2024 APASL临床实践指南：肝细胞癌的全身治疗

APASL clinical practice guidelines onsystemic therapy forhepatocellular carcinoma‑2024

GeorgeLau 1 $\circledast$ · ShuntaroObi 2 · JianZhou 3 · RyosukeTateishi 4 · ShukuiQin 5 · HaitaoZhao 6 · MotoyukiOtsuka 7 · SadahisaOgasawara 8 · JacobGeorge 9 · PierceK.H.Chow 10 · JianqiangCai 11 · ShuichiroShiina 12 · NaoyaKato 13 · OsamuYokosuka 14 · KyokoOura 15 · ThomasYau 16 · StephenL.Chan 17 · MingKuang 18 · YoshiyukiUeno 19 · MinshanChen 20 · Ann‑LiiCheng 21 · GregoryCheng 22,58 · Wan‑LongChuang 23 · OidovBaatarkhuu 24 · FengBi 25 · YockYoungDan 26 · RinoA.Gani 27 · AtsushiTanaka 28 · WasimJafri 29 · Ji‑DongJia 30 · Jia‑HorngKao 31 · KiyoshiHasegawa 32 · PatrickLau 33 · JeongMinLee 34 · JunLiang 35 · ZhenwenLiu 36 · YinyingLu 37 · HongmingPan 38 · DianaA.Payawal 39 · SalimurRahman 40 · JinsilSeong 41 · FengShen 42 · GamalShiha 43,59,60,61 · TianqiangSong 44 · Hui‑ChuanSun 45 · TsutomuMasaki 15 · EkaphopSirachainan 46 · LaiWei 47 · JinMoYang 48 · JoseD.Sallano 49 · YanqiaoZhang 50 · TawesakTanwandee 51 · AKadirDokmeci 52 · Shu‑senZheng 53 · Jiafan 54 · Sheung‑TatFan 55 · ShivKumarSarin 56 · MasaoOmata 57

Received: 11 July 2024 / Accepted: 16 September 2024 $\copyright$ Asian Pacific Association for the Study of the Liver 2024

Abstract

In Asia–Pacific region, hepatocellular carcinoma is a serious health threat attributing to over 600,000 deaths each year and account for over $70\%$ of global cases. Clinically, the major unmet needs are recurrence after curative-intent surgery, liver transplantation or local ablation and disease progression in those with hepatocellular carcinoma not eligible for resection or failed locoregional therapy. In the recent few years, new targeted therapy and immune-checkpoint inhibitors have been registered as systemic therapy to address these issues. Notably, new forms of systemic therapy, either as first-line or secondline therapy for unresectable hepatocellular or those not eligible for locoregional therapy, are now available. New data is also emerging with the use of systemic therapy to prevent hepatocellular carcinoma recurrence after curative-intent resection or local ablation therapy and to retard disease progression after locoregional therapy. In the future, further implementation of immune-checkpoint inhibitors and other forms of immunotherapy are expected to bring a new paradigm to the management of hepatocellular carcinoma. New insight related to immune-related adverse events with the use of immunotherapy has allso enabled optimization of the therapeutic approach to patients with hepatocellular carcinoma. The purpose of this clinical practice guideline is to provide an up-to-date recommendation based on clinical evidence and experience from expert Asia–Pacific key opinion leaders in the field of hepatocellular carcinoma. Three key questions will be addressed, namely: (1) Which patients with hepatocellular carcinoma should be considered for systemic therapy? (2) Which systemic therapy should be used? (3) How should a patient planned for immune checkpoint-based systemic therapy be managed and monitored?

Keywords Hepatocellular carcinoma· Systemic therapy· Guidelines· The Asian Pacific Association for the study of the liver

Introduction

Since the inception of the first Asian–Pacific Association for the study of liver (APASL) hepatocellular carcinoma (HCC) working party in 2007 and the publication of its first guidelines in 2010 ] 1 ] (revised in 2017) [ 2 ], major advances in systemic therapy for HCC have been made [ 3 – 6 ]. To

date, despite the availability of effective HCC surveillance and preventive measures, most of the HCC still present at advanced stage as reflected by the high mortality–incidence ratio across the Asia–Pacific region [ 7 ], [ 8 ]. Most of these patients diagnosed with HCC are therefore beyond curative measures such as surgical resection, local ablation or liver transplantation [ 9 ]. This is further compounded by the scarcity of living donors and organs in the Asia–Pacific region

which precludes patients with HCC eligible for liver transplantation as a curative measure [ 10 ].

Even for those patients who received curative-intent surgery, liver transplantation or local ablation in accordance to various HCC treatment guidelines, recurrence is still a very common clinical problem [ 11 , 12 ]. The major etiology of HCC in Asia–Pacific region is chronic hepatitis B (CHB) and C (CHC) infection [ 13 – 15 ], compounded by the recent rise of metabolic dysfunction-associated fatty liver diseases (MAFLD) [ 16 ]. In countries like China which accounts for nearly half of the global annual cases of HCC, CHB is the major etiology of HCC [ 7 , 8 ]. In Japan, Egypt, and Mongolia, CHC plays a major role in causing HCC [ 13 – 15 ]. In the recent few years, new targeted therapy and immune-checkpoint inhibitors (ICIs) have been registered as first-line or second-line therapy for HCC that is unresectable or not eligible for locoregional therapy [ 17 – 30 ]. There are also emerging data to support the use of ICIsbased therapy to prolong progression-free survival after locoregional therapy and recurrence-free survival after local ablation or curative-intent surgical therapy for patients with HCC [ 31 , 32 ]. The gravity of CHB and CHC as etiology of HCC in the Asia–Pacific region is of great relevance, as the response to ICIs has been suggested to be much higher, as compared to targeted therapy [ 33 ]. The purpose of this clinical practice guideline is to provide an up-to-date recommendation based on clinical evidence and experience from expert Asia–Pacific key opinion leaders in HCC.

## Development process fortheguideline

In 2023, the steering committee of the Asian Pacific Association for the Study of the Liver (APASL) initiated the working party on the use of systemic therapy for HCC. To this end, a panel of experts from different disciplines in the Asia–Pacific region with diverse and vast experiences in the management of HCC was assembled. Hepatologists, oncologists (medical and radiation), surgeons (hepatobiliary

and transplant), radiologists (diagnostic and interventional), immunologists, pathologists, oncologists and palliative care nurses from different administrative regions/countries in the Asia–Pacific region were invited to form a working party which formulated this clinical practiceguidance for the use of systemic therapy for HCC. All panel members were required to disclose their relationships with industry during the guideline formulation until accepted for publication by Hepatology International (official journal of APASL). The Chairs were responsible for writing up the guidelines with the support of all panel members. All recommendations were categorized as strong recommendation (Grade 1) or weak recommendation (Grade 2) according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system (Table 1 ) [ 34 ]. The guidelines were also presented at the 33rd APASL annual conference held at Kyoto, Japan (26th to 31st April, 2024). Further comments were incorporated into the guidelines according to open discussion (Fig. 1 ).

## Clinical management byMDT

With the evolving complexity in the management of HCC due to rapidly renewed understanding of the complex pathophysiologic and biological nature of HCC, expanded use of surgical resection and liver transplantation, and the continuous emergence and evolution of locoregional and ICIsbased systemic treatment, it is increasingly recognized that the multidisciplinary team (MDT) plays a crucial role in the comprehensive management of HCC. MDT should comprise specialists in multiple fields including hepatology, radiology, surgery, transplant surgery, interventional radiology, medical oncology, radiation oncology and palliative care. MDT could enable comprehensive discussions with collective expertise of the team in interpreting imaging, pathology results, formulating diagnoses and devising management strategies [ 35 – 38 ]. This is supported by the cumulating evidence that MDT can offer significant benefits in patient

Table1 Grading of Recommendations Assessment, Development and Evaluation (GRADE) system

|Grading of evidence|| |---|---| ||Randomized controlled trials| |II-1|Controlled trials without randomization| |I-2|Cohort or case control analytical studies| |I-3|Multiple time series, dramatic uncontrolled studies| |工|Expert opinion, descriptive epidemiology| | Grading of recommendation|| ||Strong recommendation: factors influencing the strength of the recommendation included the quality of the| ||| ||Weaker recommendation: variability in preferences and value, or more uncertainty| ||Recommendation is made with less certainty: higher cost or resource consumption|

 Fig.1 Workflow of APASL systemic therapy for the HCC working party

diagnosis, treatment planning and overall survival outcomes [ 39 – 43 ]. Based on a recent systematic review and meta-analysis, MDT was also found to be associated with increase rate of early-stage HCC detection suggesting possible referral bias contributing to improved overall survival [ 44 ].

Recommendation 1

Consider assembling a multidisciplinary team with experienced hepatologists, oncologists, radiologists (diagnostic and interventional), oncology nurse, surgeon (transplant and hepatobiliary), pathologist, molecular biologists and palliative care specialists, for the management of HCC.

