = 602; randomization ratio 1:1 sorafenib 400 mg bid vs placebo) and the sorafenib Asia-Pacific (AP) trial (N = 226; randomization ratio 2:1 sorafenib 400 mg bid vs placebo) [
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      ,
      • Cheng A.
      • Kang Y.
      • Chen Z.
      • Tsao C.
      • Qin S.
      • Kim J.
      • 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.
      ]. These trials, although from geographically different areas, had the same inclusion and exclusion criteria; patients had advanced HCC with a measurable lesion, received no prior systemic therapy, had Child–Pugh class A liver disease, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and adequate hematological, renal, and hepatic function. Sorafenib demonstrated a significant survival benefit of a similar magnitude in both SHARP and AP (Table 1): in SHARP, median OS was 10.7 months with sorafenib versus 7.9 months with placebo (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.55–0.87, P < 0.001); in AP, median OS was 6.5 months with sorafenib and 4.2 months with placebo (HR 0.68, 95% CI 0.50–0.93, P < 0.014). Median time to radiologic progression was significantly longer and the disease control rate (DCR) was significantly higher with sorafenib than with placebo in both studies (Table 1) but no difference in median time to symptomatic progression was observed between study arms. The lower absolute survival observed in the AP study compared with the SHARP study, while maintaining similar relative benefit in both studies (HR 0.69 in SHARP vs 0.68 in AP), may reflect the different patient populations, including more advanced disease in the AP study, and therapeutic options before inclusion in the two studies. The tumor response rates in both studies were low, with no complete responses and low PR rates (Table 1).
      Table 1Summary of key efficacy results of the SHARP and AP phase 3 trials and the GIDEON real-world cohort study.
      StudySHARP
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      AP
      • Cheng A.
      • Kang Y.
      • Chen Z.
      • Tsao C.
      • Qin S.
      • Kim J.
      • 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.
      GIDEON
      • Marrero J.A.
      • Kudo M.
      • Venook A.P.
      • Ye S.L.
      • Bronowicki J.P.
      • Chen X.P.
      • et al.
      Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: the GIDEON study.
      Treatment groupsSorafenib n = 299Placebo n = 303Sorafenib n = 150Placebo n = 76Sorafenib n = 2708
      Baseline patient characteristics, %
      BCLC stage C8283959669
      Child–Pugh A9598979773
      Child–Pugh B523325
      Child–Pugh C00003
      Efficacy results
      Median OS, months (95% CI)10.7 (9.4–13.3)7.9 (6.8–9.1)6.5 (5.6–7. 6)4.2 (3.8–5.6)Child–Pugh A: 13.6 (12.8–14.7)

      Child–Pugh B: 5.2 (4.6–6.3)

      Child–Pugh C: 2.6 (1.5–4.0)
       HR (95% CI), P-value0.69 (0.55–0.87), <0.0010.68 (0.50–0.93), 0.014
      Median TTSP, months (95% CI)4.1 (3.5–4.8)4.9 (4.2–6.3)3.5 (2.8–4.2)3.4 (2.4–4.1)
       HR (95% CI), P-value1.08 (0.88–1.31), 0.770.9 (0.67–1.22), 0.5
      Median TTP, months (95% CI)5.5 (4.1–6.9)2.8 (2.7–3.9)2.8 (2.6–3.6)1.4 (1.4–1.6)
       HR (95% CI), P-value0.58 (0.45–0.74), <0.0010.57 (0.42–0.79), =0.0005
      Tumor response rate, %
      Criteria usedRECIST v1.0RECIST v1.0
       Complete response0000
       Partial response213.31.3
        P-value0.05NR
       Stable disease716754.027.6
        P-value0.17NR
       DCR433235.315.8
        P-value0.0020.0019
      AP, Asia-Pacific; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; DCR, disease control rate; HR, hazard ratio; OS, overall survival; NR, not reported; RECIST, Response Evaluation Criteria in Solid Tumors; SHARP, Sorafenib HCC Assessment Randomized Protocol; TTSP, time to symptomatic progression; TTP, time to progression.
      Overall, the adverse event (AE) profile of sorafenib was generally comparable in the SHARP and AP phase 3 trials, with the most common grade 3/4 drug-related AEs being HFSR, diarrhea, and fatigue [
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      ,
      • Cheng A.
      • Kang Y.
      • Chen Z.
      • Tsao C.
      • Qin S.
      • Kim J.
      • 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.
      ]. Drug-related AEs of any grade occurring at a higher frequency (P < 0.001) in patients treated with sorafenib compared with placebo included diarrhea (39% vs 11%), weight loss (9% vs 1%), HFSR (21% vs 3%), anorexia (14% vs 3%), alopecia (14% vs 2%), and voice changes (6% vs 1%). Grade 3 drug-related AEs that were more common with sorafenib compared with placebo included diarrhea and HFSR (P < 0.001). Drug-related AEs resulted in permanent discontinuation of sorafenib in 11% of patients, dose interruptions in 44%, and dose reductions in 26%. The most frequent AEs leading to sorafenib dose reductions were diarrhea (8%), HFSR (5%), and rash or desquamation (3%). A generally similar safety profile has been observed in the sorafenib arms of other phase 3 trials in HCC [
      • Cheng A.L.
      • Kang Y.K.
      • Lin D.Y.
      • Park J.W.
      • Kudo M.
      • Qin S.
      • et al.
      Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial.
      ,
      • Johnson P.J.
      • Qin S.
      • Park J.W.
      • Poon R.T.
      • Raoul J.L.
      • Philip P.A.
      • 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.
      ,
      • Cainap C.
      • Qin S.
      • Huang W.T.
      • Chung I.J.
      • Pan H.
      • Cheng Y.
      • et al.
      Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial.
      ].

       Real-world evidence: GIDEON

      Real-world studies have been instrumental in providing additional information on sorafenib efficacy and safety in a broader population of patients [
      • Lencioni R.
      • Kudo M.
      • Ye S.L.
      • Bronowicki J.P.
      • Chen X.P.
      • Dagher L.
      • et al.
      GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and of its treatment with sorafeNib): second interim analysis.
      ,
      • Marrero J.A.
      • Kudo M.
      • Venook A.P.
      • Ye S.L.
      • Bronowicki J.P.
      • Chen X.P.
      • et al.
      Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: the GIDEON study.
      ,
      • Hollebecque A.
      • Cattan S.
      • Romano O.
      • Sergent G.
      • Mourad A.
      • Louvet A.
      • et al.
      Safety and efficacy of sorafenib in hepatocellular carcinoma: the impact of the Child-Pugh score.
      ,
      • Iavarone M.
      • Cabibbo G.
      • Piscaglia F.
      • Zavaglia C.
      • Grieco A.
      • Villa E.
      • et al.
      Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy.
      ]. The GIDEON study, a large, prospective, open-label, non-interventional study, evaluated sorafenib safety and HCC treatment practices in 3202 patients in real-world practice across 39 countries, and expanded the patient pool to Child–Pugh B patients (n = 666) [
      • Marrero J.A.
      • Kudo M.
      • Venook A.P.
      • Ye S.L.
      • Bronowicki J.P.
      • Chen X.P.
      • et al.
      Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: the GIDEON study.
      ]. The median OS in patients with Child–Pugh A liver disease was 13.6 months (95% CI 12.8–14.7) compared with 5.2 months (95% CI 4.6–6.3) for Child–Pugh B patients (Table 1). The tolerability profile of sorafenib was comparable between Child–Pugh A and B patients and was consistent with the results of the two pivotal phase 3 trials [
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      ,
      • Cheng A.
      • Kang Y.
      • Chen Z.
      • Tsao C.
      • Qin S.
      • Kim J.
      • 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.
      ,
      • Marrero J.A.
      • Kudo M.
      • Venook A.P.
      • Ye S.L.
      • Bronowicki J.P.
      • Chen X.P.
      • et al.
      Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: the GIDEON study.
      ]. Overall, the incidence of AEs was similar between Child–Pugh A and B patients, except for HFSR which was observed more frequently in Child–Pugh A patients. GIDEON also highlighted regional variation in HCC management, including differences in the prior use of TACE and patient outcomes [
      • Geschwind J.F.
      • Kudo M.
      • Marrero J.A.
      • Venook A.P.
      • Chen X.P.
      • Bronowicki J.P.
      • et al.
      TACE treatment in patients with sorafenib-treated unresectable hepatocellular carcinoma in clinical practice: final analysis of GIDEON.
      ,
      • Kudo M.L.R.
      • Marrero J.A.
      • et al.
      Regional differences in sorafenib-treated patients with hepatocellular carcinoma: GIDEON observational study.
      ]. Other studies have expanded these findings to patients who had become refractory or unresponsive to TACE, showing that survival seemed to be improved in these patients who switched early to sorafenib therapy versus those who continued on TACE [
      • Ogasawara S.
      • Chiba T.
      • Ooka Y.
      • Suzuki E.
      • Inoue M.
      • Wakamatsu T.
      • et al.
      Analysis of sorafenib outcome: focusing on the clinical course in patients with hepatocellular carcinoma.
      ,
      • Arizumi T.
      • Ueshima K.
      • Minami T.
      • Kono M.
      • Chishina H.
      • Takita M.
      • et al.
      Effectiveness of sorafenib in patients with transcatheter arterial chemoembolization (TACE) refractory and intermediate-stage hepatocellular carcinoma.
      ,
      • Ohki T.
      • Kondo M.
      • Karasawa Y.
      • Kawamura S.
      • Maeshima S.
      • Kojima K.
      • et al.
      Evaluation of the efficacy of sorafenib on overall survival in patients with hepatocellular carcinoma using FT rate: a devised index.
      ].

