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eUpdate – Hepatocellular Carcinoma Treatment Recommendations

eUpdate – Hepatocellular Carcinoma Treatment Recommendations

Published: 05 March 2021. Authors: ESMO Guidelines Committee

Note: This eUpdate replaces all previous eUpdates published for these guidelines.

Clinical Practice Guidelines

This eUpdate refers to Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Vogel A, Cervantes A, Chau I et al. Ann Oncol 2018; 29 (Suppl 4): iv238–iv255.

Acknowledgements

The ESMO Guidelines Committee would like to thank the authors who drafted and reviewed the eUpdate before it was approved by the ESMO Guidelines Committee: A. Vogel, A. Cervantes, I. Chau, B. Daniele, J. M. Llovet, T. Meyer, J.-C. Nault, U. Neumann, J. Ricke, B. Sangro, P. Schirmacher, C. Verslype, C. J. Zech, D. Arnold & E. Martinelli.

Section

Management of early and intermediate hepatocellular carcinoma (HCC), Selective internal radiotherapy

The text has been updated to include a level of evidence and grade of recommendation for selective internal radiotherapy (SIRT).

Thus, in exceptional circumstances, for patients with liver-confined disease and good liver function in whom neither transarterial chemoembolisation (TACE) nor systemic therapy is possible, SIRT may be considered [III, C].

Section

Updated Table 4.

Table 4. Barcelona Clinic Liver Cancer (BCLC) staging and treatment options according to level of evidence and approval status

BCLC stage

Treatment (standard of care)

Indication constraints based on tumour burden and liver function

Alternative treatment

0 - A

Single tumour any size or up to 3 nodules ≤3 cm

Preserved liver function

ECOG PS 0

Resection [III, A]

Adequate size and function of remnant liver

SBRT [III, C]

HDR brachytherapy [III, C]

SIRT [III, C]

Transplantation [III, A]

Size ≤5 cm, number ≤3

Thermal ablation [III, A]

Size ≤3 cm, not adjacent to vessels or bile duct

TACE [I, A]

Contraindications against resection and thermal ablation. Bridging to transplantation

B

Multinodular

Preserved liver function

ECOG PS 0

TACE [I, A]

Size 5-10 cm, tumour nodules accessible to supra-selective catheterisation

Transplantation [III, A]

Resection [III, A]

Systemic therapy (after TACE failure/ refractoriness, not suitable for local therapies) [I, A]

SIRT (liver-confined, good liver function, no systemic therapy feasible) 

C

Portal invasion

Extrahepatic spread

Preserved liver function

ECOG PS 0-2

Atezolizumab plus bevacizumab (first-line) [I, A; ESMO-MCBS v1.1 score: 5] 

 

Option:

Sorafenib (first-line) [I, A; ESMO-MCBS v1.1 score: 4] 

Lenvatinib (first-line) [I, A]a

 

Child–Pugh A

SIRT (liver- confined, good liver function, no systemic therapy feasible)

 

Standard after sorafenib:

 

Cabozantinib [I, A; ESMO-MCBS v1.1 score: 3]

 

Regorafenibb [I, A; ESMO-MCBS v1.1 score: 4]

 

Ramucirumabc [I, A; ESMO-MCBS v1.1 score:  1]

 

 

Option after

Atezolizumab plus Bevacizumab/lenvatinib:

 

Sorafenib [V, C]

Lenvatinib [V, C]

Cabozantinib [V, C]

Regorafenibb [V, C]

Ramucirumabc [V, C]

 

 

 

Child–Pugh A,

Tolerability to sorafenib, (regorafenib)

AFP ≥400 ng/ml for ramucirumab

D

End-stage liver function

ECOG PS 3-4

BSC [III, A]

 

 

AFP, α-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; BSC, best supportive care; ECOG, Eastern Cooperative Oncology Group; EMA, European Medicines Agency; HDR, high dose rate; ESMO-MCBS, European Society for Medical Oncology -Magnitude of Benefit Scale; PS, performance status; SBRT, stereotactic body radiotherapy; SIRT, selective internal radiotherapy; TACE, transarterial chemoembolisation; TKI, tyrosine kinase inhibitor.

a Non-inferiority to sorafenib established; no evaluable benefit.
b Regorafenib is not recommended in TKI-naïve patients.
c Ramucirumab is only recommended in patients with an AFP level  ≥400 ng/ml.