[Grading: Evidence_II-2__ Recommendation__1__].

Unresectable HCC ( Fig. 2 and Table 2 )

Surgical resection and local ablation remain as the mainstay of curative strategy for HCC, with a 5-year survival rate of $60\%$ and higher for patients within the Milan criteria [ 45 ] The decision to proceed with surgical resection or local ablation requires careful consideration of tumor biology, including the number of tumor nodules, tumor size, and presence of vascular involvement, as well as underlying liver dysfunction and overall patient performance status [ 46 ]. The definition of surgical resectability or feasibility of local ablation varies in different centers and treatment guidelines (Table 1 ) [ 2 , 15 , 47 – 51 ]. The ultimate decision depends on the experience of the surgeon involved. However, due to the delay in diagnosis, HCC often present at an advanced stage when resection or local ablation is no longer feasible. For cirrhotic patients with early-stage, surgically uHCC, liver transplantation (LT) is an ideal treatment. While the Milan criteria remains the accepted selection criteria for LT candidates with HCC, multiple other expanded criteria such as the Upto-7-criteria, total tumor volume, extended Toronto criteria, and Kyoto criteria, have been proposed. However, due to the scarcity of organ and living donors in the Asia–Pacific

region, many such patients cannot obtain timely liver transplantation as a curative measure [ 10 , 52 – 54 ].

Recommendation 2

Staging follows APASL 2017 version (Fig. 2 ) and resectability of HCC defined as patients without extrahepatic spread, without diffuse, infiltrative, extensive bilobar liver involvement, have well-defined nodules with preserved portal flow, but can vary with the experience of the hepatobiliary surgical team involved. Liver transplant should be considered for cirrhotic patients with early-stage surgically uHCC, within accepted selection criteria.

[Grading: Evidence_III__ Recommendation__2__].

First‑line systemic therapy ( Table 3 )

Until 2018, sorafenib (Nexavar) was the only available systemic therapy for unresectable HCC (uHCC) [ 55 , 56 ]. Then three global phase 3 clinical studies (REFLECT, IMbrave 150 and HIMALAYA) made lenvatinib, atezolizumab–bevacizumab and dual ICIs therapy with tremelimumab–durvalumab as Single Tremelimumab Regular Interval Durvalumab (STRIDE) therapy approved worldwide, as first-line therapy for uHCC [ 17 , 19 , 20 , 24 ]. Recently, the use of dual ICIs therapy with anti-CTLA4 and PD-1/PD-L1 is further supported by the phase 3 CheckMate 9DW trial which showed that treatment with first-line nivolumab in combination with ipilimumab resulted in a statistically significant and clinically meaningful improvement in overall survival (OS) compared with investigator’s choice of sorafenib or lenvatinib in patients with advanced HCC [ 25 ]. In mainland China, there were four additional phase 2–3 clinical trials (ZGDH3, ORIENT-32, CARES-310 and Rationale-301) which led to the approval of donafenib, sintilimab plus bevacizumab biosimilar IBI305, camrelizumab plus rivoceranib and tislelizumab for uHCC, by the National Medical Products Administration (NMPA), China (Table 3 ) [ 18 , 21 – 23 ].

 Fig.2 HCC staging and treatment algorithm

Table2 Definition of resectability

|Guideline| Definition of resectability| |---|---| |Barcelona Clinic Liver Cancer (BCLC) (2022 version) [47]|| || Among patients with single BCLC-A HCC, resection is favored over ablation owing to lower recurrence especially treating tumors >2 cm. Among individuals with multifocal BCLC-A HCC (three or more nodules, each≤3 cm), the 2022 BCLC updated guidelines do not recommend resection; rather, these patients are recommended to undergo ablation for non-LT candidates, while LT is suggested for acceptable LT candidates | |China liver cancer (CNLC) (2022 version) [15]|| || · Surgical resection may be considered even in patients with tumors localized to the same liver segment or the ipsilateral hemi-liver · Patients with multinodular tumors (>3 nodules, >3 cm) not consid- ered for resection by BCLC are also eligible for resection if confined to the same segment or lobe and the main portal trunk is not invaded | | EASL, Clinical Practice Guidelines: Management of hepatocellular carcinoma (2018) [48] | Liver resection is recommended for single HCC of any size and in particular for tumors >2 cm, when hepatic function is preserved, and | |Japan Society of Heptatology (JSH) guideline (2021 version) [49]| Similar to BCLC recommendation (1-3 nodules), except that patients with nodule > 3 cm may also be considered for resection | | Korean Liver Cancer Study Group (KLCSG)-National Cancer Center (NCC) Korea practice guidelines (2022 version) 50 | Similar to BCLC recommendation (1-3 nodules) without specifying tumor size (>3 cm or not) | | Indian National Association for Study of the Liver Consensus (2023 version)[51] |Similar to BCLC recommendation| |APASL (2017 version) [2]|Similar to BCLC recommendation|

Table3 Positive phase 3 studies in uHCC: first-line therapy

|Study| REFLECT [17] | ZGDH3 [18] | IMbrave150 [19,20] | ORIENT-32 [21] | CARES-310 [22】 | RATION- ALE-301 [23] | HIMALAYA [24] | CheckMate-9DW [25] | |---|---|---|---|---|---|---|---|---| |Drug| Lenvatinib AGS sorafenib | Donafenib AGS sorafenib | Atezoli- zumab + bev- acizumab vs sorafenib | Sintili- mab + IBI305 vs sorafenib | Camreli- zumab + rivo- ceranib | Tisleli- zumab AS sorafenib | Tremeli- mumab + dur- valumab vs | Nivolumab + ipili- mumab vs sorafenib or | |||||||Global|Global (181|| | Geographi- calarea | Global （154 centers in 20 coun- tries) | China (37 centers in China) | Global (111 centers in 17 countries and regions) | China (50 cent- ers in China) | Global (95 centers in 13 countries and regions) |（117||| ||||||| centers in 11 coun- tries and | countries and regions) | centres in 24 countries and regions) | |H4| 478vs 476 13.6vs | 334vs334 12.1 vs 10.3 |336 vs 165| 380 vs 191 Not reached vs 10.4 |272vs271||393vs389|335vs333| |mOS(m)| 13.6vs 12.3 || 19.2 vs 13.4 6.9 vs 4.3 ||22.1 vs 15.2| 342vs332 15.9 vs 14.1 |16.4 vs 13.8|23.7 vs 20.6| | PFS(m) Absolute survival gain |7.3 vs 3.6|3.7 vs 3.6||4.6 vs 2.8|5.6 vs 3.7|2.1 vs 3.4|3.8 vs 4.1|9.1 vs 9.2| | OS(m) PFS(m) |¥1.3|1.8|¥5.8||6.9|¥１.8|２.6|3.1| ||3.7|0.1|2.6|¥1-8㎡|2.0|—1.3|—0.3|—0.1| |OS|1.06) NI||| 0.57 (0.43- 0.75) ||| 0.78 (0.65-0.93) P=0.0035 | 0.79 (0.65-0.96) P=0.018 | ||| 0.99) P=0.0245 | 0.85) P=0.0009 || 0.80) P ||||

In REFLECT, lenvatinib (an inhibitor of VEGF receptors 1–3, FGF receptors 1–4, PDGF receptor α, RET and KIT) was compared to sorafenib in noninferiority design for uHCC. Lenvatinib at a dose of $12~\mathrm{mg/day}$ for body weight $\geq60~\mathrm{kg}$ or 8mg/day for body weight $<60~\mathrm{kg}$ was compared to sorafenib 400mg twice daily in 28-day cycles in patients with uHCC. The median OS for lenvatinib (13.6 months; $95\%$ CI 12.1–14.9) was noninferior to sorafenib (12.3months, 10.4–13.9; hazard ratio [HR] 0.92, $95\%$ CI 0.79–1.06). The most common any-grade adverse events (AEs) for lenvatinib were hypertension $(42\%)$ , diarrhea $(39\%)$ , decreased appetite $(34\%)$ and decreased weight $(31\%)$ [ 17 ].

In IMbrave 150, treatment with $1200~\mathrm{mg}$ of atezolizumab (anti-PDL1) plus $15~\mathrm{mg}$ per kilogram of body weight of bevacizumab (anti-VEGF) intravenously every 3weeks was compared to $400~\mathrm{mg}$ sorafenib orally twice daily. By month 12, atezolizumab–bevacizumab treated patients had a significantly longer OS than those treated with sorafenib ( $\times67.2\%$ Vs $54.6\%$ ) and the HR was 0.58 ( $95\%$ confidence interval [CI], 0.42 to 0.79; $p<0.001]$ ).