       Guidelines

      Currently, AASLD, EASL, and ESMO-ESDO treatment guidelines, which all use the BCLC staging system, place sorafenib as the standard first-line systemic therapy for patients with advanced HCC (BCLC stage C) [

      Galle PR, Forner A, Llovet JM, Mazzaferro V, Piscaglia F, Raoul J-L, et al. EASL clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol.

      ,
      • Bruix J.
      • Sherman M.
      American association for the study of liver diseases. Management of hepatocellular carcinoma: an update.
      ,

      Heimbach JK, Kulik LM, Finn R, Sirlin CB, Abecassis M, Roberts LR, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 2017: doi: 10.1002/hep.29086 [Epub ahead of print].

      ,

      Verslype C, Rosmorduc O, Rougier P, Group EGW. Hepatocellular carcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;23 Suppl 7:vii41-8.

      ]. The European guidelines also recommend sorafenib for patients with intermediate-stage HCC (BCLC stage B) who do not respond to TACE (at least two cycles of therapy) [
      • European Association for the Study of the Liver
      European organisation for research treatment of cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.
      ] or progress following TACE [

      Verslype C, Rosmorduc O, Rougier P, Group EGW. Hepatocellular carcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;23 Suppl 7:vii41-8.

      ]. The Japanese guidelines base their treatment recommendations on different factors (extrahepatic spread [EHS], liver function, macroscopic vascular invasion (MVI), tumor number, and tumor size) and recommend sorafenib as the first choice for patients with EHS and/or MVI and for TACE-refractory patients with Child–Pugh A liver function [
      • Kudo M.
      • Matsui O.
      • Izumi N.
      • Iijima H.
      • Kadoya M.
      • Imai Y.
      • et al.
      JSH consensus-based clinical practice guidelines for the management of hepatocellular carcinoma: 2014 update by the Liver Cancer Study Group of Japan.
      ].

      Sorafenib dosing and patient management

       Dose

      The recommended sorafenib regimen is 400 mg bid administered orally, regardless of the patient’s characteristics [

      Food and Drug Administration. Sorafenib (Nexavar) prescribing information [accessed 4 April 2018].

      ,

      European Medicines Agency. Sorafenib (NEXAVAR). Summary of Product Characteristics [accessed 4 April 2018].

      ]. In general, no dose adjustments are required for patients with renal or Child–Pugh B hepatic impairment, or for elderly patients. Dose adjustments to 400 mg once daily can be made to manage possible adverse drug reactions.
      Sorafenib, which is primarily metabolized in the liver by cytochrome p450 (CYP3A4)-mediated oxidative metabolism and UGT1A9-mediated glucuronidation, is an inhibitor of CYP2B6, CYP2C8, CYP2C9, UGT1A1, and UTG1A9 [

      Food and Drug Administration. Sorafenib (Nexavar) prescribing information [accessed 4 April 2018].

      ,

      European Medicines Agency. Sorafenib (NEXAVAR). Summary of Product Characteristics [accessed 4 April 2018].

      ]. Concomitant use of sorafenib with rifampicin and other strong inducers of CYP3A4 (e.g. carbamazepine, dexamethasone, phenobarbital, and plant extracts such as hypericum) should be avoided as these may lower sorafenib exposure. Regular monitoring of patients taking warfarin during sorafenib therapy is recommended and caution is also advised when treating patients with sorafenib in combination with docetaxel or drugs that are substrates of UTG1A1, such as irinotecan.

       Side effect management

      The management of dermatologic events represents one of the main challenges in the care of patients treated with sorafenib for HCC [
      • Porta C.
      • Paglino C.
      • Imarisio I.
      • Bonomi L.
      Uncovering Pandora's vase: the growing problem of new toxicities from novel anticancer agents. The case of sorafenib and sunitinib.
      ,
      • Bracarda S.
      • Ruggeri E.M.
      • Monti M.
      • Merlano M.
      • D'Angelo A.
      • Ferrau F.
      • et al.
      Early detection, prevention and management of cutaneous adverse events due to sorafenib: recommendations from the Sorafenib Working Group.
      ]; however, extensive clinical experience with sorafenib has led to the development of several effective strategies for managing dermatologic toxicities. These include the use of topical agents for the relief of symptoms, and sorafenib dose reduction or treatment interruption with the possibility to resume treatment [

      Food and Drug Administration. Sorafenib (Nexavar) prescribing information [accessed 4 April 2018].

      ,

      European Medicines Agency. Sorafenib (NEXAVAR). Summary of Product Characteristics [accessed 4 April 2018].

      ]. It is important to emphasize that careful clinical monitoring is required during the first 2 months of treatment when HFSR is most likely to appear [
      • Bracarda S.
      • Ruggeri E.M.
      • Monti M.
      • Merlano M.
      • D'Angelo A.
      • Ferrau F.
      • et al.
      Early detection, prevention and management of cutaneous adverse events due to sorafenib: recommendations from the Sorafenib Working Group.
      ,
      • Brose M.S.
      • Nutting C.M.
      • Jarzab B.
      • Elisei R.
      • Siena S.
      • Bastholt L.
      • et al.
      Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial.
      ]. While most strategies deal with dermatologic toxicities once they arise, the use of urea-based creams has been shown to confer a prophylactic benefit against HFSR in patients receiving sorafenib [
      • 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.
      ]. Specifically, urea-based (10%) creams reduced HFSR rates, extended the time to first occurrence of HFSR, and improved patient quality of life compared with best supportive care.
      Although current efforts focus on preventing and managing the AEs of anti-tumor agents to increase patient compliance and maximize their clinical benefit, the occurrence of certain sorafenib-related AEs, such as diarrhea, hypertension, and skin toxicities, have been positively correlated with survival and could therefore possibly act as clinical biomarkers for sorafenib efficacy in patients with HCC [
      • Abdel-Rahman O.
      • Lamarca A.
      Development of sorafenib-related side effects in patients diagnosed with advanced hepatocellular carcinoma treated with sorafenib: a systematic-review and meta-analysis of the impact on survival.
      ]. Evidence from retrospective and prospective studies shows that developing dermatologic AEs during the first 60 days of treatment (DAE60) is related to better TTP and OS [

      Reig M, Torres F, Rodriguez-Lope C, Forner A, N LL, Rimola J, et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol 2014;61:318–24.

