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Drug Evaluation

Atezolizumab-bevacizumab plus Y-90 TARE for the treatment of hepatocellular carcinoma: preclinical rationale and ongoing clinical trials

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Pages 361-369 | Received 28 Sep 2021, Accepted 18 Nov 2021, Published online: 01 Dec 2021

References

  • The global cancer observatory cancer fact sheets. 2018. [ cited 2021 Aug 14]. Available from: http://gco.iarc.fr/today
  • Llovet JM, Brú C, Bruix J., et al. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Seminars in Liver Disease. 1999;19(3):329–338. PMID: 10518312.
  • Llovet JM, Bruix J. Novel advancements in the management of hepatocellular carcinoma in 2008. Journal of Hepatology. 2008;48(Suppl 1):S20–37. Epub 2008 Feb 12. PMID: 18304676.
  • EASL clinical practice guidelines: management of hepatocellular carcinoma. Journal of Hepatology. 2018;69(1):182–236.
  • Finn RS, Qin S, Ikeda M, et al. IMbrave150 investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. New England Journal of Medicine. 2020 May 14;382(20):1894–1905. PMID: 32402160.
  • 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.
  • Rizzo A, Dadduzio V, Ricci AD, et al. Lenvatinib plus pembrolizumab: the next frontier for the treatment of hepatocellular carcinoma? Expert Opin Investig Drugs. 2021 Jun 30:1–8. DOI:https://doi.org/10.1080/13543784.2021.1948532. Epub ahead of print. PMID: 34167433.
  • Rizzo A, Ricci AD, Brandi G., et al. Atezolizumab in advanced hepatocellular carcinoma: good things come to those who wait. Immunotherapy. 2021 Jun;13(8):637–644. Epub 2021 Apr 6. PMID: 33820447.
  • Llovet JM, Ricci S, Mazzaferro V, et al. SHARP investigators study group. Sorafenib in advanced hepatocellular carcinoma. New England Journal of Medicine. 2008 July 24;359(4):378–390. PMID: 18650514.
  • 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 Mar 24;391(10126):1163–1173. PMID: 29433850.
  • Vilgrain V, Pereira H, Assenat E, et al. SARAH trial group. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. The Lancet Oncology. 2017 Dec;18(12):1624–1636.
  • Chow PKH, Gandhi M, Tan SB, et al. SIRveNIB: selective internal radiation therapy versus Sorafenib in Asia-Pacific patients with hepatocellular carcinoma. Journal of Clinical Oncology. 2018 Jul1;36(19):1913–1921. Epub 2018 Mar 2. PMID: 29498924.
  • Kennedy AS, Nutting C, Coldwell D, et al. Pathologic response and microdosimetry of (90)Y microspheres in man: review of four explanted whole livers. International Journal of Radiation Oncology*Biology*Physics. 2004 Dec 1;60(5):1552–1563. PMID: 15590187.
  • Cammà C, Schepis F, Orlando A, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology. 2002 Jul;224(1):47–54. PMID: 12091661.
  • Gramenzi A, Golfieri R, Mosconi C, et al. Yttrium-90 radioembolization vs sorafenib for intermediate-locally advanced hepatocellular carcinoma: a cohort study with propensity score analysis. Liver International. 2015 Mar;35(3):1036–1047. Epub 2014 May 20. PMID: 24750853.
  • Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252–264. PMID: 22437870; PMCID: PMC4856023.
  • Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinomapreviously 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). Journal of Clinical Oncology. 2020;38(4_suppl):518.
  • 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 Jun 24;389(10088):2492–2502. Epub 2017 Apr 20. PMID: 28434648; PMCID: PMC7539326.
  • Sangro B, Park J, Finn R, et al. LBA-3 checkMate 459: long-term (minimum follow-up 33.6 months) survival outcomes with nivolumab versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma. Ann Oncol. 2020;31:S241–S242.
  • Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab as second-Line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-Blind, phase III trial. Journal of Clinical Oncology. 2020 Jan 20;38(3):193–202. Epub 2019 Dec 2. PMID: 31790344.