Median progression-free survival (PFS) was 6.8months ( $95\%$ CI 5.7 to 8.3) and 4.3months ( $95\%$ C, 4.0 to 5.6) in the respective groups (HR for disease progression or death, 0.59; $95\%$ CI 0.47 to 0.76; $p\!<\!0.001\big>$ ) [ 19 ]. Updated analysis 12months after the primary analysis showed the median OS was 5.8months longer with atezolizumab–bevacizumab than sorafenib. Serious AEs occurred more frequently in the atezolizumab–bevacizumab treatment arm $(49\%)$ than in the sorafenib arm $(33\%)$ and were mainly gastrointestinal hemorrhage ( $2.4\%$ versus $1.9\%$ ), esophageal variceal hemorrhage ( $2.4\%$ versus $0.6\%$ ), and pyrexia ( $2.1\%$ vs $1.3\%$ ) [ 20 ].

In the HIMALAYA study, a single, high priming dose of $300\:\mathrm{mg}$ tremelimumab (anti-CTLA4) plus 1500mg durvalumab (anti–PDL1) every 4weeks, an infusion regimen termed STRIDE (Single Tremelimumab Regular Interval Durvalumab) was compared to 1500mg durvalumab every 4weeks and oral sorafenib $400~\mathrm{mg}$ twice daily. STRIDE demonstrated a statistically significant and clinically meaningful improvement in overall survival compared to sorafenib (stratified HR of 0.78 $[95\%$ CI 0.66, 0.92],

two-sided $p$ value $=\!0.0035)$ ); median OS was 16.4months ( $95\%$ CI 14.2, 19.6) versus 13.8months $95\%$ CI 12.3, 16.1). The overall survival with durvalumab monotherapy was noninferior to that with sorafenib (HR 0.86; $95.67\%$ CI 0.73 to 1.03; noninferiority margin, 1.08). Grade 3/4 treatment-emergent AEs occurred for $50.5\%$ of patients with STRIDE, $37.1\%$ with durvalumab, and $52.4\%$ with sorafenib. Recent update of 4-year OS rate with STRIDE $(n\!=\!393)$ ) was $25.2\%$ compared to $15.1\%$ with sorafenib $(n\!=\!389$ ; HR, 0.78; $95\%$ CI 0.67–0.92; 2-sided $p\!=\!0.0037)$ , showing similar magnitude of benefit from the 3-year landmark analysis, which revealed an OS rate of $30.7\%$ with the STRIDE and $19.8\%$ with sorafenib alone [ 24 ]. The Asian subpopulation analysis (including Hong Kong, India, South Korea, Taiwan, Thailand and Vietnam, but not Japan) $(n\!=\!479)$ ) revealed that median OS times for the STRIDE regimen (16.5months; $95\%$ CI 12.6–22.1; HR 0.68) and for durvalumab (16.6months; $95\%$ CI 12.2–19.2; HR 0.83) were longer for sorafenib (11.8months; $95\%$ CI 9.4–14.7) and the corresponding median OS times in the overall population $_{(n\,=\,1,171)}$ ) were 16.4months $95\%$ CI 14.2–19.6; HR 0.78) for STRIDE, 16.6months ( $95\%$ CI 14.1–19.1; HR 0.86) for durvalumab and 13.8months ( $95\%$ CI 12.3–16.1) for sorafenib. Also, results from an additional subpopulation analysis of patients from Hong Kong/Taiwan $(n\!=\!141$ ) were generally consistent with the overall Asian subpopulation analysis, with median OS of 29.4months (HR 0.44) for STRIDE, 23.6months (HR 0.64) for durvalumab and 19.1months for sorafenib [ 57 ]. Recent data showed that STRIDE significantly improved OS versus sorafenib and demonstrated durable long-term survival (OS rate $25.2\%$ vs $15.1\%)$ in the 4-year and OS rate ( $19.6\%$ vs $9.4\%$ ) in the 5-year follow-up analysis, with a manageable safety profile [ 58 , 59 ]. OS benefit with STRIDE was enhanced in participants experiencing disease control per RECIST v1.1 and the OS rate ratios for STRIDE versus sorafenib increasing over time [ 59 ].

In CheckMate 9DW, 668 patients were randomized to nivolumab $1\ \mathrm{mg/kg\;IV}$ and ipilimumab 3mg/kg IV every 3weeks (up to 4 cycles), then nivolumab 480mg every 4weeks $(n\!=\!335)$ ) or lentivinab at a dose of 12mg/day for body weight $\geq60~\mathrm{kg}$ or 8mg/day for body weight $<\!60~\mathrm{kg}$ or sorafenib $400~\mathrm{mg}$ twice daily ( $(n\!=\!333)$ ). The median OS was 23.7months with nivolumab $^+$ ipilimumab versus 20.6months with lentivinab or sorafenib (HR 0.79; $95\%$ CI 0.65–0.96; $p\!=\!0.0180)$ ), with respective 24-month OS rates of $49\%$ versus $39\%$ . Objective response rate was higher with nivolumab $+$ ipilimumab $(36\%)$ vs lentivinab or sorafenib $(13\%;p\!<\!0.0001)$ ) and complete response was observed in $7\%$ of patients treated with nivolumab+ipilimumab but only $2\%$ in patients treated with lentivinab or sorafenib. The safety profile for the combination ofnivolumab $^+$ ipilimumabremained consistent with previously reported data and was manageable

with established protocols. Treatment-related AEs of any grade were reported in $84\%$ of patients withnivolumab $^+$ ipilimumaband $91\%$ in patients with lenvatinib or sorafenib. Grade 3/4 treatment-related AEs occurred in $41\%$ and $42\%$ of patients, respectively [ 25 ]. The FDA has accepted a supplemental biologics license application (sBLA) for first-line nivolumab (Opdivo) plus ipilimumab (Yervoy) in adults with uHCC.

In the multicenter, randomized, controlled phase IIIII trial ZGDH3 conducted in mainland China, donafenib (a novel multikinase inhibitor and a deuterated sorafenib derivative) was compared to sorafenib in patients with uHCC. The median OS was significantly longer with donafenib than sorafenib treatment (HR 0.831; $95\%$ CI 0.699 to 0.988; $p\!=\!0.0245)$ ), though the median progression-free survival (PFS) was 3.7versus3.6months $(p\!=\!0.0570)$ ). Drugrelated grade $;{\underline{{\boldsymbol{\Sigma}}}}3$ AEs occurred in significantly fewer patients receiving donafenib than sorafenib (125 $[38\%]$ versus 165 $[50\%]$ ; $p\!=\!0.0018\$ ). With these data, donafenib was approved by China NMPA for uHCC in 2021 [ 18 ].

In the phase 2–3 ORIENT-32 study, sintilimab (humanized IgG4 monoclonal anti-PD-1) plus IBI305 (a bevacizumab biosimilar) group showed a significant improvement in OS (HR 0·57, $95\%$ CI 0·43–0·75; $p\!<\!0\!\cdot\!0001]$ ) and PFS (4·6months $[95\%$ CI 4·1–5·7]) than did patients in the sorafenib group (2·8months [2·7–3·2]; stratified HR 0·56, $95\%$ CI 0·46–0·70; $p\!<\!0\!\cdot\!0001)$ ) [ 21 ]. In CARES-310, 543 patients with uHCC were randomly assigned to receive either camrelizumab (humanized IgG4 monoclonal anti-PD-1) $200~\mathrm{mg}$ intravenously every 2weeks plus rivoceranib (also known as apatinib, a highly selective VEGFR2-targeted TKI) $250\,\mathrm{mg}$ orally once daily or sorafenib $400~\mathrm{mg}$ orally twice daily. Median PFS was significantly improved with camrelizumab–rivoceranib versus sorafenib (5·6months $[95\%$ CI 5·5–6·3] vs 3·7months [2·8–3·7]; HR 0·52 $[95\%$ CI 0·41–0·65]; one-sided $p\!<\!0\!\cdot\!0001)$ ) and median OS was significantly extended with camrelizumab–rivoceranib versus sorafenib (22·1months $[95\%$ CI 19·1–27·2] vs 15·2months [13·0–18·5]; HR 0·62 $[95\%$ CI 0·49–0·80]; one-sided $p\!<\!0\!\cdot\!0001\!)$ ). Treatment-related serious AEs were reported in 66 $(24\%)$ patients in the camrelizumab–rivoceranib group and 16 (6%) in the sorafenib group [ 22 ]. In RATIONALE-301, 674 patients with uHCC were randomized 1:1 to receive tislelizumab (anti-PD1), $200~\mathrm{mg}$ intravenously every 3weeks, or sorafenib tosylate, $400~\mathrm{mg}$ orally twice daily. The primary end point of OS noninferiority of tislelizumab versus sorafenib was met in the intentionto-treat population and the median OS was 15.9 ( ${}^{95\%}\mathrm{CI}$ , 13.2–19.7) months versus 14.1 ( $\mathbf{\it{95\%CI}}$ , 12.6–17.4) months, respectively (HR 0.85 [9 $5.003\%\mathrm{CI}$ , 0.71–1.02]). However, the superiority of tislelizumab versus sorafenib was not met and the median PFS was 2.1 $\mathbf{\it{(95\%CI}}$ , 2.1–3.5) months versus 3.4 (95%CI, 2.2–4.1) months with tislelizumab (HR 1.11 $[95\%\mathrm{CI}$ , 0.92–1.33]). The incidence of treatment-emergent

AEs was $96.2\%$ (325 of 338 patients) for tislelizumab and $100\%$ ( $(n\!=\!324)$ ) for sorafenib. Grade 3 or greater treatmentrelated AEs were reported in 75 patients $(22.2\%)$ receiving tislelizumab and 173 $(53.4\%)$ receiving sorafenib. There was a lower incidence of treatment-related AEs leading to drug discontinuation $21[6.2\%]$ vs 33 $[10.2\%]$ ) and drug modification (68 $[20.1\%]$ vs 187 $[57.7\%]$ ) with tislelizumab vs sorafenib [ 23 ] (Table 4 ).

