Lenalidomide to Reverse Drug Resistance After First-line Treatment of Advanced HCC

Summary

The ORR of the lenvatinib combination (lenvatinib combined with PD-1 inhibitor) was largely similar to that of the "A+T" combination (bevacizumab and atelelizumab). The disease control rate (DCR) for the combination of lenvatinib was 88%, demonstrating the efficacy of lenvatinib in combination with immunotherapy. However, progression to second-line therapy after first-line treatment for advanced HCC still faces many challenges. In our clinical practice and review of the literature, we focused on lenalidomide showing some efficacy in second-line treatment of advanced HCC. Lenalidomide is a new generation derivative of thalidomide, which has dual anti-angiogenic and immunomodulatory anti-tumor effects. Lenalidomide may have the potential to reverse drug resistance and increase the efficacy of synergistic immune-targeted therapy. Based on the preliminary data of its effectiveness in the second-line treatment of advanced HCC alone or in combination with TKI, we propose to conduct a prospective, exploratory, single-arm, open, multicenter phase II clinical study of advanced HCC PD-1 inhibitor in combination with lenvatinib after progression of first-line treatment, to initially evaluate the efficacy and safety of this regimen.

Timeline

Start

2023-06-05

Primary completion

2025-06-05

Completion

2025-10-05

Publications

• Background Finn RS, Ikeda M, Zhu AX, Sung MW, Baron AD, Kudo M, Okusaka T, Kobayashi M, Kumada H, Kaneko S, Pracht M, Mamontov K, Meyer T, Kubota T, Dutcus CE, Saito K, Siegel AB, Dubrovsky L, Mody K, Llovet JM. Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma. J Clin Oncol. 2020 Sep 10;38(26):2960-2970. doi: 10.1200/JCO.20.00808. Epub 2020 Jul 27.
• Background IMbrave150: Exploratory Efficacy and Safety Results in Patients With Hepatocellular Carcinoma Without Macrovascular Invasion or Extrahepatic Spread Treated With Atezolizumab + Bevacizumab or Sorafenib. Gastroenterol Hepatol (N Y). 2021 Nov;17(11 Suppl 6):14-15. No abstract available.
• Background Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, Meinhardt G, Han G; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Jan 7;389(10064):56-66. doi: 10.1016/S0140-6736(16)32453-9. Epub 2016 Dec 6.
• Background Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I, Merle P, Chen Y, Park JW, Blanc JF, Bolondi L, Klumpen HJ, Chan SL, Zagonel V, Pressiani T, Ryu MH, Venook AP, Hessel C, Borgman-Hagey AE, Schwab G, Kelley RK. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med. 2018 Jul 5;379(1):54-63. doi: 10.1056/NEJMoa1717002.
• Background Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, Assenat E, Brandi G, Pracht M, Lim HY, Rau KM, Motomura K, Ohno I, Merle P, Daniele B, Shin DB, Gerken G, Borg C, Hiriart JB, Okusaka T, Morimoto M, Hsu Y, Abada PB, Kudo M; REACH-2 study investigators. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Feb;20(2):282-296. doi: 10.1016/S1470-2045(18)30937-9. Epub 2019 Jan 18.
• Background Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B, Melero I, Kudo M, Hou MM, Matilla A, Tovoli F, Knox JJ, Ruth He A, El-Rayes BF, Acosta-Rivera M, Lim HY, Neely J, Shen Y, Wisniewski T, Anderson J, Hsu C. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA Oncol. 2020 Nov 1;6(11):e204564. doi: 10.1001/jamaoncol.2020.4564. Epub 2020 Nov 12.
• Background Safran H, Charpentier KP, Kaubisch A, Mantripragada K, Dubel G, Perez K, Faricy-Anderson K, Miner T, Eng Y, Victor J, Plette A, Espat J, Bakalarski P, Wingate P, Berz D, Luppe D, Martel D, Rosati K, Aparo S. Lenalidomide for second-line treatment of advanced hepatocellular cancer: a Brown University oncology group phase II study. Am J Clin Oncol. 2015 Feb;38(1):1-4. doi: 10.1097/COC.0b013e3182868c66.
• Background Shao YY, Chen BB, Ou DL, Lin ZZ, Hsu CH, Wang MJ, Cheng AL, Hsu C. Lenalidomide as second-line therapy for advanced hepatocellular carcinoma: exploration of biomarkers for treatment efficacy. Aliment Pharmacol Ther. 2017 Oct;46(8):722-730. doi: 10.1111/apt.14270. Epub 2017 Aug 17.
• Background Richardson P, Anderson K. Immunomodulatory analogs of thalidomide: an emerging new therapy in myeloma. J Clin Oncol. 2004 Aug 15;22(16):3212-4. doi: 10.1200/JCO.2004.05.984. Epub 2004 Jul 12. No abstract available.
• Background Lindner S, Kronke J. The molecular mechanism of thalidomide analogs in hematologic malignancies. J Mol Med (Berl). 2016 Dec;94(12):1327-1334. doi: 10.1007/s00109-016-1450-z. Epub 2016 Aug 5.
• Background Guirguis AA, Ebert BL. Lenalidomide: deciphering mechanisms of action in myeloma, myelodysplastic syndrome and beyond. Curr Opin Cell Biol. 2015 Dec;37:61-7. doi: 10.1016/j.ceb.2015.10.004. Epub 2015 Nov 11.
• Background Nicholas NS, Apollonio B, Ramsay AG. Tumor microenvironment (TME)-driven immune suppression in B cell malignancy. Biochim Biophys Acta. 2016 Mar;1863(3):471-482. doi: 10.1016/j.bbamcr.2015.11.003. Epub 2015 Nov 7.
• Background Chong EA, Ahmadi T, Aqui NA, Svoboda J, Nasta SD, Mato AR, Walsh KM, Schuster SJ. Combination of Lenalidomide and Rituximab Overcomes Rituximab Resistance in Patients with Indolent B-cell and Mantle Cell Lymphomas. Clin Cancer Res. 2015 Apr 15;21(8):1835-42. doi: 10.1158/1078-0432.CCR-14-2221. Epub 2015 Jan 28.

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Indications