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Lenvatinib in Hepatocellular Carcinoma

Published Online: December 13th 2018 European Oncology & Haematology, 2018;14(2):80–1 DOI: https://doi.org/10.17925/EOH.2018.14.2.80
Authors: Miguel Marcao
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Liver cancer is the second leading cause of cancer-related death, and has limited treatment options and a poor prognosis.1 Mortality owing to liver cancer has increased in the past 20 years, with a reported incidence of 841,080 cases per year.2 Hepatocellular carcinoma (HCC) represents about 90% of primary liver cancer cases.1 Multiple single agent and combination therapies have been investigated for the treatment of HCC but failed to show clinical benefit.3 Recently, the European Commission granted marketing authorisation to the oral receptor tyrosine kinase inhibitor lenvatinib mesylate (Lenvima®; Eisai, Tokyo, Japan), for the first-line treatment of adult patients with advanced or unresectable HCC who have not received prior systemic therapy. This is the first new first-line treatment option for advanced or unresectable HCC to be approved in Europe in 10 years. Approval was based on the results of the REFLECT study.4 In an expert interview, Miguel Marcao discusses the findings of this study and the next steps in the clinical development of lenvatinib for the treatment of HCC.

Q. Why is the treatment of unresectable hepatocellular carcinoma such an important unmet need?

Firstly, because there is a very high level of mortality in HCC; it is the second leading cause of cancer death globally, with 70,000 deaths per year in Europe and about 4,000–5,000 deaths in the UK alone depending on the source of the data.5 It is a disease with a very poor prognosis; every year in Europe 82,466 cases are diagnosed and there are 77,375 deaths.2 Part of the reason for this is that, for the last 10 years, only one systemic therapy, sorafenib, has been available for the treatment of advanced HCC; therefore, treatment options are limited for these patients.

Q. Could you tell us a little about the rationale behind and objectives of the REFLECT clinical trial?

The REFLECT trial aimed to demonstrate non-inferiority of lenvatinib when compared with sorafenib, the leading reference treatment, in terms of overall survival.4 This has been the objective of many trials of other drugs for HCC in the last 10 years, but REFLECT is the first study that met the primary endpoint.

Q. What were the key findings of this study?

The primary endpoint of overall survival by statistical confirmation of non-inferiority against standard of care was met.4 Within the secondary endpoints, lenvatinib demonstrated benefit compared with sorafenib in the response rate, i.e., progression-free survival, time to progression and objective response rate. Lenvatinib also showed statistically significant superiority and clinically meaningful improvements in the secondary efficacy endpoints. Progression-free survival was around 7.4 months with lenvatinib, which is double that of current treatment, and response rate was around 3.5 times higher with lenvatinib: 41% of patients experienced significant shrinkage of the tumour.4

Q. What was the safety profile of lenvatinib in this study?

The safety profile was consistent with that seen with lenvatinib in other indications and with other drugs in this class. The most common adverse events were observed in around 30% of patients. These were hypertension, diarrhoea, loss of appetite, fatigue and weight loss.4 We are experienced in managing these symptoms. The study found nothing surprising in terms of safety.

Q. What are the next steps in the clinical development of lenvatinib for unresectable hepatocellular carcinoma?

Currently we are in the early stages of an extensive clinical trial programme investigating the combination of lenvatinib with pembrolizumab, in partnership with Merck Sharp & Dohme (Hoddesdon, Hertfordshire, UK). Two ongoing phase III studies are investigating this combination in metastatic renal cell carcinoma (Clinicaltrials.gov Identifier: NCT02811861)6 and advanced endometrial carcinoma (Clinicaltrials.gov Identifier: NCT03517449).7 Depending on the data, this combination will be studied in phase III studies in other indications including HCC.

Article Information:
Disclosure

Miguel Marcao is an employee of Eisai.

Review Process

This is an expert interview and, as
such, has not undergone the journal’s standard peer
review process.

Authorship

The named author meets the International
Committee of Medical Journal Editors (ICMJE) criteria
for authorship of this manuscript, takes responsibility
for the integrity of the work as a whole, and has given
final approval for the version to be published.

Correspondence

Miguel Marcao, Eisai, Mosquito
Way, Hatfield AL10 9SN, UK. E: Miguel_Marcao@eisai.net

Support

No funding was received in the publication of this article.

Access

This article is published under the Creative
Commons Attribution Non-commercial License, which
permits any non-commercial use, distribution, adaptation,
and reproduction provided the original author and
source are given appropriate credit. © The Author 2018.

Acknowledgements

Medical writing assistance
was provided by Katrina Mountfort of Touch Medical
Media and was supported by Touch Medical Media.

Received

2018-08-28T00:00:00

References

  1. Llovet JM, Zucman-Rossi J, Pikarsky E, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2016;2:16018.
  2. World Health Organization. Estimated Incidence, Mortality and Prevalence Worldwide in 2012. GLOBOCAN Cancer Fact Sheets: liver cancers. Available at: https://gco.iarc.fr/today/data/factsheets/cancers/11-Liver-fact-sheet.pdf (accessed 16 October 2018).
  3. Pinter M, Peck-Radosavljevic M. Review article: systemic treatment of hepatocellular carcinoma. Aliment Pharmacol Ther. 2018;48:598–609.
  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. Cancer research UK. Liver cancer statistics. Available at: www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/liver-cancer (accessed 16 October 2018).
  6. Clinicaltrials.gov. Lenvatinib/Everolimus or Lenvatinib/Pembrolizumab Versus Sunitinib Alone as Treatment of Advanced Renal Cell Carcinoma (CLEAR). ClinicalTrials.gov Identifier: NCT02811861. Available at: https://clinicaltrials.gov/ct2/show/NCT02811861 (accessed 13 September 2018).
  7. Clinicaltrials.gov. Lenvatinib in Combination With Pembrolizumab Versus Treatment of Physician’s Choice in Participants With Advanced Endometrial Cancer (MK-3475-775/E7080-G000-309 Per Merck Standard Convention [KEYNOTE-775]). ClinicalTrials.gov Identifier: NCT03517449. Available at: https://clinicaltrials.gov/ct2/show/NCT03517449 (accessed 13 September 2018).

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