Patients withimpaired liver function test

In the real world, a substantial number of patients with advanced HCC have impaired liver function. Despite this, most pivotal randomized controlled trials have excluded patients with moderate liver dysfunction (Child–Pugh–Turcotte B, CPT-B) [ 60 ]. Among HCC patients treated with sorafenib, OS was significantly lower in patients with CPT-B vs CPT-A liver function, suggesting treatment should be individualized for patients with CPT-B cirrhosis [ 61 ]. However, the efficacy and tolerability of ICIs for CPT-B patients with advanced HCC remain unclear. In a recent systematic review and meta-analysis which included 22 studies with 699 CPT-B patients and 2114 CPT-A patients with advanced HCC, ICIs therapy in the CPT-B group appeared to be safe and showed a significant number of radiologic responses, but survival outcomes were inferior compared with the CPT-A group [ 62 ]. Notably, further subgroup analyses did not reveal any significant differences in radiologic response, survival, or incidence of AEs between patients with CTP-B with 7 and 8/9 scores. However, due to the limited sample size (fewer than 100 cases with CTP-B with 8/9 scores across 6 studies,

further multicenter prospective cohort studies are needed to evaluate the association of CTP-B score with the efficacy and tolerability of ICI treatment in these patients [ 63 – 68 ].

Recommendation 3a (Fig. 3 a)

Patients with uHCC not eligible for locoregional therapy with ECOG PS 0–1 and CPT- A and B, including those with portal vein tumor thrombus, should be offered systemic therapy.

[Grading: Evidence_I__ Recommendation__1__].

The first choice of systemic therapy should be anti-VEGF+anti-PD-1/anti-PD-L1\*

(in those without risk of bleeding) or dual ICIs with antiCTLA-4 and anti-PD1/anti-PDL1 or anti-PD-1 # /anti-PD-L1 ## . For those patients with limited resources or have contraindications to immunotherapy, lentivinab or sorafenib should be considered.

Table4 Positive Phase 3 studies in uHCC: second-line therapy

|Study|RESORCE [26]|KEYNOTE-394 [27]|CELESTIAL [28]|REACH-2 [30]|AHELP[29]| |---|---|---|---|---|---| |Drug| Regorafenib vs placebo | Pembrolizumab vs placebo | Cabozantinib vs placebo |Ramucirumab|Apatinib| |||||vs placebo|vs placebo| |Geographical area| Global (152 centers in 21 countries) |Asia| Global (95 centers in 19 |Global| China (31 centers in China) | |H74|||countries)| (92 centres in 20 countries) || ||379 vs 194|300 vs 153|470vs237|197vs 95|267vs 133| |mOS(m)|10.6 vs 7.8|14.6 vs 13.0|10.2 vs 8.0|8.5 vs 7.3|8.7 vs 6.8| |PFS(m)|3.1 vs 1.5|2.6 vs 2.3|5.2 vs 1.9|2.8 vs 1.6|4.5 vs 1.9| |Absolute survival gain|||||| |OS|¥2.8|1-6||1.２|１-9| |PFS|¥1.6|0.3|3.3|1.２|２.６| |HR (95% CI)|||||| |OS| 0.63 (0.50-0.79) p |||||

\*Atezolizumab $^+$ bevacizumab or sintilimab+IBI305 or camrelizumab $+$ rivoceranib (apatinib).

anti-PD-1 in mainland China; ## anti-PD-L1 in Japan.

[Grading: Evidence_I__ Recommendation__1__].

Second‑line therapy forunresectable HCC ( Table 4 )

For those patients with uHCC who failed to respond or have disease progression with sorafenib, regorafenib, cabozantinib and ramucirumab (at $\upalpha$ -fetoprotein concentrations of $400\ \mathrm{ng/mL}$ or higher), pembrolizumab and apatinib (in mainland China) have become the treatment options based on positive phase 3 clinical trials results (Table 4 ) [ 26 – 30 ].

a.First-line systemic therapy for advanced HCC

Indications and treatment options of systemic therapies for advanced hepatocellular carcinoma (Fist line systemic therapy)

Advanced HCC Ineligibility for surgery and any local therapy (local ablation, trasarterial chemoembolization, etc)

Indications for

immunotherapy

Yes

Select after verifying tolerance for adverse events due to VEGF inhibition

• Atezolizumab plus Bevacizumab • Camrelizumab plus Rivoceranib\* • Sintilimab plus Bevacizumab biosimilar (IBI351)\*

 Select after verifying tolerance for adverse events due to adding on anti-CTLA-4 antibody • Durvalumab plus Tremelimumab • Nivolumab/Ipilimumab Difficult to select combined immunotherapy (if anticipated to offer advantages over VEGF-TKIs). • Durvalumab • Tislelizumab

Select VEGF-TKIs with evidence as front line setting

• Lenvatinib • Sorafenib • Donafenib\*

\*Available in limited countries/regions

b. Second line systemic therapy for advanced HCC

Indications and treatment options of systemic therapies for advanced hepatocellular carcinoma (Second line systemic therapy)

Select regimens not used in the first line after in subsequent line systemic therapy Select VEGF-TKIs/VEGFR2-Ab with evidence as front line or later line setting

• Lenvatinib • Sorafenib • Donafenib\* • Regorafenib • Cabozantinib • Ramucrumab • Atezolizumab plus Bevacizumab • Durvalumab plus Tremelimumab • Nivolumab/Ipilimumab • Camrelizumab plus Rivoceranib • Sintilimab plus Bevacizumab biosimilar (IBI351)\* • Durvalumab • Tislelizumab

\*Available in limited countries/regions \*\*Evidence for administrating ICI after ICI is insufficient

Fig.3 Indications and treatment options of systemic therapies for advanced HCC. a. First-line systemic therapy for advanced HCC. b. Secondline systemic therapy for advanced HCC

Most of the second-line therapy was based on the use of sorafenib as first-line therapy. However, with the rapid development of new first-line therapy (see above) with ICIs-based

therapy, there are limited data on the choice of second-line after such ICIs-based therapy [ 66 , 67 ].

In the RESORCE study, adults with uHCC who progressed on sorafenib, and regorafenib at the dose of $160\,\mathrm{mg}$ once daily

during weeks 1–3 of each 4-week cycle, as compared to placebo, had improved OS with a hazard ratio of 0·63 ( $95\%$ CI 0·50–0·79; one-sided $P{<}0{\cdot}0001$ ). The median survival was 10·6months $95\%$ CI 9·1–12·1) for regorafenib versus 7·8months (6·3–8·8) for placebo. However, AEs were reported in all regorafenib recipients (374 $[100\%]$ of 374) and 179 $(93\%)$ of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent AEs were hypertension, hand–foot skin reaction, fatigue and diarrhea [ 26 ].

In KEYNOTE-394, 453 Asian with uHCC with disease progression or intolerance with sorafenib or oxaliplatinbased chemotherapy were randomly assigned in a 2:1 ratio to receive pembrolizumab $(200\;\mathrm{mg})$ or placebo once every 3weeks for $\leq35$ cycles plus best supportive care. The median OS was longer in the pembrolizumab group than in the placebo group (14.6versus13.0months; hazard ratio for death, 0.79; $95\%$ CI, 0.63 to 0.99; $p\!=\!0.0180)$ ). Median PFS was also longer in the pembrolizumab group than in the placebo group (2.6versus2.3months; hazard ratio for progression or death, $0.74\,95\%$ CI, 0.60 to 0.92; $p\!=\!0.0032\!,$ ). Treatment-related AEs occurred in $66.9\%$ of patients (grade 3, $12.0\%$ ; grade 4, $1.3\%$ ; grade 5, $1.0\%$ ) in the pembrolizumab group and $49.7\%$ of patients (grade 3, $5.9\%$ ; grade 4, $0\%$ ; grade 5, $0\%$ ) in the placebo group [ 27 ].