      ,
      • Branco F.
      • Alencar R.S.
      • Volt F.
      • Sartori G.
      • Dode A.
      • Kikuchi L.
      • et al.
      The impact of early dermatologic events in the survival of patients with hepatocellular carcinoma treated with sorafenib.
      ]. In addition, in a multicenter Spanish study, 11/12 patients who achieved a complete radiologic response with sorafenib treatment had developed DAE60 [

      Rimola J, Diaz-Gonzalez A, Darnell A, Varela M, Pons F, Hernandez-Guerra M, et al. Complete response under sorafenib in patients with hepatocellular carcinoma. Relationship with dermatologic adverse events. Hepatology 2017:doi: http://doi.org/10.1002/hep.29515 [Epub ahead of print].

      ]. The BCLC group suggests that patients who develop DAE60 (HFSR, erythema, edema, rash, folliculitis, or pruritus) should not be considered as ‘intolerant’ to sorafenib, but should stay on treatment and have their sorafenib dose modified if necessary until a tolerated dose is achieved [

      Reig M, Torres F, Rodriguez-Lope C, Forner A, N LL, Rimola J, et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol 2014;61:318–24.

      ,

      Rimola J, Diaz-Gonzalez A, Darnell A, Varela M, Pons F, Hernandez-Guerra M, et al. Complete response under sorafenib in patients with hepatocellular carcinoma. Relationship with dermatologic adverse events. Hepatology 2017:doi: http://doi.org/10.1002/hep.29515 [Epub ahead of print].

      ]. According to BCLC recommendations, dose modifications due to AEs or cirrhosis complications should be based on AE severity: symptomatic treatment without sorafenib dose modification for mild AEs (grade 1), dose reduction for moderate AEs (grade 2), and dose interruption for severe AEs (grade 3/4) [
      • Reig M.
      • Gazzola A.
      • Di Donato R.
      • Bruix J.
      Systemic treatment.
      ]. For certain AEs, such as an ischemic event, the dose may need to be modified in all cases [

      Food and Drug Administration. Sorafenib (Nexavar) prescribing information [accessed 4 April 2018].

      ]. If the AEs return to baseline status, the relationship with sorafenib is confirmed and the tolerated dose for that patient needs to be defined. If the AEs do not return to baseline status, tumor progression, cirrhosis complications, or other causes need to be ruled out [

      Food and Drug Administration. Sorafenib (Nexavar) prescribing information [accessed 4 April 2018].

      ,
      • Reig M.
      • Gazzola A.
      • Di Donato R.
      • Bruix J.
      Systemic treatment.
      ].

      Patient selection: Identifying patients who benefit from sorafenib treatment

      In order to identify factors that may affect individual responses to sorafenib treatment, a pre-planned subgroup analysis was carried out in the SHARP and AP trials [
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      ,
      • Cheng A.
      • Kang Y.
      • Chen Z.
      • Tsao C.
      • Qin S.
      • Kim J.
      • 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.
      ]. These studies showed similar results across subgroups, with sorafenib providing treatment benefit (OS) in subgroups based on ECOG performance status, tumor burden (EHS, MVI, MVI and/or EHS), age, and HBV infection. Only in patients with EHS in the SHARP trial was the benefit less prominent. These results were confirmed and expanded in subsequent exploratory subgroup analyses in both studies, which demonstrated that sorafenib efficacy is unaffected by baseline performance status, viral status (HCV, HBV), tumor burden, tumor stage, prior therapy, and hepatic markers [
      • Bruix J.
      • Raoul J.L.
      • Sherman M.
      • Mazzaferro V.
      • Bolondi L.
      • Craxi A.
      • et al.
      Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial.
      ,
      • Cheng A.L.
      • Guan Z.
      • Chen Z.
      • Tsao C.J.
      • Qin S.
      • Kim J.S.
      • et al.
      Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: subset analyses of the phase III Sorafenib Asia-Pacific trial.
      ,
      • Raoul J.L.
      • Bruix J.
      • Greten T.F.
      • Sherman M.
      • Mazzaferro V.
      • Hilgard P.
      • et al.
      Relationship between baseline hepatic status and outcome, and effect of sorafenib on liver function: SHARP trial subanalyses.
      ]. A pooled, exploratory analysis of the two studies showed that, although sorafenib benefit was observed in all subgroups, HCV-positive patients (HR 0.47; 95% CI 0.32–0.69), those without EHS (HR 0.55; 95% CI 0.42–0.72), and those with a lower neutrophil:lymphocyte ratio (HR 0.59; 95% CI 0.46–0.77) derived the greatest benefit [
      • Bruix J.
      • Cheng A.L.
      • 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.
      ]. This effect, which was particularly clear in HCV-infected patients, has also been observed in head-to-head comparisons of first-line sorafenib versus other drugs [
      • Cheng A.L.
      • Kang Y.K.
      • Lin D.Y.
      • Park J.W.
      • Kudo M.
      • Qin S.
      • et al.
      Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial.
      ,
      • Johnson P.J.
      • Qin S.
      • Park J.W.
      • Poon R.T.
      • Raoul J.L.
      • Philip P.A.
      • 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.
      ] and could be related to the mechanism of action of sorafenib [
      • Himmelsbach K.
      • Sauter D.
      • Baumert T.F.
      • Ludwig L.
      • Blum H.E.
      • Hildt E.
      New aspects of an anti-tumour drug: sorafenib efficiently inhibits HCV replication.
      ,
      • Ma W.
      • Tao L.
      • Wang X.
      • Liu Q.
      • Zhang W.
      • Li Q.
      • et al.
      Sorafenib inhibits renal fibrosis induced by unilateral ureteral obstruction via inhibition of macrophage infiltration.
      ,
      • Pinter M.
      • Sieghart W.
      • Reiberger T.
      • Rohr-Udilova N.
      • Ferlitsch A.
      • Peck-Radosavljevic M.
      The effects of sorafenib on the portal hypertensive syndrome in patients with liver cirrhosis and hepatocellular carcinoma – a pilot study.
      ]. Unfortunately, at present, none of the biomarkers tested have predicted response to sorafenib [
      • Llovet J.M.
      • Pena C.E.
      • Lathia C.D.
      • Shan M.
      • Meinhardt G.
      • Bruix J.
      Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma.
      ].

