846
Views
48
CrossRef citations to date
0
Altmetric
Perspective

Lenvatinib plus pembrolizumab: the next frontier for the treatment of hepatocellular carcinoma?

, , , , , & show all
Pages 371-378 | Received 26 May 2021, Accepted 23 Jun 2021, Published online: 30 Jun 2021

References

  • Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391(10127):1301–1304.
  • Villanueva A. Hepatocellular Carcinoma. N Engl J Med. 2019 Apr 11;380(15):1450–1462. PMID: 30970190.
  • Waidmann O, Trojan J. Novel drugs in clinical development for hepatocellular carcinoma. Expert Opin Investig Drugs. 2015;24;(8):1075–1082. Epub 2015 Jun 24. PMID: 26108356. DOI:https://doi.org/10.1517/13543784.2015.1058776
  • Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021 Jan 21;7(1):6. PMID: 33479224.
  • De Lorenzo S, Tovoli F, Barbera MA, et al. Metronomic capecitabine vs. best supportive care in child-pugh B hepatocellular carcinoma: a proof of concept. Sci Rep. 2018 July 3;8(1):9997. PMID: 29968763; PMCID: PMC6030080.
  • Noonan A, Pawlik TM. Hepatocellular carcinoma: an update on investigational drugs in phase I and II clinical trials. Expert Opin Investig Drugs. 2019 Nov;28(11):941–949. Epub 2019 Oct 12. PMID: 31590579.
  • Gadaleta-Caldarola G, Divella R, Mazzocca A, et al. Sorafenib: the gold standard therapy in advanced hepatocellular carcinoma and beyond. Future Oncol. 2015;11(16):2263–2266. PMID: 26260805.
  • Faivre S, Rimassa L, Finn RS. Molecular therapies for HCC: looking outside the box. J Hepatol. 2020 Feb;72(2):342–352. PMID: 31954496.
  • Llovet JM, Ricci S, Mazzaferro V, et al. SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 July 24;359(4):378–390. PMID: 18650514.
  • Bouattour M, Mehta N, He AR, et al. Systemic treatment for advanced hepatocellular carcinoma. Liver Cancer. 2019 Oct 8;(5):341–358. Epub 2019 Mar 6. PMID: 31768344; PMCID: PMC6873089. Doi:https://doi.org/10.1159/000496439
  • Rizzo A, Nannini M, Novelli M, et al. Dose reduction and discontinuation of standard-dose regorafenib associated with adverse drug events in cancer patients: a systematic review and meta-analysis. Ther Adv Med Oncol. 2020 July 7;12:1758835920936932. PMID: 32684988; PMCID: PMC7343359.
  • Deeks ED. Cabozantinib: a review in advanced hepatocellular carcinoma. Target Oncol. 2019 Feb;14(1):107–113. PMID: 30767164.
  • Ingles Garces AH, Au L, Mason R, et al. Building on the anti-PD1/PD-L1 backbone: combination immunotherapy for cancer. Expert Opin Investig Drugs. 2019 Aug;28(8):695–708. Epub 2019 Aug 6. PMID: 31359805.
  • Finn RS, Qin S, Ikeda M, et al. IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020 May 14;382(20):1894–1905. PMID: 32402160.
  • 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(3_suppl): 267-267. DOI:https://doi.org/10.1200/JCO.2021.39.3_suppl.267.
  • Llovet JM, Montal R, Sia D, et al. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol. 2018 Oct;15(10):599–616. PMID: 30061739.
  • Rizzo A, Ricci AD, Brandi G. Atezolizumab in advanced hepatocellular carcinoma: good things come to those who wait. Immunotherapy. 2021 June;13(8):637–644. Epub 2021 Apr 6. PMID: 33820447.
  • Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252–264. PMID: 22437870; PMCID: PMC4856023.
  • Alsaab HO, Sau S, Alzhrani R, et al. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol. 2017 Aug 23;8:561. PMID: 28878676; PMCID: PMC5572324.
  • Barrueto L, Caminero F, Cash L, et al. Resistance to Checkpoint Inhibition in Cancer Immunotherapy. Transl Oncol. 2020 Mar;13(3):100738. Epub 2020 Feb 27. PMID: 32114384; PMCID: PMC7047187.
  • Riley RS, June CH, Langer R, et al. Delivery technologies for cancer immunotherapy. Nat Rev Drug Discov. 2019 Mar;18(3):175–196. PMID: 30622344; PMCID: PMC6410566.
  • Van Den Bulk J, Verdegaal EM, De Miranda NF. Cancer immunotherapy: broadening the scope of targetable tumours. Open Biol. 2018 June;8(6):180037. PMID: 29875199; PMCID: PMC6030119.