In the CELESTIAL study, the efficacy and safety of cabozantinib (inhibitor of tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL) was evaluated in uHCC. Seven hundred and seven patients were randomly assigned in a 2:1 ratio to receive cabozantinib (60mg once daily) or matching placebo. Median OS was 10.2months with cabozantinib and 8.0months with placebo (hazard ratio for death, 0.76; $95\%$ confidence interval [CI], 0.63 to 0.92; $p{=}0.005)$ . Median PFS was 5.2months with cabozantinib and 1.9months with placebo (HR for disease progression or death, 0.44; $95\%$ CI 0.36 to 0.52; $p{<}0.001\rangle$ ), and the objective response rates were $4\%$ and less than $1\%$ , respectively $_{p=0.009)}$ ). Grade 3 or 4 AEs occurred in $68\%$ of patients in the cabozantinib group and in $36\%$ in the placebo group. The most common highgrade events were palmar–plantar erythrodysesthesia $17\%$ with cabozantinib vs. $0\%$ with placebo), hypertension ( $16\%$ vs. $2\%$ ), increased aspartate aminotransferase level ( $12\%$ vs. $7\%$ ), fatigue ( $10\%$ vs. $4\%$ ), and diarrhea ( $10\%$ vs. $2\%$ ) [ 28 ].

In REACH-2, sorafenib-experienced uHCC with $\upalpha$ -fetoprotein concentrations of $400\;\mathrm{ng/mL}$ or greater were randomly assigned to the ramucirumab $(n\!=\!197)$ ) or placebo $(\mathtt{n\,=\,}95)$ ) group. As compared to the placebo group, the ramucirumab group had a significantly improved median OS (8·5months $[95\%$ CI 7·0–10·6]vs7·3months [5·4–9·1]; HR 0·710 $[95\%$ CI 0·531–0·949]; $P\!=\!0\!\cdot\!0199$ ) and PFS (2·8months [2·8–4·1]vs1·6months [1·5–2·7]; 0·452 [0·339–0·603]; $p<0{\cdot}0001$ ). Grade 3 or worse treatment-emergent AEs that occurred in at least $5\%$ of patients in either group were hypertension (25 [13%] in

the ramucirumab group vs 5 $[5\%]$ in the placebo group), hyponatremia (11 $[6\%]$ vs0) and increased aspartate aminotransferase $(6\,[3\%]$ vs5 $[5\%]_{\sim}$ ) [ 30 ].

In the AHELP study conducted in China, patients with uHCC, who failed at least one line of systemic chemotherapy or targeted therapy, were randomly assigned (2:1) to receive apatinib $750~\mathrm{mg}$ or placebo orally once daily in 28-day treatment cycles. The OS was significantly improved in the apatinib group compared to the placebo group (median 8·7months $[95\%$ CI 7·5 ‒ 9·8]vs6·8months [5·7 ‒ 9·1]; HR 0·785 $[95\%$ CI 0·617 ‒ 0·998], $p\!=\!0\!\cdot\!048)$ . The most common treatment-related AEs of grade 3 or 4 were hypertension (71 $[28\%]$ patients in the apatinib groupvs3 $[2\%]$ in the placebo group), hand–foot syndrome ( $46\,[18\%]$ vsnone) and decreased platelet count (34 [13%]vs $1\;[1\%])$ [ 29 ].

Recommendation 3b (Fig. 3 b)

Second-line therapy should be considered when there is disease progression after 8–12weeks of first-line therapy.

[Grading: Evidence_II__ Recommendation__2__].

Second-line therapy for consideration includes dual ICIs with anti-CTLA-4 and anti-PD1/anti-PDL1 or lenvatinib for those who failed anti-VEGF $+$ anti-PD-1/ anti-PD-L1\*. For those who failed dual ICIs with antiCTLA-4 and anti-PD1/anti-PDL1, one should consider anti- $\scriptstyle\mathrm{VEDF}\,+$ anti-PD-1/anti-PD-L1\* or lenvatinib.

[Grading: Evidence_III__ Recommendation__2__].

Third-line therapy for those who failed second-line therapy includes regorafenib/cabozantinib/ramucirumab\*\*

\*\*AFP greater than or equal to $400\,\mathrm{ng/mL}$ .

[Grading: Evidence_2__ Recommendation__2__].

Immune‑related adverse events (irAEs)and their management ( Table 5 )

The use of ICIs, either as monotherapy or in combination with anti-VEGF or with another ICIs, has greatly improved the OS of the patients with uHCC [ 19 , 20 , 23 – 25 ]. However, its use is associated with a spectrum of side effects, termed immune-related adverse events (irAEs) which are quite different from other systemic therapies such as cytotoxic chemotherapy. IrAEs may involve any organ or system of the body, but is mainly related to gastrointestinal, dermatologic, hepatic, endocrine, and pulmonary system. The exact mechanism is still largely unknown and might be related to increasing T-cell activity against antigens that are present in the tumors and healthy tissue, increasing levels of preexisting autoantibodies or inflammatory cytokines, and enhanced complement-mediated inflammation due to direct binding of an antibody against cytotoxic T-lymphocyte antigen 4 (CTLA-4) with CTLA-4 expressed on normal tissue, such as the pituitary gland [ 69 – 71 ].

Table5 Summary of treatment-related adverse events

|Study| IMbrave150 [19, 201 |ORIENT-32 [21]|CARES-310 [22]|[23】|| CheckMate-9DW [25] | |---|---|---|---|---|---|---| |Event| Atezoli- zumab + bevaci- zumab (n=329) | Sintili- mab + IBI305 (n=380) | Camreli- zumab + rivocer- anib (n=272) | Tislelizumab (n=338) | Tremeli- mumab + dur- valumab (n=388) | Nivolumab + ipili- mumab (n=332) | | Immune-mediated event requir- ing high-dose steroids |n.a|n.a||47 (13.9%)|78 (20.1%)|| ||||n.a|||96 (29%)| | Any grade 3 or 4 immune-medi- ated event |n.a|n.a|45(17%)|28 (8.3%)|49 (12.6%)|93(28%)| | Immune-mediated event leading to death |n.a|n.a|1 (0.4%)||6 (1.5%)|| ||Treatment-related adverse events||294 (75.8%)|||| |Any| 284 (86%) 76(23%) |337(89%)|265 (97%)| 259 (76.6%) 40 (11.8%) ||278 (84%)| | Any serious Grade 3 or 4 |143(43%)| 65(17%) 128(34%) | 66 (24.3%) 220 (81%) |75 (22.2%)| 68 (17.5%) 100 (25.8%) |94 (28%)| | Leading to discon- tinuation |34(10%)|||21 (6.2%)||137 (41%)| |||52(14%)|41 (15.1%)||32 (8.2%)|59 (18%)| | Leading to dose delay |195 (59%)|188 (49%)|n.a|68 (20.1%)|83 (21.4%)|| |Leading to death|6(2%)|6(2%)|1 (0.4%)|3 (0.9%)|9 (2.3%)|12(4%)|

Most of the toxic effects are reversible, aside from the effects on the endocrine system, which may be permanent. The early identification and timely management of irAEs is key to preventing irAE progression and mitigating severity [ 72 – 74 ]. However, due to the incomplete understanding of the pathophysiology of irAE, there is a lack of precise treatment for this important clinical problem. Several professional organizations have provided expert consensus on managing specific irAE, based largely on retrospective studies and case series rather than prospective studies. These treatment guidelines have been formulated to enable earlier recognition, appropriate management, and better patient outcomes related to irAEs [ 75 , 76 ].

Furthermore, the understanding of the overall incidence of irAEs is hampered by the different or unclear definition used in various studies. In HIMALAYA, irAEs were defined as AEs of special interest associated with exposure ICIs therapy and consistent with an immune-mediated mechanism of action for which there is no alternate etiology. Participants with $\geq\!1$ irAEs were counted once. With such definition, among participants in HIMALAYA who received STRIDE or durvalumab monotherapy, irAEs were manageable and generally low grade. In keeping with other reports, the majority of the irAEs occurred within the first 3months of treatment and were more frequent with combination therapy with anti-CTLA-4 and anti-PDL1 (STRIDE) than with monotherapy with anti-PDL1 [ 69 – 76 ] Very

importantly, the occurrence of irAEs did not preclude participants from experiencing an OS benefit with STRIDE, and longterm survival was observed with STRIDE, irrespective of irAEs occurrence [ 74 ].

Recommendation 4 (Fig. 4 )

Patients should be monitored 1–2 weekly for irAEs toxicity if dual ICIs therapy is given and 2–4 weekly if only antiPD-1/PD-L1 is given.

Diagnosis of irAEs should be made only after careful ruling out other differential diagnoses. Management will be based on grading of the irAEs per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 6, and classified according to the Medical Dictionary for Regulatory Activities, version 26.1.

For grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities, one should consider continuing ICIs with close monitoring for further toxicities,

For grade 2 toxicities, one should consider withholding ICIs andinitiating prednisone with an initial dose of 0.5 to 1mg/kg/ day. Apart from prednisone, other corticosteroids at equivalent doses may be considered. ICI can be resumed when symptoms and/or laboratory values revert to grade 1 or less.