      Treatment after progression on sorafenib

      Until the approval of regorafenib in 2017, there were no systemic treatment options after progression on sorafenib. Prior to that, several potential second-line treatments were assessed in phase 3 studies but failed [
      • Llovet J.M.
      • Decaens T.
      • Raoul J.L.
      • Boucher E.
      • Kudo M.
      • Chang C.
      • et al.
      Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study.
      ,
      • Zhu A.X.
      • Kudo M.
      • Assenat E.
      • Cattan S.
      • Kang Y.K.
      • Lim H.Y.
      • et al.
      Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial.
      ,
      • Zhu A.X.
      • Park J.O.
      • 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.
      ]. Regorafenib was the first agent to show a survival benefit over placebo in patients progressing on sorafenib [
      • Bruix J.
      • Qin S.
      • Merle P.
      • Granito A.
      • Huang Y.-H.
      • 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.
      ]. Regorafenib, an oral multikinase inhibitor, potently blocks the activity of multiple protein kinases involved in tumor angiogenesis, proliferation, the tumor microenvironment, metastasis, and tumor immunity [
      • Wilhelm S.M.
      • Dumas J.
      • Adnane L.
      • Lynch M.
      • Carter C.A.
      • Schutz G.
      • et al.
      Regorafenib (BAY 73–4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity.
      ,
      • Abou-Elkacem L.
      • Arns S.
      • Brix G.
      • Gremse F.
      • Zopf D.
      • Kiessling F.
      • et al.
      Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model.
      ]. Regorafenib was initially explored in early-phase HCC studies in pretreated patients with evidence of tumor control, which supported further development of regorafenib in this patient population [
      • Bruix J.
      • Tak W.Y.
      • Gasbarrini A.
      • Santoro A.
      • Colombo M.
      • Lim H.Y.
      • et al.
      Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study.
      ,
      • Finn R.S.
      • Blumenschein G.R.
      • Tolcher A.W.
      • Leong S.
      • Boix O.
      • Diefenbach K.
      Continuous-dose regorafenib (REG) in hepatocellular carcinoma (HCC): Phase I safety and pharmacokinetic (PK) study.
      ]. RESORCE was a randomized, double-blind, parallel-group, phase 3 trial that enrolled patients with HCC and Child–Pugh A disease who tolerated (≥400 mg daily for at least 20 of the 28 days before discontinuation) but progressed on prior sorafenib [
      • Bruix J.
      • Qin S.
      • Merle P.
      • Granito A.
      • Huang Y.-H.
      • 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.
      ]. Patients were required to have documented radiologic progression during sorafenib treatment. The patients had received prior sorafenib for a median of 7.8 months in both treatment arms. The median OS (primary endpoint) was 10.6 months with regorafenib versus 7.8 months with placebo (HR 0.63, 95% CI 0.50–0.79; P < 0.0001). The survival of the control arm in this study was consistent with other phase 3 studies in the second line [
      • Llovet J.M.
      • Decaens T.
      • Raoul J.L.
      • Boucher E.
      • Kudo M.
      • Chang C.
      • et al.
      Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study.
      ,
      • Zhu A.X.
      • Kudo M.
      • Assenat E.
      • Cattan S.
      • Kang Y.K.
      • Lim H.Y.
      • et al.
      Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial.
      ,
      • Zhu A.X.
      • Park J.O.
      • 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.
      ]. Regorafenib also improved progression-free survival (PFS; HR 0.46, 95% CI 0.37–0.56; P < 0.0001), with a median PFS of 3.1 months versus 1.5 months for placebo, and TTP (HR 0.44, 95% CI 0.36–0.55; P < 0.0001) with a median of 3.2 months for regorafenib and 1.5 months for placebo, based on modified Response Evaluation Criteria in Solid Tumors (mRECIST). Patients treated with regorafenib had a significantly higher objective response rate (11% vs 4%; P = 0.0037) and DCR (65% vs 36%; P < 0.0001) than those receiving placebo. Treatment-emergent AEs (TEAEs) were reported in all patients treated with regorafenib and 93% of patients receiving placebo. The most common clinically relevant grade 3/4 TEAEs (regorafenib vs placebo) were hypertension (15% vs 5%), HFSR (13% vs 1%), fatigue (9% vs 5%), and diarrhea (3% vs 0%) [
      • Bruix J.
      • Qin S.
      • Merle P.
      • Granito A.
      • Huang Y.-H.
      • 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.
      ]. An exploratory analysis of the RESORCE trial assessing the time from the start of prior sorafenib treatment to death during RESORCE (in patients who tolerated sorafenib and were ECOG performance status 0 or 1) reported a median of 26.0 months (95% CI 22.6–28.1) in the regorafenib group versus 19.2 months (95% CI 16.3–22.8) in the placebo group [
      • Finn R.S.
      • Merle P.
      • Granito A.
      • Huang Y.H.
      • Bodoky G.
      • Pracht M.
      • et al.
      Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: additional analyses from the phase 3 RESORCE trial.
      ]. This analysis also showed that regorafenib conferred a survival benefit regardless of the last dose of prior sorafenib (HR 0.67 for 800 mg/day; 0.68 for <800 mg/day).
      More recently, the monoclonal antibody nivolumab, which targets the cell surface receptor programmed death-1 (PD-1), received an accelerated FDA approval based on tumor response and durability of response for the treatment of patients with HCC who had previously been treated with sorafenib in the phase 1/2 single-arm CheckMate 040 study [

      Food and Drug Administration. Nivolumab (Opdivo) prescribing information [accessed 4 April 2018].

      ,
      • El-Khoueiry A.B.
      • Sangro B.
      • Yau T.
      • Crocenzi T.S.
      • 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.
      ]. The ORR was 15% in the dose-escalation phase (n = 48) and 20% in the dose-expansion phase (n = 214). Median duration of response was 17 months in the dose-escalation phase. The results from randomized phase 3 trials of immunotherapy (nivolumab and pembrolizumab) in first and second line are pending and will help us to further build on the current treatment strategy for HCC.
      Further approvals are on the horizon, with positive results emerging from phase 3 trials evaluating cabozantinib and ramucirumab in the second-line setting. Cabozantinib is a small-molecule multikinase inhibitor which was superior to placebo in the randomized, phase 3 CELESTIAL trial [
      • Abou-Alfa G.K.
      • Meyer T.
      • Cheng A.-L.
      • El-Khoueiry A.B.
      • Rimassa L.
      • Ryoo B.-Y.
      • et al.
      Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: results from the randomized phase III CELESTIAL trial.
      ]. The trial, which at the time of the analysis had evaluated 707 patients (Child–Pugh A, ECOG performance status 0–1) with advanced HCC who had previously received sorafenib, demonstrated that cabozantinib significantly improved OS over placebo (10.2 vs 8.0 months, respectively; HR 0.76, 95% CI 0.63–0.92; P = 0.0049) [
      • Abou-Alfa G.K.
      • Meyer T.
      • Cheng A.-L.
      • El-Khoueiry A.B.
      • Rimassa L.
      • Ryoo B.-Y.
      • et al.
      Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: results from the randomized phase III CELESTIAL trial.
      ]. The safety profile was as expected, with HFSR, hypertension, increased aspartate aminotransferase, fatigue, and diarrhea the most common grade 3/4 AEs with higher incidence in the cabozantinib arm versus sorafenib. Positive results for the antiangiogenic agent ramucirumab versus placebo in the phase 3 REACH-2 trial were recently announced, with REACH-2 meeting its OS endpoint in patients with high AFP (≥400 ng/mL) and who were intolerant to or had progression on sorafenib [

      Lilly Press Release. Lilly announces CYRAMZA® (ramucirumab) phase 3 REACH-2 study in second-line hepatocellular carcinoma patients met overall survival endpoint <https://investor.lilly.com/news-releases/news-release-details/lilly-announces-cyramzar-ramucirumab-phase-3-reach-2-study> [accessed 4 April 2018].

      ].
      With the approval of regorafenib and nivolumab, and the continued search for additional second-line treatment options, the optimal time to stop sorafenib treatment and initiate a new therapy needs to be determined. This decision is complicated by the lack of guidance in treatment guidelines on the frequency of tumor assessments during sorafenib treatment. The EASL-EORTC 2012 guidelines recommend the assessment of tumor progression every 6–8 weeks [
      • European Association for the Study of the Liver
      European organisation for research treatment of cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.
      ]. In the SHARP trial, tumor measurements were performed every 6 weeks during treatment [
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      ].