  • Reck M. Pembrolizumab as first-line therapy for metastatic non-small-cell lung cancer. Immunotherapy. 2018 Feb;10(2):93–105. Epub 2017 Nov 17. PMID: 29145737.
  • Affo S, Yu LX, Schwabe RF. The role of cancer-associated fibroblasts and fibrosis in liver cancer. Annu Rev Pathol. 2017 Jan 24;12:153–186.
  • Yin Z, Dong C, Jiang K, et al. Heterogeneity of cancer-associated fibroblasts and roles in the progression, prognosis, and therapy of hepatocellular carcinoma. J Hematol Oncol. 2019 Sept 23;12(1):101. PMID: 31547836; PMCID: PMC6757399.
  • Kudo M. Scientific rationale for combined immunotherapy with PD-1/PD-L1 antibodies and VEGF inhibitors in advanced hepatocellular carcinoma. Cancers (Basel). 2020 Apr 27;12(5):1089. PMID: 32349374; PMCID: PMC7281246.
  • Finkelmeier F, Waidmann O, Trojan J. Nivolumab for the treatment of hepatocellular carcinoma. Expert Rev Anticancer Ther. 2018 Dec;18(12):1169–1175. Epub 2018 Oct 22. PMID: 30304963.
  • El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017 June 24;389(10088):2492–2502. Epub 2017 Apr 20. PMID: 28434648; PMCID: PMC7539326.
  • Zhu AX, Finn RS, Edeline J, et al. KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018 July;19(7):940–952. Epub 2018 Jun 3. Erratum in: Lancet Oncol. 2018 Sep;19(9):e440.PMID: 29875066.
  • Kudo M, Finn RS, Edeline J, et al. Updated efficacy and safety of KEYNOTE-224: a phase II study of pembrolizumab (pembro) in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2020;38(4_suppl): 518-518. DOI:https://doi.org/10.1200/JCO.2020.38.4_suppl.518
  • Pinter M, Jain RK, Duda DG. The current landscape of immune checkpoint blockade in hepatocellular carcinoma: a review. JAMA Oncol. 2020 Oct 22. Epub ahead of print. PMID: 33090190. DOI:https://doi.org/10.1001/jamaoncol.2020.3381.
  • Lee MS, Ryoo BY, Hsu CH, et al. Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study. Lancet Oncol. 2020;21(6):808–820.
  • Kelley RK. Atezolizumab plus bevacizumab - a landmark in liver cancer. N Engl J Med. 2020 May 14;382(20):1953–1955. PMID: 32402168.
  • Hato T, Zhu AX, Duda DG. Rationally combining anti-VEGF therapy with checkpoint inhibitors in hepatocellular carcinoma. Immunotherapy. 2016;8(3):299–313. Epub 2016 Feb 11. PMID: 26865127; PMCID: PMC5619018.
  • Park R, Eshrat F, Al-Jumayli M, et al. Immuno-oncotherapeutic approaches in advanced hepatocellular carcinoma. Vaccines (Basel). 2020 Aug 8;8(3):447. PMID: 32784389; PMCID: PMC7563532.
  • Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016 Feb;39(1):98–106. PMID: 26558876; PMCID: PMC4892769.
  • Chen HL, Tu YK, Chang HM, et al. Systematic review and network meta-analysis of immune checkpoint inhibitors in combination with chemotherapy as a first-line therapy for extensive-stage small cell carcinoma. Cancers (Basel). 2020 Dec 3;12(12):E3629. PMID: 33287455.
  • Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020 Nov;5(6):e001079. PMID: 33246931; PMCID: PMC7703447.
  • Boutros C, Tarhini A, Routier E, et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol. 2016 Aug;13(8):473–486. Epub 2016 May 4. PMID: 27141885.
  • Rotte A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res. 2019 June 13;38(1):255. PMID: 31196207; PMCID: PMC6567914.
  • Bergerot P, Lamb P, Wang E, et al. Cabozantinib in combination with immunotherapy for advanced renal cell carcinoma and urothelial carcinoma: rationale and clinical evidence. Mol Cancer Ther. 2019 Dec;18(12):2185–2193. PMID: 31792125.
  • Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1103–1115. Epub 2019 Feb 16. PMID: 30779531; PMCID: PMC6716603.
  • Hegde PS, Wallin JJ, Mancao C. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin Cancer Biol. 2018 Oct;52(Pt 2):117–124. Epub 2017 Dec 8. PMID: 29229461.
  • Cheng AL, Hsu C, Chan SL, et al. Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma. J Hepatol. 2020 Feb;72(2):307–319. PMID: 31954494.
  • Ramjiawan RR, Griffioen AW, Duda DG. Anti-angiogenesis for cancer revisited: is there a role for combinations with immunotherapy? Angiogenesis. 2017 May;20(2):185–204. Epub 2017 Mar 30. PMID: 28361267; PMCID: PMC5439974.