 Fig.4 Management of immune-related adverse events

For grade 3 or 4 toxicities, one should consider withholding ICIs andinitiating high-dose prednisone at 1 to $2~\mathrm{mg/}$ kg/day orother corticosteroids at equivalent doses. Relevant specialist should be consulted. Prednisone or other corticosteroids at equivalent doses should be tapered over the course of at least 4–6weeks. If symptoms do not improve with 48 to 72h of high-dose prednisone or equivalent biologic disease-modifying anti-rheumatic drugs (bDMARDs), conventional synthetic (cs)DMARDs or targeted synthetic DMARDs could be considered after careful clinical evaluation, in conjunction with relevant specialists. For grade 3 toxicities, ICIs can be resumed when symptoms and/or laboratory values revert to grade 1 or less. For grade 4 toxicities, permanent discontinuation of ICIs with the exception of endocrinopathies that have been controlled by hormone replacement.

[Grading: evidence_III__ recommendation__2__].

Management foruHCC treated withlocal regional therapy

Patients with uHCC treated with locoregional therapy such as drug-eluting bead (DEB)-transcatheter arterial chemoembolization (TACE) or conventional TACE (cTACE) usually will have disease progression within 1 year with a median PFS of 7–8months [ 31 ].In EMERALD-1, 616 patients with uHCC who received (DEB)-TACE/cTACE were randomized 1:1:1 to durvalumab during TACE and then following the last TACE procedure, durvalumab $+$ placebo

$\mathrm{(D+TACE)}$ or durvalumab $+$ bevacizumab $\mathrm{(D+B+TACE)}$ , or DEB-TACE/ cTACE (TACE). Durvalumab was given after at least 7days following the initial TACE procedure. Durvalumab $\pm$ bevacizumab began after at least 14days following the last TACE procedure. Patients with a history of nephrotic or nephritic syndrome, clinically significant cardiovascular disease, extrahepatic disease or main portal vein thrombosis (Vp3/Vp4) is excluded. As compared to TACE alone, PFS was significantly improved with $\mathrm{D+B+TACE}$ (median PFS 8.2 vs 15.0months; hazard ratio [HR], 0.77; $95\%$ confidence interval [CI], 0.61–0.98; $p\!=\!0.032$ [threshold 0.0434]). ORR was $43.6\%$ , $41.0\%$ and $29.6\%$ , and mTTP was 22.0, 11.5 and 10.0months for $\mathrm{D+B+TACE}$ , $\mathrm{D+TACE}$ , and TACE, respectively. However, PFS was not significantly improved with $\mathrm{D+TACE}$ versus TACE alone. The incidence of maximum grade 3 or 4 AEs was low across all arms $\mathrm{D+B+TACE}$ $(32.5\%)$ , D+TACE $(15.1\%)$ , and TACE alone $(13.5\%)$ , with no unexpected safety signals [ 31 ].

Recommendation 5

For those embolization-eligible uHCC, DEB-TACE or cTACE+durvalumab, followed by durvalumab $^+$ bevacizumab should be considered.

[Grading: Evidence_II__ Recommendation__2__].

Prevention ofHCC recurrence after“curative” surgery orablation

After curative-intent resection or ablation defined by the Milan Criteria , HCC recurs in $70–80\%$ of cases [ 77 , 78 ].From both invivo and invitro studies, the immunosuppressive liver microenvironment, modulated by VEGF and/or immune checkpoints such as PD-L1, has been implicated to play a key role in recurrence [ 79 ].Based on this observation, IMbrave 050, a phase III randomized multicenter open-label study was designed to evaluate atezolizumab plus bevacizumab versus active surveillance in patients at high risk of disease recurrence following curative resection or ablation (tumor size>5cm, tumor number $\geq3$ , vascular invasion such as microvascular invasion or macrovascular invasion—Vp1/Vp2—of the portal vein and grade 3 or 4 tumor differentiation). Altogether, 668 patients were randomly assigned in a 1:1 ratio to receive intravenous $1200\,\mathrm{mg}$ atezolizumab plus $15\,\mathrm{mg/kg}$ bevacizumab every 3weeks for 17 cycles (12months) or to active surveillance. For the first interim analysis with the median duration of follow-up of 17·4months (IQR 13·9–22·1), adjuvant atezolizumab plus bevacizumab was associated with significantly improved recurrence-free survival (median, not evaluable [NE]; $[95\%$ CI 22·1-NE]) compared with active surveillance (median, NE [21·4-NE]; HR 0·72 [adjusted $95\%$ CI 0·53–0·98]; $\scriptstyle P=0\cdot012$ ). As the recurrence-free survival curve of the two arms start to merge on follow-up, one needs longer follow-up data to understand whether the benefit of recurrence-free survival could be sustained over time and whether there is any significant difference in overall survival. Grade 3 or 4 adverse events occurred in 136 $(41\%)$ of 332 patients who received atezolizumab plus bevacizumab and 44 $(13\%)$ of 330 patients in the active surveillance group. Grade 5 adverse events occurred in six patients ${\it2\%}$ , two of which were treatment related) in the atezolizumab plus bevacizumab group, and one patient $(<\!1\%)$ in the active surveillance group. Both atezolizumab and bevacizumab were discontinued because of

adverse events in 29 patients $(9\%)$ who received atezolizumab plus bevacizumab [ 32 ].

Recommendations 6

For those patients who received curative-intent surgery or local ablation for HCC at high risk of disease recurrence, combination therapy with atezolizumab plus bevacizumab post-operatively is premature to be recommended.

[Grading: Evidence_II__ Recommendation__2__].

Use ofsystemic therapy forHCC inthesetting ofliver transplantation

One of the major indications for liver transplantation (LT) is for the treatment of uHCC within LT-eligible criteria [ [80 – 83 ] and systemic therapy for HCC might be considered as a “bridging” or “downstaging” strategy before transplantation [ 84 – 100 ]. Despite strict adherence to LTeligibility criteria, post-transplant HCC recurrence occurs in up to $20\%$ of cases and constitute a significant clinical problem [ 101 – 117 ]. With the registration of ICIs as effective systemic therapy for uHCC, the major concern of its use in pre- and post-LT setting is whether the risk of rejection will be enhanced. To date, there is a lack of comprehensive evaluation of the safety and efficacy of ICIs in uHCC patients before and after LT. The use of ICIs in the LT setting needs a careful balance between cancer immunology and transplant tolerance. Through the activation of effector T cells, the ICIs will not only reduce tumor burden but also increase the risk of graft rejection.

Recently, several studies have shown positive outcomes post-LT after pre-transplant use of ICIs therapy for uHCC and this has enabled the use of ICIs not to be precluded from consideration of liver transplantation (Table 6 ) [ 88 – 100 ]. Although pre-LT ICIs may increase the incidence

Table6 Summary of case reports on the use of ICI-based therapy in pre-LT patients with HCC [ 86 – 99 ]

|No. of patients|Sex (M/F)|Age (yrs)|Cycles| Time between last ICI and LT (weeks) |Rejection| Outcome (success- ful LT at last FU) | |---|---|---|---|---|---|---| |ICI—monotherapy (anti-PD-1/PD-L1)||||||| |32|26/6|58 (30-71)*|8(1-44)*|4.3 (0.1-94)*|31.3% (10/32)|Alive 96.8% (31/32)| |ICI—combination therapy (anti-PD-1/PD-L1 + anti-VEGF/TKIs)||||||| |26|24/2|51 (37-68)*|6(1-27)*|6.1 (1-32.7)*|38.5% (10/26)|Alive 96.2% (25/26)| |ICI—dual immunotherapy (anti-PD-1/PD-L1 + anti-CTLA-4)||||||| ||2/0|60.5 (58-63)*|7.5 (7-8)*|4.65 (0.3-9)*|0%(0/2)|Alive 100% (2/2)| |Total||||||| |61|53/8|56 (30-71)*|7(1-44)*|5 (0.1-94)*|34.4% (21/61)|Alive 96.7% (59/61)|

HCC : hepatocellular carcinoma \* Median (range)

of post-LT rejection, it is not associated with increased immune-related graft loss and patient death. Short intervals (within 3months) between ICIs and LT may increase the incidence of liver injury, including graft rejection. Therefore, the intervals between the last ICIs treatment and LT should be chosen appropriately. A multicenter prospective clinical trial mandates a 6-week washout period [ 87 ]. So far there is no definitive study to examine the “window” for the use of ICIs before and after LT. Therefore, the feasibility and optimal timing of LT after receiving ICIs need to be further investigated in the setting of clinical trial.