      Assessing clinical efficacy in HCC

      For any cancer treatment, it is essential to use appropriate treatment response measures to ensure that treatment discontinuation decisions are based on an accurate assessment of clinical benefit. Tumor size is a key factor in the decision to stop or continue treatment. However, targeted therapies such as sorafenib and other angiogenesis inhibitors demonstrate improved survival without a significant response rate [
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      ,
      • Cheng A.
      • Kang Y.
      • Chen Z.
      • Tsao C.
      • Qin S.
      • Kim J.
      • 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.
      ,
      • Bruix J.
      • Qin S.
      • Merle P.
      • Granito A.
      • Huang Y.-H.
      • 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.
      ,
      • Raoul J.L.
      • Adhoute X.
      • Gilabert M.
      • Edeline J.
      How to assess the efficacy or failure of targeted therapy: deciding when to stop sorafenib in hepatocellular carcinoma.
      ]. Thus, more appropriate measures for assessing the clinical efficacy of systemic therapies in advanced HCC are needed [
      • Bruix J.
      • Reig M.
      • Sangro B.
      Assessment of treatment efficacy in hepatocellular carcinoma: response rate, delay in progression or none of them.
      ].
      Tumor size is commonly measured using RECIST [
      • Therasse P.
      • Arbuck S.
      • Eisenhaue r.E.
      New guidelines to evaluate the response to treatment in solid tumors (RECIST Guidelines).
      ]. These criteria sum the longest diameters of the tumors, reflecting changes in the size of existing tumors and the appearance of new tumors (Table 2). The revised criteria, RECIST 1.1, were published in 2009 and aimed to improve and further standardize the assessment of tumor size [
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • Schwartz L.H.
      • Sargent D.
      • Ford R.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      ]. The contribution of underlying liver cirrhosis and viral hepatitis to the development of some parameters assessed by RECIST 1.1 as tumor-related (ascites, pleural effusion, and lymph nodes <15 mm still considered non-measurable lesions) make these criteria unreliable when assessing tumor burden in HCC [
      • Raoul J.L.
      • Adhoute X.
      • Gilabert M.
      • Edeline J.
      How to assess the efficacy or failure of targeted therapy: deciding when to stop sorafenib in hepatocellular carcinoma.
      ]. Nevertheless, RECIST has been widely used to categorize tumor responses and enable the measurement of surrogate endpoints such as TTP in clinical studies of systemic treatments for HCC. However, it is now increasingly recognized in HCC and in other cancers that there is no strong correlation between TTP and survival. For example, a recent pooled analysis of data from the sorafenib phase 3 clinical studies indicated only a weak correlation between TTP and survival [
      • Huang L.
      • Yoriko D.
      • Minghua S.
      • Bruix J.
      • Llovet J.
      • Cheng A.-L.
      Weak correlation of overall survival and time to progression in advanced hepatocellular carcinoma.
      ].
      Table 2Comparison of RECIST (1.0 vs 1.1) and mRECIST.
      RECIST v 1.0
      • Therasse P.
      • Arbuck S.
      • Eisenhaue r.E.
      New guidelines to evaluate the response to treatment in solid tumors (RECIST Guidelines).
      RECIST v 1.1
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • Schwartz L.H.
      • Sargent D.
      • Ford R.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      mRECIST for HCC
      • Lencioni R.
      • Llovet J.M.
      Modified RECIST (mRECIST) assessment for hepatocellular carcinoma.
      CRDisappearance of all target lesionsDisappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mmDisappearance of any intratumoral arterial enhancement in all target lesions
      PRAt least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diametersAt least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diametersAt least a 30% decrease in the sum of diameters of viable (contrast enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions
      SDNeither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter recorded since the start of treatmentNeither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameters while on studyAny cases that do not qualify as either PR or PD
      PDAt least a 20% increase in the sum of the longest diameters of the target lesions, taking as reference the smallest sum of the longest diameter recorded since the treatment started, or the appearance of one or more new lesionsAt least a 20% increase in the sum of the diameters of the target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression)An increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since the start of treatment
      CR, complete response; HCC, hepatocellular carcinoma; mRECIST, modified Response Evaluation Criteria in Solid Tumors; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.
      To overcome some of the limitations of the standard RECIST, and specifically to consider the value of tumor necrosis as a marker of response to locoregional ablative or antiangiogenic treatments, mRECIST was developed specifically for the assessment of HCC [
      • Lencioni R.
      • Llovet J.M.
      Modified RECIST (mRECIST) assessment for hepatocellular carcinoma.
      ]. These new criteria include the use of contrast-enhanced imaging techniques and consider as target only the enhancing component of the tumor (Table 2). Recently, assessments of response using mRECIST to predict survival with targeted therapies has been reported. Objective response as measured by mRECIST had an independent prognostic value for survival in an analysis of individual patient data from a negative phase 3 randomized trial, BRISK-PS [
      • Lencioni R.
      • Montal R.
      • Torres F.
      • Park J.W.
      • Decaens T.
      • Raoul J.L.
      • et al.
      Objective response by mRECIST as a predictor and potential surrogate end-point of overall survival in advanced HCC.
      ], comparing brivanib, a tyrosine kinase inhibitor with antiangiogenic effects, with placebo after sorafenib progression or intolerance [
      • Llovet J.M.
      • Decaens T.
      • Raoul J.L.
      • Boucher E.
      • Kudo M.
      • Chang C.
      • et al.
      Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study.
      ]. However, recent results of a pooled analysis of the SHARP and AP trials suggested that the response rate by RECIST with SHARP–BCLC amendments (which formed the basis for mRECIST [
      • Lencioni R.
      • Llovet J.M.
      Modified RECIST (mRECIST) assessment for hepatocellular carcinoma.
      ]) was not a reliable surrogate endpoint for sorafenib OS in advanced HCC [

      Huang L, Sanctis YD, Shan M, Bruix J, LLovet J, Cheng A-L, et al. Weak correlation of overall survival (OS) and response rate (RR) by RECIST in advanced hepatocellular carcinoma (HCC). Presented at ILCA 2017; abstract P-056 [accessed 4 April 2018].

      ]. Another analysis based on data from two trials of nintedanib suggested that, while both mRECIST and RECIST were associated with improved survival, mRECIST might not be a better surrogate of survival than RECIST [
      • Meyer T.
      • Palmer D.H.
      • Cheng A.L.
      • Hocke J.
      • Loembe A.B.
      • Yen C.J.
      MRECIST to predict survival in advanced hepatocellular carcinoma: analysis of two randomised phase II trials comparing nintedanib vs sorafenib.
      ]. This is an important consideration for tyrosine kinase inhibitors with antiangiogenic function because contrast enhancement may be lost due to reduced perfusion rather than necrosis, which can be misleading [
      • Bruix J.
      • Reig M.
      • Sangro B.
      Assessment of treatment efficacy in hepatocellular carcinoma: response rate, delay in progression or none of them.
      ].
      While mRECIST provides a step forward in the identification of optimal surrogates for assessing responses to angiogenesis inhibitors in HCC, they do not clearly discriminate between different patterns of progression [
      • Reig M.
      • Rimola J.
      • Torres F.
      • Darnell A.
      • Rodriguez-Lope C.
      • Forner A.
      • et al.
      Postprogression survival of patients with advanced hepatocellular carcinoma: rationale for second-line trial design.
      ]. HCC progression can be classified into four patterns: intrahepatic growth, extrahepatic growth, new intrahepatic lesion, and new extrahepatic lesion and/or vascular invasion. Survival may depend on the type of progression experienced rather than simply on tumor burden.
      A prospective study carried out by the BCLC group showed that the development of a new extrahepatic lesion and/or vascular invasion, regardless of the baseline BCLC stage at the time of starting sorafenib, was an independent predictor of reduced OS and reduced post-progression survival (PPS) during sorafenib treatment [
      • Reig M.
      • Rimola J.
      • Torres F.
      • Darnell A.
      • Rodriguez-Lope C.
      • Forner A.
      • et al.
      Postprogression survival of patients with advanced hepatocellular carcinoma: rationale for second-line trial design.
      ]. This data was confirmed by Iavarone et al. [
      • Iavarone M.
      • Cabibbo G.
      • Biolato M.
      • Della Corte C.
      • Maida M.
      • Barbara M.
      • et al.
      Predictors of survival in patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib.
      ] and Ogasawara et al. [
      • Ogasawara S.
      • Chiba T.
      • Ooka Y.
      • Suzuki E.
      • Kanogawa N.
      • Saito T.
      • et al.
      Post-progression survival in patients with advanced hepatocellular carcinoma resistant to sorafenib.
      ]. Furthermore, an exploratory analysis of the regorafenib phase 3 trial, RESORCE, confirmed the finding that the pattern of progression influences PPS. Regorafenib provided an OS benefit regardless of the pattern of progression on prior sorafenib; however, in both regorafenib and placebo treatment groups, PPS was reduced for patients who developed new extrahepatic lesions [
      • Bruix J.
      • Merle P.
      • Granito A.
      • Huang Y.-H.
      • Bodoky G.
      • Pracht M.
      • et al.
      Survival by pattern of tumor progression during prior sorafenib (SOR) treatment in patients with hepatocellular carcinoma (HCC) in the phase III RESORCE trial comparing second-line treatment with regorafenib (REG) or placebo.
      ]. This suggests that the progression pattern may be a key prognostic parameter and should be considered when designing and analyzing future trials.

