eUpdate – Hepatocellular Carcinoma Treatment Recommendations

Published: 8 February 2019. Authors: ESMO Guidelines Committee

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.