Despite the use of restrictive criteria, post-transplant HCC recurrence is still high, affecting between 8 and $20\%$ of cases, usually within 2–3 years [ 118 , 119 ]. Before the availability of ICIs, both sorafenib and lenvatinib had been shown to significantly prolong the survival of post-LT patients with HCC recurrence evaluated [ 120 , 121 ]. Recently, several case series have suggested that ICIs may be used successfully in this population, although graft rejection has been reported (Table 7 ) [ 101 – 117 ]. For those patients with high immunological risk factors (transplantation performed less than 12months ago, young women with autoimmune disease, preformed or de novo donor-specific antibodies (DSA) and previous episodes of rejection) [ 122 ], the use of ICIs is strongly discouraged. On the other hand, graft-negative PD-L1 expression in HCC recurrent patient, in whom other anti-tumor therapy is ineffective, might be considered for ICIs salvage therapy [ 114 ].

Recommendation 7

ICI-based systemic therapy can be used in the pre-transplant setting and transplant can be performed after a 6-week washout period for patients who meet local transplant criteria.

[Grading: evidence_II__ recommendation__2__].

Recommendation 8

Post-transplant, both sorafenib and lenvatinib can be used to treat HCC recurrence.

[Grading: evidence_II__ recommendation__2__].

ICIs may be used with extreme caution as salvage therapy for HCC recurrence in liver transplant recipients after weighing the individual immunological risk and oncological benefit.

[Grading: evidence_III__ recommendation__3__].

Future development

Due to the complexity in the management of HCC, with its different treatment modalities and diversity in tumor

response, artificial intelligence (AI) with machine and deep learning has been proposed to play a future role [ 123 ]. Specifically, there are cumulating evidences suggesting that the application of deep learning with the date recorded by an electronic health system, imaging modalities, histopathology and biomarkers can improve the selection of therapy to enhance patient survival and quality of life [ 124 – 127 ]. However, to fully utilize AI in the clinical management of HCC patients to be treated with systemic therapy, one needs to develop robust approaches for structured data collection, sharing and storage, and to demonstrate the reliability and robustness of models. To this end, the APASL oncology working party has initiated A-hoc ( APASL Hepatology/Oncology Consortium) study for HCC in Asia–Pacific region [ 128 ]. These type of registries will allow one to capturing real-world data regarding treatment response and irAE in patient populations that are underrepresented in clinical trials should be undertaken. In the near future, AI will play a pivotal role in assisting MDT in the management of patients with HCC to be treated with systemic therapy.

Discussion

In 2024 and beyond, one is expected to see an increasing use of systemic therapy, especially those related to the ICIs in the management of HCC for disease progression in patients with unresectable HCC, TACE-treated patients and HCC recurrence after local ablative surgery or radiofrequency ablation and liver transplantation. With the proper selection and use of systemic therapy, preferably with MDT approach, new opportunities are available to prolong the progression-free and overall survival with good quality life. In the future, we should aim not just to control disease progression, but bring “cure” to our patients with HCC. More clinical research is also called upon to understand the basis of diverse response to systemic therapy, so that we can tailor therapy to our HCC patients. Very importantly, one also needs to elucidate the mechanisms of irAE (i.e., events mediated by antibodies, T cells, and cytokines) to develop more precise treatments for irAE.

With more clinical, radiological, histological and omics data, aided with the proper use of AI, especially machine and deep learning, the best up-to-date management could be brought to our patients. With the rapid development in the understanding of host immunity in the control of HCC, one is expected to see a new wave of immunotherapies available for the management of unresectable HCC. Since the burden of HCC in the Asian region is the highest, APASL will stay alert and provide updated clinical practice guidelines to aid our fellow colleagues and the global community who are managing HCC.

Case reports on the use of ICI-based therapy in HCC recurrence patients post-LT Table7

(continued) Table7

(continued) Table7

Immunofluorescence analysis for PD-1 and PD-L1 expression of transplanted liver was positive \*

hepatocellular carcinoma

HCC #

Median (range)

Acknowledgements We acknowledge the contributions of Professor Masatoshi KUDO (Department of Gastroenterology and Hepatology, Kindai University of Medicine, Osaka-Sayama, Osaka, Japan), Professor Masafumi IKEDA (Department of Hepatobiliary & Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan) and Dr. Filza ASLAM (APAC Disease Area Network, HCC) for formulations of this CPG.

Author contributions GL, SS and MO contributed to the design of the work, drafting of the manuscript and critical revision. CCY, MR, HCL, MO and SKS performed critical revision. All authors have reviewed and agreed on the manuscript.

Funding The authors declare that no funds, grants or other support was received during the preparation of this manuscript.

Data availability This article does not have separate data to provide.

Declarations

Conflict of interest George LAU reported lecture fees from AstraZeneca. Shuntaro OBI reported research grants from Eisai, Otsuka pharmaceutical, and Mochida pharmaceutical.Ryosuke TATEISHI reported lecture fees from Abbvie, AstraZeneca, Chugai, Eisai, Gilead Sciences, MSD and Takeda. Sadahisa OGASAWARA reported honoraria from Bayer, Eisai, Eli Lilly, consulting or advisory fees from Bayer, Eisai, Merck & Co. Inc., Chugai Pharma, Eli Lilly, and research grants from Bayer and Eisai.Naoya KATO reported honoraria payment from Bayer and Chugai; research funding from Bayer, Chugai, and Roche. Stephen L CHAN reported consulting or advisory board fees from AstraZeneca, Eisai, and MSD; reports being an invited speaker for AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, IPSEN, MSD, and Roche; and research funding from Bayer, Eisai, IPSEN, MSD, and Sirtex Medical. Yoshiyuki UENO reported honoraria payment from Chugai and Eisai. Ann-Lii CHENG reported consulting or advisory board fees from AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Eisai, Genentech/Roche, Ipsen, IQVIA, MSD, Ono Pharmaceutical, and Roche; and honoraria from AstraZeneca, Bayer, Eisai, and Genentech/Roche. Yock Young DAN reported consulting or advisory board fees from Boehringer Ingelheim, MSD, Norvo Nordisk, Roche, and research grants from MSD, Norvo Nordisk, Perspectum, Siemens. Jeong Min LEE reported lecture fees from Samsung Medison, GE Healthcare, Philips Healthcare, Starmed, and research grants from Samsung Medison, Siemens Healthineers, Philips Healthcare, GE Healthcare, Bayer, Guerbet, CMS, Canon Healthcare, Dongkuk Pharma. Diana A. Payawal reported lecture, consulting or advisory board fees from Gilead Sciences, Mylan Pharmaceuticals, Echosense, Getz and Abbott. Ekaphop SIRACHAINAN reported honoraria payment from MSD, Sanofi/Aventis, Merck, Amgen, Roche, Mundipharma, AstraZeneca, LF Asia, Diethelm Keller Group, Bristol Myers Squibb, Boehringer Ingelheim, Taiho Pharmaceutical, Dr Reddy's Laboratories, Zuellig Pharma, Meda Pharmaceuticals, Pfizer, Novo Nordisk, Novartis. Tawesak Tanwandee reported research grants from Bristol Myers Squibb and Merck. Masao Omata reported lecture, consulting or advisory board fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Otsuka, Astellas, Gilead Sciences, Chugai, Mitsubishi Tanabe, Kyorin, Merck Sharp and Dohme, Dainippon Sumitomo, Vertex Pharmaceuticals, Takeda, Merck Serono, and Zeria.Jian ZHOU, Shukui QIN, Haitao ZHAO, Motoyuki OTSUKA, Jacob GEORGE, Pierce KH CHOW, Jianqiang CAI, Shuichiro SHIINA, Osamu YOKOSUKA, Kyoko OURA, Thomas YAU, Ming KUANG, Minshan CHEN, Gregory CHENG, Wan-Long CHUANG, Oidov BAATARKHUU, Feng BI, Rino A GANI, Atsushi TANAKA, Wasim JAFRI, Ji-Dong JIA, JiaHorng KAO, Kiyoshi HASEGAWA, Patrick LAU, Jun LIANG, Zhenwen LIU, Yinying LU, Hongming PAN, Salimur RAHMAN, Jinsil

SEONG, Feng SHEN, Gamal SHIHA, Tianqiang SONG, Hui-Chuan SUN, Tsutomu MASAKI, Lai WEI, Jin Mo YANG, Jose D SALLANO, Yanqiao ZHANG,, A Kadir DOKMECI, Shu-sen ZHENG, Jia FAN, Sheung-Tat FAN and Shiv Kumar Sarin reported that they have no conflict of interest.

Ethical approval Not applicable.