Section

Management of advanced disease, Systemic therapies for advanced HCC

New text to replace sub-sections ‘Targeted first-line therapies’ and ‘Targeted second-line therapies’

Treatment sequencing

In recent years, several first- and second-line treatment options have been approved for advanced HCC and recommended in ESMO Clinical Practice Guidelines. Exploratory analyses of the reported first- and second-line trials indicate that a cumulative median overall survival (OS) of more than 20 months can be reached in patients with maintained liver function, and sequential systemic therapy is therefore strongly recommended.

Atezolizumab plus bevacizumab is the first treatment to demonstrate a significant OS benefit compared with sorafenib with a hazard ratio for death of 0.66 [95% confidence interval (CI) 0.52 to 0.85; P=0.0009], data reported from a recent abstract [1]. Consequently, atezolizumab plus bevacizumab will become the standard of care in first-line systemic therapy in HCC. However, 20% of patients do not respond to atezolizumab plus bevacizumab and the median progression-free survival (PFS) is only 6.8 months, raising the need to define options for second-line therapy [2]. Drugs in the second-line setting have so far only been tested after sorafenib failure/intolerance and there are currently no phase III trial data to inform the choice of second-line therapy in HCC patients that received alternative front-line therapies. There is, however, a clear rationale for offering a multikinase inhibitor given the existing evidence for efficacy in first and second line. Since there is no evidence for any drug in particular, it is recommended that all the currently approved first- and second-line agents could be considered as second-line therapy (see Figure 1; efficacy data are summarised in a new Table 9; see below).

Current evidence base:

  • Sorafenib: sorafenib has only been evaluated in the first-line setting. Phase-IV/observational studies have not revealed new safety signals in patients with Child-Pugh B cirrhosis [3] ESMO-Magnitude of Clinical Benefit Scale (MCBS) v1.1 score of 4 [I, A; ESMO-MCBS 4].
  • Lenvatinib:  lenvatinib has only been evaluated in the first-line setting. The drug has shown a higher response rate compared with other tyrosine kinase inhibitors (TKIs) and ramucirumab in HCC [4] [I, A], with non-inferiority to sorafenib established and no evaluable benefit.
  • Regorafenib: regorafenib has only been evaluated in the second-line setting after progression on sorafenib. One main inclusion criterion for the RESORCE study was the tolerance to sorafenib, therefore the drug is preferably recommended in patients that have tolerated sorafenib and not in TKI-naïve patients [5] [I, A; ESMO-MCBS v1.1 score 4].
  • Cabozantinib: cabozantinib has been evaluated in the second- and third-line (28% of patients in the CELESTIAL trial) setting after intolerance to or progression under sorafenib treatment. Efficacy and safety of cabozantinib is independent of the duration of sorafenib pretreatment [6] [I, A; ESMO-MCBS v1.1 score 3].
  • Ramucirumab: ramucirumab has only been evaluated in the second-line setting after intolerance to/progression under sorafenib treatment. Ramucirumab has only shown efficacy in patients with an α-fetoprotein (AFP) level ≥400 ng/ ml [7] [I, A; ESMO-MCBS v1.1 score 1].

The majority of ESMO Guideline authors recommend considering all approved agents (sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab) in the second-line setting after atezolizumab plus bevacizumab. A minority of the authors (3/14) recommended that only sorafenib or lenvatinib should be used in second line after atezolizumab plus bevacizumab and that regorafenib, cabozantinib and ramucirumab should be used in third line.