  • Yau T, Kang YK, Kim TY, et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the checkMate 040 randomized clinical trial. JAMA Oncology. 2020 Nov 1;6(11):e204564. Epub 2020 Nov 12. Erratum in: JAMA Oncol. 2021 Jan 1;7(1):140. PMID: 33001135; PMCID: PMC7530824.
  • 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). Journal of Clinical Oncology. 2021;39(3_suppl):267.
  • 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.
  • Rizzo A, Dadduzio V, Ricci AD, et al. Lenvatinib plus pembrolizumab: the next frontier for the treatment of hepatocellular carcinoma? Expert Opin Investig Drugs. Jun 30 2021:1–8. Epub ahead of print. PMID: 34167433. DOI:https://doi.org/10.1080/13543784.2021.1948532.
  • Olsson AK, Dimberg A, Kreuger J, et al. VEGF receptor signalling - in control of vascular function. Nature Reviews Molecular Cell Biology. 2006 May 7;7(5):359–371. PMID: 16633338.
  • Itakura J, Ishiwata T, Shen B, et al. Concomitant over-expression of vascular endothelial growth factor and its receptors in pancreatic cancer. Int J Cancer. 2000 Jan 1;85(1):27–34. PMID: 10585578.
  • Knizetova P, Ehrmann J, Hlobilkova A, et al. Autocrine regulation of glioblastoma cell cycle progression, viability and radioresistance through the VEGF-VEGFR2 (KDR) interplay. Cell Cycle. 2008 Aug 15;7(16):2553–2561. Epub 2008 Aug 12. PMID: 18719373.
  • Bao P, Kodra A, Tomic-Canic M, et al. The role of vascular endothelial growth factor in wound healing. Journal of Surgical Research. 2009 May 15;153(2):347–358. Epub 2008 May 12. PMID: 19027922; PMCID: PMC2728016.
  • Ntellas P, Mavroeidis L, Gkoura S, et al. Old player-New tricks: non angiogenic effects of the VEGF/VEGFR pathway in cancer. Cancers (Basel). 2020 Oct 27;12(11):3145. PMID: 33121034; PMCID: PMC7692709.
  • Chouaib S, Messai Y, Couve S, et al. Hypoxia promotes tumor growth in linking angiogenesis to immune escape. Frontiers in Immunology. 2012 Feb 23;3:21. PMID: 22566905; PMCID: PMC3341970.
  • Théry C, Amigorena S. The cell biology of antigen presentation in dendritic cells. Current Opinion in Immunology. 2001 Feb;13(1):45–51. PMID: 11154916.
  • Gabrilovich DI, Chen HL, Girgis KR, et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nature Medicine. 1996 Oct 2;2(10):1096–1103. Erratum in: Nat Med 1996 Nov;2(11):1267.PMID: 8837607.
  • Gabrilovich D, Ishida T, Oyama T, et al.Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood. 1998 Dec 1;92(11):4150–4166. PMID: 9834220.
  • Oyama T, Ran S, Ishida T, et al. Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol. 1998 Feb 1;160(3):1224–1232. PMID: 9570538.
  • Curiel TJ, Wei S, Dong H, et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nature Medicine. 2003 May 9;9(5):562–567. Epub 2003 Apr 21. PMID: 12704383.
  • Alfaro C, Suarez N, Gonzalez A, et al. Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes. British Journal of Cancer. 2009 Apr 7;100(7):1111–1119. Epub 2009 Mar 10. PMID: 19277038; PMCID: PMC2670006.
  • Osada T, Chong G, Tansik R, et al. The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients. Cancer Immunol Immunother. 2008 Aug;57(8):1115–1124. Epub 2008 Jan 10. PMID: 18193223; PMCID: PMC4110970.
  • Voron T, Colussi O, Marcheteau E, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. Journal of Experimental Medicine. 2015 Feb 9;212(2):139–148. Epub 2015 Jan 19. PMID: 25601652; PMCID: PMC4322048.
  • Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994 Jan 28;76(2):301–314. PMID: 7507411.
  • Griffioen AW, Damen CA, Blijham GH, et al.Tumor angiogenesis is accompanied by a decreased inflammatory response of tumor-associated endothelium. Blood. 1996 Jul 15;88(2):667–673. PMID: 8695814.