      Therapeutic agents in development

      There is an active search for agents that provide an improved survival benefit over sorafenib in the first-line setting and for additional treatment options in the second-line setting. Several phase 3 trials evaluating multikinase inhibitors such as sunitinib, brivanib, and linifanib failed to demonstrate clinical superiority over sorafenib in the first line [
      • Cheng A.L.
      • Kang Y.K.
      • Lin D.Y.
      • Park J.W.
      • Kudo M.
      • Qin S.
      • et al.
      Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial.
      ,
      • Johnson P.J.
      • Qin S.
      • Park J.W.
      • Poon R.T.
      • Raoul J.L.
      • Philip P.A.
      • 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.
      ,
      • Cainap C.
      • Qin S.
      • Huang W.T.
      • Chung I.J.
      • Pan H.
      • Cheng Y.
      • et al.
      Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial.
      ,
      • Zhu A.X.
      • Rosmorduc O.
      • Evans T.R.
      • Ross P.J.
      • Santoro A.
      • Carrilho F.J.
      • et al.
      SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma.
      ]. Candidate first-line therapies face a challenge due to the accumulating clinical experience with sorafenib which is constantly shifting the bar as healthcare professionals become more efficient at preventing and managing sorafenib AEs and identifying patients who are likely to respond to treatment. This is illustrated by the trend toward increased OS in the sorafenib arms of clinical studies (Table 3).
      Table 3Median overall survival with sorafenib in advanced hepatocellular carcinoma.
      Enrollment periodStudyPatient populationMedian sorafenib, monthsReference
      OSTTP
      RECIST v1.0 unless otherwise specified.
      2005–2006SHARP: sorafenib (n = 299)

      vs placebo (n = 303); NCT00105443
      Western patients10.75.5
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      2005–2007AP: sorafenib (n = 150)

      vs placebo (n = 76); NCT00492752
      Asian patients6.52.8
      • Cheng A.
      • Kang Y.
      • Chen Z.
      • Tsao C.
      • Qin S.
      • Kim J.
      • 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.
      2008–2010Sunitinib (n = 530) vs sorafenib (n = 544);

      NCT00699374
      All patients

      Non-Asian patients (24%)

      Asian patients (76%)
      10.2

      15.1

      8.8
      3.8

      6.0

      2.8
      • Cheng A.L.
      • Kang Y.K.
      • Lin D.Y.
      • Park J.W.
      • Kudo M.
      • Qin S.
      • et al.
      Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial.
      2009–2011Brivanib (n = 577) vs sorafenib (n = 578); NCT00858871All patients

      Non-Asian patients (36%)

      Asian patients (64%)
      9.9

      11.8

      8.9
      4.1
      mRECIST.
      • Johnson P.J.
      • Qin S.
      • Park J.W.
      • Poon R.T.
      • Raoul J.L.
      • Philip P.A.
      • 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.
      2010–2012Linifanib (n = 514) vs sorafenib (n = 521); NCT01009593All patients

      Non-Asian patients (33%)

      Japanese patients (8%)

      Rest of Asia patients (59%)
      9.8

      12.4

      9.5

      8.5
      4.0
      RECIST v1.1.
      • Cainap C.
      • Qin S.
      • Huang W.T.
      • Chung I.J.
      • Pan H.
      • Cheng Y.
      • et al.
      Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial.
      2013–2017Lenvatinib (n = 478) vs sorafenib (n = 476); NCT01761266All patients

      Asia-Pacific (67%)

      Western
      12.3

      11.0

      14.2
      3.7
      mRECIST.


      3.6

      5.6
      • Kudo M.
      • Finn R.S.
      • Qin S.
      • Han K.H.
      • 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.
      AP, Asia-Pacific; OS, overall survival; TTP, time to progression.
      a RECIST v1.0 unless otherwise specified.
      b RECIST v1.1.
      c mRECIST.
      While most of the new agents currently being evaluated are systemic, two recent randomized, controlled phase 3 trials evaluated the efficacy and safety of sorafenib compared to selective internal radiation therapy (SIRT) with yttrium-90 (Y90) resin microspheres in patients with advanced HCC. Neither study demonstrated a statistically significant improvement in OS compared with sorafenib: in the SARAH trial, treatment with SIRT resulted in a median OS of 8.0 months compared with 9.9 months with sorafenib (P = 0.18; intent-to-treat (ITT) analysis) [
      • Vilgrain V.
      • Pereira H.
      • Assenat E.
      • Guiu B.
      • Ilonca A.D.
      • Pageaux G.P.
      • 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.
      ]; in the SIRveNIB trial, treatment with SIRT resulted in a median OS of 8.8 months compared with 10.0 months with sorafenib (P = 0.36; ITT analysis) [

      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:Jco2017760892.

      ]. Recently, the phase 3 SORAMIC study failed to meet its primary endpoint of improved OS with the addition of Y-90 to sorafenib [
      • Ricke J.
      • Sangro B.
      • Amthauer H.
      • Bargellini I.
      • Bartenstein P.
      • De Toni E.
      • et al.
      The impact of combining Selective Internal Radiation Therapy (SIRT) with Sorafenib on overall survival in patients with advanced hepatocellular carcinoma: the Soramic trial palliative cohort.
      ].
      Some of the systemic agents which have shown promise and are being evaluated in phase 3 clinical trials are summarized below and in Table 4. Lenvatinib is an oral multikinase inhibitor approved for the treatment of differentiated thyroid cancer [

      European Medicines Agency. Lenvatinib (LENVIMA). Summary of Product Characteristics [accessed 4 April 2018].

      ,

      Food and Drug Administration. Lenvatinib (Lenvima) prescribing information [accessed 4 April 2018].

      ] and renal cell cancer [

      Food and Drug Administration. Lenvatinib (Lenvima) prescribing information [accessed 4 April 2018].

      ]. In a phase 2 trial in patients with HCC carried out in Japan and South Korea, lenvatinib treatment was associated with a 37% objective response rate (by mRECIST), a median TTP of 7.4 months, and an acceptable toxicity profile [
      • Ikeda K.
      • Kudo M.
      • Kawazoe S.
      • Osaki Y.
      • Ikeda M.
      • Okusaka T.
      • et al.
      Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma.
      ]. This led to further evaluation in the open-label phase 3 REFLECT trial. In this non-inferiority trial, 954 patients (67% from Asia-Pacific) were randomized 1:1 to receive sorafenib or lenvatinib [
      • Kudo M.
      • Finn R.S.
      • Qin S.
      • Han K.H.
      • 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.
      ]. Inclusion criteria were more restrictive than in the SHARP trial; patients with ECOG performance status 0–1 and less advanced HCC (no invasion of the main portal vein and hepatic involvement less than 50%) were included. Lenvatinib demonstrated non-inferiority to sorafenib with a median OS of 13.6 months versus 12.3 months, respectively (HR 0.92, 95% CI 0.79–1.06), with OS results consistent across subgroups. For HBV-infected patients, and those with certain tumor characteristics (extrahepatic spread, portal vein invasion or both, and AFP blood level ≥200 ng/mL) there was also a trend in favor of lenvatinib. Safety was not an endpoint of the REFLECT trial but the lenvatinib safety profile was consistent with that observed in previous trials with lenvatinib with hypertension (42%) and diarrhea (39%) the most frequent lenvatinib-related TEAEs while HFSR was the most frequent for sorafenib (52%).
      Table 4Overview of systemic agents in phase 3 development for the treatment of HCC.
      AgentMOAPhase 2 resultsPhase 3 trials
      Efficacy outcomesOutcomes
      Lenvatinib

      (first line)
      Multiple TKI that targets VEGFR1–3, FGFR1–4, PDGFRα, RET, and KIT

      European Medicines Agency. Lenvatinib (LENVIMA). Summary of Product Characteristics [accessed 4 April 2018].