Text update

Immunotherapies

Atezolizumab plus bevacizumab, which showed superior efficacy compared with sorafenib, is recommended as standard of care in first-line therapy of patients with advanced HCC and received European Medicines Agency (EMA) approval in late 2020 [2, 8] [ESMO-MCBS v1.1 score 5].

Immunotherapy in the form of monotherapy has been evaluated in patients in two phase III studies. The first-line phase III CheckMate 459 trial, comparing sorafenib with nivolumab as a first-line treatment option, failed to meet the primary endpoint of overall survival (OS) [9]. The second-line phase III KEYNOTE-240 trial of pembrolizumab versus placebo also failed to meet its co-primary endpoints of OS and PFS [10]. Neither drug has received EMA approval and they are not recommended as monotherapy for the treatment of advanced HCC.

Updated Table 8. ESMO-MCBS table for new therapies/indications in hepatocellular cancera

The ESMO-MCBS table is updated to include scores for ramucirumab and atezolizumab plus bevacizumab.

Therapy

Lenvatinib versus sorafenib in first-line treatment

Disease setting

First-line advanced or unresectable hepatocellular carcinoma

Trial

A multicentre, open-label, phase 3 trial to compare the efficacy and safety of lenvatinib (E7080) versus sorafenib in first-line treatment of participants with unresectable hepatocellular carcinoma (REFLECT) [4]

NCT01761266

Phase

III

Control

Sorafenib

OS control: 12.3 months

PFS control: 3.7 months

Absolute survival gain

OS gain: 1.3 months

OS non-inferiority, inferiority margin: 1.08

PFS gain: 3.7 months

HR (95% CI)

OS HR: 0.92 (0.79-1.06)

PFS HR: 0.66 (0.57-0.77)

QoL/toxicity

No evaluable benefit

ESMO-MCBS scoreb

Non-inferiority to sorafenib established, no evaluable benefit. Not scorable.

Therapy

Cabozantinib versus placebo in second-line treatment

Disease setting

Second-line unresectable hepatocellular carcinoma after TKI

Trial

Study of cabozantinib (XL184) vs placebo in subjects with hepatocellular carcinoma who have received prior sorafenib (CELESTIAL) [6]

NCT01908426

Phase

III

Control

Placebo

OS control: 8.0 months

PFS control: 1.9 months

Absolute survival gain

OS gain: 2.2 months

PFS gain: 3.3 months

HR (95% CI)

OS HR: 0.76 (0.63-0.92)

PFS HR: 0.44 (0.36-0.52)

QoL/toxicity

Increased toxicity

ESMO-MCBS scoreb

3 (Form 2a)

Therapy

Regorafenib after sorafenib in second-line treatment

Disease setting

Second-line unresectable hepatocellular carcinoma after TKI

Trial

Study of regorafenib after sorafenib in patients with hepatocellular carcinoma (RESORCE) [5]

NCT01774344

Phase

III

Control

Placebo

OS control: 7.8 months

PFS control: 1.5 months

Absolute survival gain

OS gain: 2.8 months

2-year survival gain >10%

PFS gain: 1.6 months

HR (95% CI)

OS HR: 0.63 (0.50-0.79)

PFS HR: 0.46 (0.37-0.56)

QoL/toxicity

Increased toxicity

ESMO-MCBS scoreb

4 (Form 2a)

Therapy

Ramucirumab versus placebo in advanced HCC

Disease setting

Patients with advanced HCC or cannot be removed by surgery with a high blood level of AFP and previously treated with sorafenib

Trial

A study of ramucirumab (LY3009806) versus placebo in participants with hepatocellular carcinoma and elevated baseline alpha-fetoprotein (REACH-2) [7, 11]

NCT02435433

Phase

III

Control

Placebo

OS control 7.3 months

Absolute survival gain

OS gain: 1.2 months

HR (95% CI)