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Authors and Affiliations

GeorgeLau 1 $\circledast$ · ShuntaroObi 2 · JianZhou 3 · RyosukeTateishi 4 · ShukuiQin 5 · HaitaoZhao 6 · MotoyukiOtsuka 7 · SadahisaOgasawara 8 · JacobGeorge 9 · PierceK.H.Chow 10 · JianqiangCai 11 · ShuichiroShiina 12 · NaoyaKato 13 · OsamuYokosuka 14 · KyokoOura 15 · ThomasYau 16 · StephenL.Chan 17 · MingKuang 18 · YoshiyukiUeno 19 · MinshanChen 20 · Ann‑LiiCheng 21 · GregoryCheng 22,58 · Wan‑LongChuang 23 · OidovBaatarkhuu 24 · FengBi 25 · YockYoungDan 26 · RinoA.Gani 27 · AtsushiTanaka 28 · WasimJafri 29 · Ji‑DongJia 30 · Jia‑HorngKao 31 · KiyoshiHasegawa 32 · PatrickLau 33 · JeongMinLee 34 · JunLiang 35 · ZhenwenLiu 36 · YinyingLu 37 · HongmingPan 38 · DianaA.Payawal 39 · SalimurRahman 40 · JinsilSeong 41 · FengShen 42 · GamalShiha 43,59,60,61 · TianqiangSong 44 · Hui‑ChuanSun 45 · TsutomuMasaki 15 · EkaphopSirachainan 46 · LaiWei 47 · JinMoYang 48 · JoseD.Sallano 49 · YanqiaoZhang 50 · TawesakTanwandee 51 · AKadirDokmeci 52 · Shu‑senZheng 53 · Jiafan 54 · Sheung‑TatFan 55 · ShivKumarSarin 56 · MasaoOmata 57

\* George Lau gkklau@hnhmgl.com; gkklau@netvigator.com 1 Humanity andHealth Clinical Trial Center, Humanity andHealth Medical Group, Zhongshan Hospital, Fudan University, Hong Kong SAR, Shanghai, China 2 Department ofInternal Medicine, Teikyo University Chiba Medical Center, Chiba, Japan 3 Department ofLiver Surgery andTransplantation, Key Laboratory ofCarcinogenesis andCancer Invasion (Fudan University), Ministry ofEducation, Shanghai Key Laboratory ofOrgan Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Zhongshan Hospital, Fudan University, Shanghai, China 4 Department ofGastroenterology, Graduate School ofMedicine, The University ofTokyo, Tokyo, Japan 5 Cancer Centre ofJinling Hospital, Nanjing University ofChinese Medicine, Nanjing, China

6 Department ofLiver Surgery, State Key Laboratory ofComplex Severe andRare Diseases, Peking Union Medical College Hospital, Chinese Academy ofMedical Sciences & Peking Union Medical College, Beijing, China 7 Department ofGastroenterology andHepatology, Okayama University Graduate School ofMedicine, Dentistry, andPharmaceutical Sciences, Okayama700‑8558, Japan 8 Department ofGastroenterology, Graduate School ofMedicine, Chiba University, 1‑8‑1 Inohana, Chuo‑Ku, Chiba260‑8670, Japan 9 Storr Liver Centre, Westmead Institute forMedical Research, Westmead Hospital andUniversity ofSydney, Westmead, NSW2145, Australia 10 Department ofHPB Surgery andTransplantation, Duke‑NUS Medical School, National Cancer Center Singapore andSingapore General Hospital, Surgery Academic Clinical Program, Singapore, Singapore 11 Department ofHepatobiliary Surgery, National Cancer Center/National Clinical Research Center forCancer/Cancer Hospital, Chinese Academy ofMedical Sciences andPeking Union Medical College, Beijing, China 12 Department ofGastroenterology, Juntendo University, 2‑1‑1, Hongo, Bunkyo‑Ku, Tokyo113‑8421, Japan 13 Department ofGastroenterology andNephrology, Graduate School ofMedicine, Chiba University, Chiba, Japan 14 Department ofGastroenterology, Graduate School ofMedicine, Chiba University, Chiba, Japan 15 Department ofGastroenterology andNeurology, Faculty ofMedicine, Kagawa University, 1750‑1 Ikenobe, Kita, Miki, Kagawa761‑0793, Japan 16 Department ofMedicine, The University ofHong Kong, HongKong, China 17 Department ofClinical Oncology, State Key Laboratory ofTranslational Oncology, Sir YK Pao Centre forCancer, The Chinese University ofHong Kong, HongKongSAR, China 18 Center ofHepato‑Pancreato‑Biliary Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China 19 Faculty ofMedicine, Department ofGastroenterology, Faculty ofMedicine, Yamagata University, 2‑2‑2 Iida‑Nishi, Yamagata990‑9585, Japan 20 Department ofLiver Surgery, Collaborative Innovation Center forCancer Medicine, State Key Laboratory ofOncology inSouth China, Sun Yat-Sen University Cancer Center, Guangzhou510060, China 21 Department ofOncologyDepartment ofMedical OncologyGraduate Institute ofOncologyDepartmentof Internal Medicine, National Taiwan University Cancer CenterNational Taiwan University HospitalNational Taiwan University College ofMedicine, Taipei, Taiwan 22 Humanity andHealth Clinical Trial Center, Humanity & Health Medical Group, HongKongSAR, China 23 Hepatobiliary Division, Department ofInternal Medicine, andHepatitis Center, Center forInfectious Disease andCancer Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 24 School ofMedicine, Mongolian National University ofMedical Sciences, UlanBator, Mongolia 25 Department ofMedical Oncology, Laboratory ofMolecular Targeted Therapy inOncology, West China Hospital, Sichuan University, Chengdu, China 26 Division ofGastroenterology andHepatology, Department ofMedicine, National University Health System, Singapore, Singapore 27 Hepatobiliary Division, Staff Medic Group ofInternal Medicine, Faculty ofMedicine, Universitas Indonesia, Dr. Cipto Mangunkusumo Hospital, Jakarta10430, Indonesia 28 Department ofMedicine, Teikyo University School ofMedicine, Tokyo, Japan 29 The Aga Khan University Hospital, Karachi, Pakistan 30 Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China 31 Department ofInternal Medicine Division ofGastroenterology andHepatology, Department ofInternal MedicineHepatitis Research Center, Graduate Institute ofClinical Medicine, National Taiwan University Hospital Bei-Hu BranchNational Taiwan University HospitalNational Taiwan University College ofMedicine, Taipei, Taiwan 32 Department ofSurgery, Graduate School ofMedicine, Hepato-Biliary-Pancreatic Surgery Division, The University ofTokyo, Tokyo, Japan 33 Humanity andHealth Clinical Trial Center, Humanity & Health Medical Group, HongKongSAR, China 34 Department ofRadiology, Seoul National University College ofMedicine, Seoul, Korea 35 Department ofMedical Oncology, Peking University International Hospital, Beijing, China 36 Senior Department ofHepatology, The Fifth Medical Center ofChinese People’s Liberation, Army General Hospital, Beijing, China 37 Department ofComprehensive Liver Cancer Center, The Fifth Medical Center ofChinese, PLA General Hospital, Beijing, China 38 Department ofMedical Oncology, College ofMedicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China 39 Department ofMedicine, Fatima University Medical Center, Manila, Philippines 40 Department ofHepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka1000, Bangladesh 41 Department ofRadiation Oncology, Yonsei Cancer Center, Yonsei University College ofMedicine, Seoul, RepublicofKorea 42 Department ofHepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China 43 European Liver Patients’ Association (ELPA), Brussels, Belgium 53 Department ofHepatobiliary andPancreatic Surgery, Department ofLiver Transplantation, Shulan (Hangzhou) Hospital, Zhejiang Shuren University School ofMedicine, Hangzhou, China 54 Department ofLiver Surgery andTransplantation, Key Laboratory ofCarcinogenesis andCancer Invasion (Ministry ofEducation), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China 55 Liver Surgery andTransplant Centre, Hong Kong Sanatorium andHospital, HongKong, Japan 56 Department ofHepatology, Institute ofLiver andBiliary Sciences, NewDelhi, India 57 Department ofGastroenterology, Yamanashi Prefectural Center Hospital, Kofu‑City, Yamanashi, Japan 58 Faculty ofHealth Science, Macau University, MacauSAR, China 59 World Hepatitis Alliance, London, UK 60 African Liver Patient Association (ALPA), Cairo, Egypt 61 The Association ofLiver Patients Care (ALPC), Hepatology andGastroenterology Unit, Internal Medicine Department, Faculty ofMedicine, Mansoura University, Egyptian Liver Research Institute andHospital (ELRIAH), Sherbin, ElMansoura, Egypt 44 Department ofHepatobiliary, HCC Research Center forPrevention andTherapy, Tianjin Medical University Cancer Institute andHospital, National Clinical Research Center forCancer, Tianjin, China 45 Department ofLiver Surgery andTransplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China 46 Division ofMedical Oncology, Department ofInternal Medicine, Faculty ofMedicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand 47 Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China 48 Department ofInternal Medicine, College ofMedicine, The Catholic University ofKorea, Seoul, SouthKorea 49 Section ofGastroenterology, University ofSanto Tomas, Manila, Philippines 50 Department ofGastrointestinal Medical Oncology, Institute ofPrevention andTreatment ofCancer ofHeilongjiang Province, Harbin Medical University Cancer Hospital, Harbin,Heilongjiang, China 51 Division ofGastroenterology, Department ofMedicine, Faculty ofMedicine Siriraj Hospital, Mahidol University, Bangkok, Thailand 52 Department ofMedicine, Ankara University School ofMedicine, Ankara, Turkey