      ,

      Food and Drug Administration. Lenvatinib (Lenvima) prescribing information [accessed 4 April 2018].

      12 mg qd: mTTP 7.4 months; mOS 18.7 months; ORR 37%, DCR 78%; DR 74%; DC 22%
      • Ikeda K.
      • Kudo M.
      • Kawazoe S.
      • Osaki Y.
      • Ikeda M.
      • Okusaka T.
      • et al.
      Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma.
      mRECIST.
      REFLECT: non-inferiority of lenvatinib 8 mg/12 mg qd versus sorafenib 400 mg bid (NCT01761266)Non-inferior OS

      Improved PFS, TTP, and ORR
      • Kudo M.
      • Finn R.S.
      • Qin S.
      • Han K.H.
      • 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.
      Nivolumab

      (first line)
      PD-1 inhibitor
      • El-Khoueiry A.B.
      • Sangro B.
      • Yau T.
      • Crocenzi T.S.
      • 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.
      CheckMate 040: 3 mg/kg q2w: ORR 15%, DCR 58%; mOS 15 months
      • El-Khoueiry A.B.
      • Sangro B.
      • Yau T.
      • Crocenzi T.S.
      • 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.
      CheckMate 459: comparison with sorafenib (NCT02576509)Ongoing
      Ramucirumab

      (second line)
      VEGFR2 inhibitor
      • Zhu A.X.
      • Ryoo B.-Y.
      • Yen C.-J.
      • Kudo M.
      • Poon R.T.-P.
      • Pastorelli D.
      • et al.
      Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): analysis of patients with elevated α-fetoprotein (AFP) from the randomized phase III REACH study.
      8 mg/kg IV q2w: mTTP 4.2 months; mOS 12.0 months; ORR 9.5%, DCR 69%; DR 7%; DC 14%
      • Zhu A.X.
      • Finn R.S.
      • Mulcahy M.
      • Gurtler J.
      • Sun W.
      • Schwartz J.D.
      • et al.
      A phase II and biomarker study of ramucirumab, a human monoclonal antibody targeting the VEGF receptor-2, as first-line monotherapy in patients with advanced hepatocellular cancer.
      REACH: 8 mg/kg IV q2w versus placebo
      • Zhu A.X.
      • Park J.O.
      • 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.


      REACH-2: 8 mg/kg IV q2w versus placebo in patients with AFP ≥ 400 ng/mL (NCT02435433)
      REACH: Survival benefit for the subgroup with AFP ≥ 400 ng/mL
      • Zhu A.X.
      • Park J.O.
      • 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.
      ,
      • Zhu A.X.
      • Ryoo B.-Y.
      • Yen C.-J.
      • Kudo M.
      • Poon R.T.-P.
      • Pastorelli D.
      • et al.
      Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): analysis of patients with elevated α-fetoprotein (AFP) from the randomized phase III REACH study.


      REACH-2: met primary OS endpoint

      Lilly Press Release. Lilly announces CYRAMZA® (ramucirumab) phase 3 REACH-2 study in second-line hepatocellular carcinoma patients met overall survival endpoint <https://investor.lilly.com/news-releases/news-release-details/lilly-announces-cyramzar-ramucirumab-phase-3-reach-2-study> [accessed 4 April 2018].

      Pembrolizumab

      (second line)
      PD-1 inhibitor
      • Khoja L.
      • Butler M.O.
      • Kang S.P.
      • Ebbinghaus S.
      • Joshua A.M.
      Pembrolizumab.
      KEYNOTE 224: Pembrolizumab 200 mg IV q3w: ORR 16%, DCR 61.5%, mPFS 4.8 months

      Zhu AX, Finn RS, Cattan S, Edeline J, Ogasawara S, Palmer DH, et al. KEYNOTE-224: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. J Clin Oncol 2018;36:209.

      KEYNOTE-240: pembrolizumab 200 mg IV q3w versus placebo (NCT02702401)Ongoing
      Cabozantinib

      (second line)
      Multiple TKI that targets TIE-1, TIE-2, FLT3, c-MET, KIT, RET, and VEGFR
      • Yakes F.M.
      • Chen J.
      • Tan J.
      • Yamaguchi K.
      • Shi Y.
      • Yu P.
      • et al.
      Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth.
      100 mg qd: DCR 66%; mPFS 5.2 months; mOS 11.5 months
      • Kelley R.K.
      • Verslype C.
      • Cohn A.L.
      • Yang T.S.
      • Su W.C.
      • Burris H.
      • et al.
      Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study.
      CELESTIAL: 60 mg qd versus placebo in patients who progressed on sorafenib (NCT01908426)Significant improvement in OS, PFS, and ORR
      • Abou-Alfa G.K.
      • Meyer T.
      • Cheng A.-L.
      • El-Khoueiry A.B.
      • Rimassa L.
      • Ryoo B.-Y.
      • et al.
      Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: results from the randomized phase III CELESTIAL trial.
      AFP, alpha-fetoprotein; bid, twice daily; DC, discontinuation due to adverse event; DCR, disease control rate; DR, dose reduction; HCC, hepatocellular carcinoma; IV, intravenous; MOA, mechanism of action; mRECIST, modified Response Evaluation Criteria in Solid Tumors; (m)OS, (median) overall survival; ORR, objective response rate; (m)PFS, (median) progression-free survival; q2w, every 2 weeks; q3w, every 3 weeks; qd, once daily; TKI, tyrosine kinase inhibitor; (m)TTP, (median) time to progression.
      a mRECIST.
      The receptor tyrosine kinase c-MET has emerged as a possible therapeutic target in HCC and other cancers, with aberrant expression of the receptor promoting cellular proliferation and metastasis observed in numerous cancers [
      • Scagliotti G.V.
      • Novello S.
      • von Pawel J.
      The emerging role of MET/HGF inhibitors in oncology.
      ]. However, tivantinib, a selective oral c-MET inhibitor, failed to meet its primary endpoint of improved OS over placebo in its pivotal phase 3 METIV-HCC trial, in which patients with advanced HCC with high MET expression were evaluated in the second-line setting [
      • 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.
      ,
      • Best J.
      • Schotten C.
      • Lohmann G.
      • Gerken G.
      • Dechene A.
      Tivantinib for the treatment of hepatocellular carcinoma.
      ]. While reasons for its failure are unclear, it has been speculated that the efficacy of tivantinib may be c-MET independent and therefore the patient selection based on c-MET expression was inappropriate [
      • Best J.
      • Schotten C.
      • Lohmann G.
      • Gerken G.
      • Dechene A.
      Tivantinib for the treatment of hepatocellular carcinoma.
      ]. Cabozantinib is a multikinase inhibitor which targets c-MET but also VEGFRs, AXL, RET, KIT, and FLT3 [
      • Yakes F.M.
      • Chen J.
      • Tan J.
      • Yamaguchi K.
      • Shi Y.
      • Yu P.
      • et al.
      Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth.
      ]. In a phase 2 trial, cabozantinib demonstrated signs of clinical activity in patients with HCC in both treatment-naïve and sorafenib-treated patients [
      • Kelley R.K.
      • Verslype C.
      • Cohn A.L.
      • Yang T.S.
      • Su W.C.
      • Burris H.
      • et al.
      Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study.
      ]. The most common grade 3/4 AEs (regardless of causality) were diarrhea, HFSR, and thrombocytopenia, which were effectively managed with dose reductions. As described previously, the cabozantinib data in the phase 3 CELESTIAL trial were positive, with the trial meeting its primary endpoint of superiority in OS for cabozantinib over placebo [
      • Abou-Alfa G.K.
      • Meyer T.
      • Cheng A.-L.
      • El-Khoueiry A.B.
      • Rimassa L.
      • Ryoo B.-Y.
      • et al.
      Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: results from the randomized phase III CELESTIAL trial.
      ]. However, unlike the phase 3 tivantinib study which selected patients based on elevated c-MET expression, patient selection in the phase 3 cabozantinib study was not based on a specific biomarker.
      Ramucirumab is an IgG1 monoclonal antibody to VEGFR2 which has demonstrated improved OS alone and in combination with paclitaxel in patients receiving second-line treatment for metastatic gastric cancer [
      • Clarke J.M.
      • Hurwitz H.I.
      Targeted inhibition of VEGF receptor 2: an update on ramucirumab.
      ,
      • Wilke H.
      • Muro K.
      • Van Cutsem E.
      • Oh S.C.
      • Bodoky G.
      • Shimada Y.
      • et al.
      Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial.
      ]. In a phase 3 study (REACH), ramucirumab failed to improve OS compared with placebo in patients with HCC after sorafenib failure (due to progression or intolerance); however, PFS was increased compared with placebo [
      • Zhu A.X.
      • Park J.O.
      • 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.
      ]. A prespecified subgroup analysis of this study showed that 250 patients with AFP ≥400 ng/mL experienced a clinically meaningful improvement in OS compared with placebo (HR 0.67, 95% CI 0.51–0.90; P = 0.0059) [
      • Zhu A.X.
      • Ryoo B.-Y.
      • Yen C.-J.
      • Kudo M.
      • Poon R.T.-P.
      • Pastorelli D.
      • et al.
      Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): analysis of patients with elevated α-fetoprotein (AFP) from the randomized phase III REACH study.
      ]. Following on from these results, ramucirumab was investigated in another randomized, double-blind, placebo-controlled phase 3 study REACH-2, which enrolled patients with elevated AFP levels at baseline (≥400 ng/mL). A recent press release announced the trial met its primary OS endpoint, however detailed results are still to be presented [