OS HR 0.71 (0.53-0.95)

QoL/toxicity

Benefit for delayed deterioration in global QoL not significant

ESMO-MCBS

scoreb

1 (Form 2a)

Therapy

Atezolizumab plus bevacizumab versus sorafenib in first-line treatment

Disease setting

First-line advanced or unresectable hepatocellular carcinoma

Trial

A Study of atezolizumab in combination with bevacizumab compared with sorafenib in patients with untreated locally advanced or metastatic hepatocellular carcinoma (IMbrave150) [2] NCT03434379

Phase

III

Control

Sorafenib

OS control: 13.2 months

Absolute survival gain

OS gain: 9.6c months

HR (95% CI)

0.58 (0.42-0.79) P<0.001 crossed the first interim boundary of 0.0033

QoL/toxicity

Delayed deterioration

ESMO-MCBS

scoreb

5 (form 2a)

AFP, α-fetoprotein; CI, confidence interval; EMA, European Medicines Agency; ESMO-MCBS, Magnitude of Clinical Benefit Scale; HR, hazard ratio; OS, overall survival; PE, point estimate; PFS, progression-free survival; QoL, quality of life; TKI, tyrosine kinase inhibitor.

a EMA approvals since January 2016.
b ESMO-MCBS version 1.1 [12]. The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee.
c Estimation of gain based on the PE HR 0.58.

New Table 9. Summary of efficacy data for HCC

eUpdate-Hepatocellular-Carcinoma-Treatment-Recommendations-New-table-9

Albi, albumin-bilirubin score; CI, confidence interval; CR, complete response; DCR, disease control rate; HCC, hepatocellular carcinoma; HR, hazard ratio; mOS, median overall survival; NR, not reached; ORR, overall response rate; OS, overall survival: PD, progressive disease; PFS,  progression-free survival; PR, partial response; RECIST, response evaluation criteria in solid tumours; SD, stable disease. 

a Pooled data.
b Response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).
c Modified RECIST.

References

  1. Finn RS, Qin S, Ikeda M, et al. IMbrave150: Updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). J Clin Oncol.2021;39: (suppl 3) 267-267 doi: 10.1200/JCO.2021.39.3_suppl.267.
  2. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382(20):1894-1905.
  3. Di Marco V, De Vita F, Koskinas J et al. Sorafenib: from literature to clinical practice. Ann Oncol. 2013; 24(suppl 2): 30-37.
  4. Kudo M, Finn RS, Qin S et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018; 391:1163-73.
  5. Bruix J, Qin S, Merle P et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017; 389: 56-66.
    a randomised phase 3 non-inferiority trial. Lancet 2018; 391: 1163-1173.
  6. Abou-Alfa GK, Meyer T, Cheng A-L et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018; 379: 54-63.
  7. Zhu A X, Kang Y-K, Yen C-J et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019; S1470-2045(18)30937-9
  8. Summary of opinion (post-authorisation) EMA/CHMP/488242/2020. EMA CHMP. Published 17 Sept 2020. Accessed: 19 Nov 2020.
  9. Yau T, Park JW, Finn RS et al. CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2019; 30(5): v874-v875.
  10. Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2020;38(3):193-202.
  11. Zhu AX, Nipp RD, Finn RS, et al. Ramucirumab in the second-line for patients with hepatocellular carcinoma and elevated alpha-fetoprotein: patient-reported outcomes across two randomised clinical trials. ESMO Open 2020;5:e000797.
  12. Cherny NI, Dafni U, Bogaerts J et al. ESMO-Magnitude of Clinical Benefit Scale Version 1.1. Ann Oncol. 2017; 28: 2340-2366.
  13. Rimassa L, Santoro A. Sorafenib therapy in advanced hepatocellular carcinoma: the SHARP trial. Expert Rev Anticancer Ther. 2009; 9(6): 739-45.

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