eUpdate – Hepatocellular Carcinoma Treatment Recommendations

Published: 8 February 2019. Authors: ESMO Guidelines Committee

Note: Other eUpdates may have been published for these guidelines. All currently valid eUpdates can be accessed from the page displaying the full guidelines on this topic

Clinical Practice Guidelines

This update 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.

Section

Management of advanced disease, Systemic therapies for advanced HCC, Targeted first-line therapies

Text update

Lenvatinib showed non-inferiority efficacy compared with sorafenib and can be considered in patients with advanced HCC without main portal vein invasion and with ECOG PS 0–1 as a front-line systemic treatment, received European Medicines Agency (EMA) approval in late 2018 and is associated with an ESMO-Magnitude of Clinical Benefit Scale (MCBS) score of 4 [I, A; MCBS 4].

Section

Management of advanced disease, Systemic therapies for advanced HCC, Targeted first-line therapies, Lenvatinib

Text update

These results position lenvatinib as an option in first-line treatment for advanced HCC, now that the drug is EMA-approved [I, A; MCBS 4].

Section

Management of advanced disease, Systemic therapies for advanced HCC, Targeted second-line therapies

Text update

Regorafenib is the standard of care for patients with advanced HCC who have tolerated sorafenib but progressed. It is recommended in patients with well-preserved liver function and ECOG PS 0–1 [I, A; MCBS 4].

Cabozantinib can be considered for patients who had progressive disease on one or two systemic therapies with well-preserved liver function and ECOG PS 0–1. It received EMA approval in late 2018 and is associated with an ESMO-MCBS score of 3 [I, A; MCBS 3].

Ramucirumab (RAM) can be considered for patients in second-line treatment with baseline AFP ≥ 400 ng/mL, well-preserved liver function and ECOG PS 0–1, pending EMA approval [I, A].

Section

Table 4. BCLC staging and treatment options according to level of evidence and approval status, BCLC stage C

Text update

Under “Treatment (standard of care)”:
Sorafenib (first-line) [I, A]
Regorafenib (second-line) [I, A]

Is replaced with:
Sorafenib (first-line) [I, A]
Regorafenib (second-line) [I, A; MCBS 4]
Lenvatinib (first-line) [I, A; MCBS 4]
Cabozantinib (second-line) [I, A; MCBS 3]

Under “Alternative treatment; Not EMA-approved”:
Lenvatinib (first-line) [I, A]
Cabozantinib (second-line) [I, A]
Ramucirumab (AFPhigh; second-line) [I, A]

Is replaced with:
Ramucirumab (AFPhigh; second-line) [I, A]

Section

Table 6. Summary of Recommendations, Management of advanced disease

Text update

  • Chemotherapy has not been shown to improve survival in randomised trials and is not recommended as a standard of care [II, C]
  • Sorafenib is the standard of care for patients with advanced HCC and those with intermediate-stage (BCLC B) disease not eligible for, or progressing despite, locoregional therapies. It is recommended in patients with well-preserved liver function and ECOG PS 0–2 [I, A]
  • Lenvatinib showed non-inferiority efficacy compared with sorafenib, and can be considered as first-line therapy in patients with advanced HCC without main portal vein invasion, clear bile duct invasion and ≥ 50% of tumour to total liver volume occupancy [I, A; MCBS 4]
  • Regorafenib is the standard of care for patients with advanced HCC who have tolerated sorafenib but progressed. It is recommended in patients with well-preserved liver function and ECOG PS 0–1 [I, A; MCBS 4]
  • Cabozantinib can be considered for patients who had progressive disease on one or two systemic therapies with well-preserved liver function and ECOG PS 0–1 [I, A; MCBS 3]
  • Ramucirumab can be considered for patients in second-line patients with baseline AFP ≥ 400 ng/mL, well-preserved liver function and ECOG PS 0–1, pending EMA approval [I, A]
  • Immunotherapy with nivolumab and pembrolizumab can be considered in patients who are intolerant to, or have progressed under, approved tyrosine kinase inhibitors, pending EMA approval [III, B]. For a definitive recommendation, it is necessary to wait for the results of randomised trials

Section

Table 7. ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) table for new therapies/indications in Hepatocellular Carcinoma*

Therapy Disease setting Trial Control Absolute survival gain HR (95% CI) Toxicity/Qol MCBS score**
Lenvatinib First-line unresectable hepatocellular carcinoma

Lenvatinib versus sorafenib in first-line treatment of
patients with unresectable hepatocellular carcinoma:
a randomised phase 3 non-inferiority trial [2]

Phase III

NCT01761266 (REFLECT trial)

Sorafenib

OS gain: 1.3 months

PFS gain: 3.7 months

OS HR: 0.92 (0.79–1.06)

PFS HR: 0.66 (0.57–0.77)

Delayed deterioration 4
(Form 2c)
Cabozantinib Second-line unresectable hepatocellular carcinoma after TKI

Cabozantinib in patients with advanced
and progressing hepatocellular carcinoma [3]

Phase III

NCT01908426 (CELESTIAL trial)

Placebo

OS gain: 2.2 months

PFS gain: 1.6 months

OS HR: 0.76 (0.63–0.92)

PFS HR: 0.44 (0.36–0.52)

       3
(Form 2a)
Regorafenib Second-line unresectable hepatocellular carcinoma after TKI

Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial [1]

Phase III

NCT01774344

Placebo

OS gain: 2.8 months
2-year survival gain >10%

PFS gain: 3.3 months

OS HR: 0.63 (0.50–0.79)

PFS HR: 0.46 (0.37–0.56)

        4
(Form 2a)

*EMA approvals since January 2016.

**ESMO-MCBS version 1.1 [2].

CI, confidence interval; EMA, European Medicines Agency; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; QoL, quality of life; TKI, tyrosine kinase inhibitor.

References

  1. 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.
  2. 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: 1163–1173.
  3. 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.
  4. Cherny NI, Dafni U, Bogaerts J et al. ESMO-Magnitude of Clinical Benefit Scale Version 1.1. Ann Oncol 2017; 28: 2340–2366.