      Lilly Press Release. Lilly announces CYRAMZA® (ramucirumab) phase 3 REACH-2 study in second-line hepatocellular carcinoma patients met overall survival endpoint <https://investor.lilly.com/news-releases/news-release-details/lilly-announces-cyramzar-ramucirumab-phase-3-reach-2-study> [accessed 4 April 2018].

      ].
      As mentioned previously, the PD-1 blocking antibody nivolumab was recently approved by the FDA in the second-line setting based on results of the single-arm phase 1/2 CheckMate 040 study [

      Food and Drug Administration. Nivolumab (Opdivo) prescribing information [accessed 4 April 2018].

      ,
      • El-Khoueiry A.B.
      • Sangro B.
      • Yau T.
      • Crocenzi T.S.
      • 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.
      ]. Nivolumab is being evaluated in the CheckMate 459 phase 3 trial (NCT02576509) which is evaluating nivolumab in comparison with sorafenib as a first-line treatment in patients with advanced HCC. Primary endpoints are OS; secondary endpoints are PFS, ORR, and evaluation of the relationship between PD-L1 expression and efficacy.
      Pembrolizumab is another monoclonal antibody targeting the PD-1 interaction with PD-L1, first approved for metastatic melanoma [
      • Khoja L.
      • Butler M.O.
      • Kang S.P.
      • Ebbinghaus S.
      • Joshua A.M.
      Pembrolizumab.
      ]. Results from the single-arm phase 2 KEYNOTE 224 trial in 104 patients with advanced HCC previously treated with sorafenib were recently reported, in which treatment with pembrolizumab resulted in 1 complete response (1%) and 16 partial response (15%) [

      Zhu AX, Finn RS, Cattan S, Edeline J, Ogasawara S, Palmer DH, et al. KEYNOTE-224: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. J Clin Oncol 2018;36:209.

      ]. The placebo-controlled phase 3 (KEYNOTE 240) trial is in progress to assess pembrolizumab safety and efficacy in patients previously treated with sorafenib which is due to complete in February 2019 (NCT02702401).

      Future scenario in HCC treatment

      With the increasing availability of drugs for first- and second-line treatment for HCC, a prominent question among physicians will be regarding treatment strategy. To date, we do not have results from randomized phase 3 trials evaluating immunotherapy in either first or second line. At present, there are two drugs that are recognized for the treatment of HCC in the first-line setting: sorafenib and lenvatinib which have different safety profiles. Lenvatinib is associated with a higher incidence of hypertension, anorexia, and fatigue while sorafenib is associated with HFSR. Several agents have been evaluated in the second-line setting following sorafenib; regorafenib was only assessed in patients who tolerated prior sorafenib therapy, while the nivolumab populated was not limited to those who tolerated prior sorafenib in an uncontrolled phase 1/2 trial. Since then, cabozantinib has also been evaluated in patients with prior sorafenib exposure, and the ramucirumab REACH-2 study was restricted to patients treated in second-line after sorafenib but with elevated AFP. How to integrate new drugs and data into the evolving sequence paradigm needs to be determined. One approach, would be to propose regorafenib as second-line treatment in patients who tolerated sorafenib, whereas for patients discontinuing sorafenib because of toxicity, cabozantinib and perhaps nivolumab may be more appropriate second-line treatment options, while ramucirumab should be restricted to patients with high AFP levels. However, this treatment strategy may be significantly modified following data from upcoming trials with immunotherapy drugs. Furthermore, the cost of newer drugs will be an important factor in treatment decisions, whereby the cost may fall significantly in the future when generic options become available. Still, patients likely will benefit from treatment at centers that have multi-disciplinary teams to assess and manage patients with HCC.

      Conclusions

      The HCC treatment landscape changed a decade ago following the approval of sorafenib, the first systemic therapy demonstrating a survival benefit. More recently, lenvatinib, regorafenib, cabozantinib, nivolumab, and ramucirumab have provided additional options in the first- and second-line setting, with regorafenib demonstrating a survival benefit in patients who tolerated, but progressed on, sorafenib. It is imperative that patients eligible for sorafenib treatment receive it in a timely manner (for example early after progression on TACE) and that toxicities are managed prospectively and effectively to ensure that patients could benefit from all currently available therapies. The emergence of novel treatment options is likely to transform the treatment landscape in the near future, placing further emphasis on the value of systemic therapies in HCC treatment and ultimately improving the care of out-patients.

      Financial disclaimers

      Bayer funded editorial assistance for the development of the review and was allowed to review the manuscript for factual correctness, but did not influence the content or decision to publish.

      Author contributions

      All authors contributed to the conception, writing, and critically reviewing the content of the article. All authors approved the final version for submission.

      Conflicts of interest

      Dr. Raoul reports personal fees∗ from AstraZeneca, Bayer, BMS, BTG, Terumo, Guerbet, and GenoScience, and grants from Celgene.
      Dr. Kudo reports speaker fees from Bayer, Eisai, MSD, Ajinomoto, Kowa, and Taiho, grants from Chugai, Otsuka, Takeda, Taiho, Sumitomo Dainippon, and Daiichi Sankyo, advisory board attendance for MSD, Eisai, Bayer, AbbVie, Medico’s Hirata, Astellas Pharma, and BMS, and consultancy fees from Kowa, MSD, BMS, Bayer, Chugai, Taiho, and Eisai.
      Dr. Finn reports consultancy fees from Bayer, Eisai, BMS, Novartis, Pfizer, MSD, and Roche.
      Dr. Edeline reports personal fees∗ from Bayer, BMS, and BTG.
      Dr. Reig reports personal fees∗ from Bayer, BMS, and BTG.
      Dr. Galle reports personal fees∗ from Adaptimmune, AstraZeneca, Bayer, Blueprint, BMS, Eli Lilly, MSD, and Sirtex, and grants from Bayer.
      Personal fees as defined by ICMJE as “Monies paid to you for services rendered, generally honoraria, royalties, or fees for consulting, lectures, speakers bureaus, expert testimony, employment, or other affiliation (e.g. advisory boards) etc.”

      Acknowledgments

      Editorial assistance in the preparation of this article was provided by Esther Race and Katrin Gudmundsdottir of SuccinctChoice Medical Communications (London, UK), with financial support from Bayer .

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