  • Pinato DJ, Guerra N, Fessas P, et al. Immune-based therapies for hepatocellular carcinoma. Oncogene. 2020 Apr;39(18):3620–3637. Epub 2020 Mar 10. PMID: 32157213; PMCID: PMC7190571.
  • Mo DC, Luo PH, Huang SX, et al. Safety and efficacy of pembrolizumab plus lenvatinib versus pembrolizumab and lenvatinib monotherapies in cancers: a systematic review. Int Immunopharmacol. 2020 Dec 16;91:107281.
  • Taylor MH, Lee CH, Makker V, et al. Phase IB/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J Clin Oncol. 2020 Apr 10;38(11):1154–1163. Epub 2020 Jan 21. Erratum in: J Clin Oncol. 2020 Aug 10;38(23):2702.PMID: 31961766; PMCID: PMC7145588.
  • Motzer R, Alekseev B, Rha SY, et al. CLEAR trial investigators. lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289–1300. Epub 2021 Feb 13. PMID: 33616314.
  • Makker V, Rasco D, Vogelzang NJ, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019 May;20(5):711–718. Epub 2019 Mar 25. PMID: 30922731.
  • Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol. 2020 Sept 10;38(26):2981–2992. Epub 2020 Mar 13. PMID: 32167863; PMCID: PMC7479759.
  • Rizzo A, Ricci AD, Brandi G. Recent advances of immunotherapy for biliary tract cancer. Expert Rev Gastroenterol Hepatol. 2021 Jan 8:1–10. Epub ahead of print. PMID: 33215952. DOI:https://doi.org/10.1080/17474124.2021.1853527
  • Kawazoe A, Fukuoka S, Nakamura Y, et al. Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial. Lancet Oncol. 2020 Aug;21(8):1057–1065. Epub 2020 Jun 23. PMID: 32589866.
  • Finn RS, Ikeda M, Zhu AX, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin Oncol. 2020;38(26):2960–2970.
  • Kelley RK, Sangro B, Harris WP, et al. Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab (T) in combination with durvalumab (D) for patients (pts) with advanced hepatocellular carcinoma (aHCC). J Clin Oncol. 2020;38(15_suppl): 4508-4508. DOI:https://doi.org/10.1200/JCO.2020.38.15_suppl.4508
  • Abou-Alfa GK, Chan SL, Furuse J, et al. A randomized, multicenter phase 3 study of durvalumab (D) and tremelimumab (T) as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC): HIMALAYA study. J Clin Oncol. 2018;36:TPS4144.
  • Kudo M, Motomura K, Wada Y, et al. First-line avelumab + axitinib in patients with advanced hepatocellular carcinoma: results from a phase 1b trial (VEGF Liver 100). J Clin Oncol. 2019;37(Suppl. 15):4072.
  • Raybould AL, Sanoff H. Combination antiangiogenic and immunotherapy for advanced hepatocellular carcinoma: evidence to date. J Hepatocell Carcinoma. 2020 Sept 15;7:133–142.
  • Pfister D, Núñez NG, Pinyol R, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021 Apr;592(7854):450–456. Epub 2021 Mar 24. PMID: 33762733; PMCID: PMC8046670.
  • Tamura R, Tanaka T, Akasaki Y, et al. The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: perspectives for therapeutic implications. Med Oncol. 2019 Nov 11;37(1):2. PMID: 31713115.
  • Rahma OE, Hodi FS. The intersection between tumor angiogenesis and immune suppression. Clin Cancer Res. 2019 Sept 15;25(18):5449–5457. Epub 2019 Apr 3. PMID: 30944124.
  • Personeni N, Pressiani T, Rimassa L. Lenvatinib for the treatment of unresectable hepatocellular carcinoma: evidence to date. J Hepatocell Carcinoma. 2019 Jan 31;6:31–39. PMID: 30775342; PMCID: PMC6362912.
  • Cheng H, Sun G, Chen H, et al. Trends in the treatment of advanced hepatocellular carcinoma: immune checkpoint blockade immunotherapy and related combination therapies. Am J Cancer Res. 2019 Aug 1;9(8):1536–1545. PMID: 31497341; PMCID: PMC6726979.
  • Abd El Aziz MA, Facciorusso A, Nayfeh T, et al. Immune Checkpoint Inhibitors for Unresectable Hepatocellular Carcinoma. Vaccines (Basel). 2020 Oct 19;8(4):616. PMID: 33086471; PMCID: PMC7712941.
  • Rizzo A, Ricci AD, Brandi G. Immune-based combinations for advanced hepatocellular carcinoma: shaping the direction of first-line therapy. Future Oncol. 2021 Mar;17(7):755–757. Epub 2021 Jan 29. PMID: 33508960.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.