  • Hegde PS, Wallin JJ, Mancao C., et al. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Seminars in Cancer Biology. 2018 Oct;52(Pt 2):117–124. Epub 2017 Dec 8. PMID: 29229461.
  • Motz GT, Santoro SP, Wang LP, et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nature Medicine. 2014 Jun;20(6):607–615. Epub 2014 May 4. PMID: 24793239; PMCID: PMC4060245.
  • Dirkx AE, Oude Egbrink MG, Castermans K, et al. Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors. The FASEB Journal. 2006 Apr;20(6):621–630. PMID: 16581970.
  • Wallin JJ, Bendell JC, Funke R, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nature Communications. 2016 Aug 30;7(1):12624. PMID: 27571927; PMCID: PMC5013615.
  • Hodi FS, Lawrence D, Lezcano C, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunology Research. 2014 Jul 2;2(7):632–642. Epub 2014 Apr 21. Erratum in: Cancer Immunol Res. 2014 Sep;2(9):923.PMID: 24838938; PMCID: PMC4306338.
  • Li S, Zhang Q, Hong Y., et al. Tumor vessel normalization: a window to enhancing cancer immunotherapy. Technol Cancer Res Treat. 2020;19:1533033820980116.
  • Huang B, Pan PY, Li Q, et al. Gr-1+CD115+ Immature myeloid suppressor cells mediate the development of tumor-Induced T Regulatory Cells and T-Cell anergy in tumor-Bearing host. Cancer Research. 2006 Jan 15;66(2):1123–1131. PMID: 16424049.
  • Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nature Reviews Immunology. 2009 Mar 9;9(3):162–174. PMID: 19197294; PMCID: PMC2828349.
  • 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.
  • Ren Z, Xu J, Bai Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. The Lancet Oncology. 2021 Jul;22(7):977–990. Epub 2021 Jun 15. Erratum in: Lancet Oncol. 2021 Aug;22(8):e347.PMID: 34143971.
  • Kato Y, Tabata K, Kimura T, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS One. 2019 Feb 27;14(2):e0212513. PMID: 30811474; PMCID: PMC6392299.
  • Torrens L, Montironi C, Puigvehí M, et al. Immunomodulatory effects of lenvatinib plus anti-PD1 in mice and rationale for patient enrichment in hepatocellular carcinoma. Hepatology. 2021 Jun 22;74(5):2652–2669. Epub ahead of print. PMID: 34157147.
  • Vignali DA, Collison LW, Workman CJ., et al. How regulatory T cells work. Nature Reviews Immunology. 2008 Jul 8;8(7):523–532. PMID: 18566595; PMCID: PMC2665249.
  • Kudo M, Matilla A, Santoro A, et al. Checkmate-040: nivolumab (NIVO) in patients (pts) with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B (CPB) status. Journal of Clinical Oncology. 2019;37(4_suppl):327.
  • Den Brok MH, Sutmuller RP, Nierkens S, et al. Efficient loading of dendritic cells following cryo and radiofrequency ablation in combination with immune modulation induces anti-tumour immunity. Br J Cancer. 2006 Oct 9;95(7):896–905. Epub 2006 Sep 5. PMID: 16953240; PMCID: PMC2360548.
  • Formenti SC, Rudqvist NP, Golden E, et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nature Medicine. 2018 Dec;24(12):1845–1851. Epub 2018 Nov 5. PMID: 30397353; PMCID: PMC6286242.
  • Grass GD, Krishna N, Kim S., et al. The immune mechanisms of abscopal effect in radiation therapy. Curr Probl Cancer. 2016 Jan-Feb;40(1):10–24. Epub 2015 Nov 21. PMID: 26612692.
  • Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015 Apr 16;520(7547):373–377. Epub 2015 Mar 9. PMID: 25754329; PMCID: PMC4401634.
  • Formenti SC, Rudqvist NP, Golden E, et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nature Medicine. 2018 Dec;24(12):1845–1851. Epub 2018 Nov 5. PMID: 30397353; PMCID: PMC6286242.
  • Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. Journal of Experimental Medicine. 2006 May 15;203(5):1259–1271. Epub 2006 Apr 24. PMID: 16636135; PMCID: PMC3212727.
  • Reap EA, Roof K, Maynor K, et al. Radiation and stress-induced apoptosis: a role for Fas/Fas ligand interactions. Proc Natl Acad Sci U S A. 1997 May 27;94(11):5750–5755. PMID: 9159145; PMCID: PMC20851.
  • Wattenberg MM, Fahim A, Ahmed MM, et al. Unlocking the combination: potentiation of radiation-induced antitumor responses with immunotherapy. Radiation Research. 2014 Aug;182(2):126–138. Epub 2014 Jun 24. PMID: 24960415; PMCID: PMC4128341.
  • Jagodinsky JC, Jin WJ, Bates AM, et al. Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy. Theranostics. 2021 Apr 15;11(13):6120–6137. PMID: 33995649; PMCID: PMC8120207.
  • Deng L, Liang H, Burnette B, et al. Radiation and anti-PD-L1 antibody combinatorial therapy induces T cell-mediated depletion of myeloid-derived suppressor cells and tumor regression. Oncoimmunology. 2014 Apr 17;3(4):e28499. PMID: 25050217; PMCID: PMC4063144.
  • Golden EB, Pellicciotta I, Demaria S, et al. The convergence of radiation and immunogenic cell death signaling pathways. Frontiers in Oncology. 2012 Aug 7;2:88. PMID: 22891162; PMCID: PMC3413017.
  • Nehs MA, Lin CI, Kozono DE, et al. Necroptosis is a novel mechanism of radiation-induced cell death in anaplastic thyroid and adrenocortical cancers. Surgery. 2011 Dec;150(6):1032–1039. PMID: 22136818.
  • Chew V, Lee YH, Pan L, et al. Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma. Gut. 2019 Feb;68(2):335–346. Epub 2018 Feb 13. PMID: 29440463; PMCID: PMC6352403.
  • Craciun L, de Wind R, Demetter P, et al. Retrospective analysis of the immunogenic effects of intra-arterial locoregional therapies in hepatocellular carcinoma: a rationale for combining selective internal radiation therapy (SIRT) and immunotherapy. BMC Cancer. 2020 Feb 19;20(1):135. PMID: 32075608; PMCID: PMC7032008.
  • Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005 Jan 7;307(5706):58–62. PMID: 15637262.
  • Batchelor TT, Sorensen AG, Di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 2007 Jan;11(1):83–95. PMID: 17222792; PMCID: PMC2748664.
  • Williams KJ, Telfer BA, Shannon AM, et al. Combining radiotherapy with AZD2171, a potent inhibitor of vascular endothelial growth factor signaling: pathophysiologic effects and therapeutic benefit. Molecular Cancer Therapeutics. 2007 Feb 6;6(2):599–606. PMID: 17308057.
  • Buckel L, Advani SJ, Frentzen A, et al. Combination of fractionated irradiation with anti-VEGF expressing vaccinia virus therapy enhances tumor control by simultaneous radiosensitization of tumor associated endothelium. Int J Cancer. 2013 Dec 15;133(12):2989–2999. Epub 2013 Aug 5. PMID: 23729266.
  • Gorski DH, Beckett MA, Jaskowiak NT, et al. Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Research. 1999 Jul 15;59(14):3374–3378. PMID: 10416597.
  • Geng L, Donnelly E, McMahon G, et al. Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Research. 2001 Mar 15;61(6):2413–2419. PMID: 11289107.
  • Harada H, Itasaka S, Kizaka-Kondoh S, et al. The Akt/mTOR pathway assures the synthesis of HIF-1alpha protein in a glucose- and reoxygenation-dependent manner in irradiated tumors. J Biol Chem. 2009 Feb 20;284(8):5332–5342. Epub 2008 Dec 19. PMID: 19098000.
  • Zips D, Eicheler W, Geyer P, et al. Enhanced susceptibility of irradiated tumor vessels to vascular endothelial growth factor receptor tyrosine kinase inhibition. Cancer Research. 2005 Jun 15;65(12):5374–5379. PMID: 15958586.
  • Kanthou C, Tozer G. Targeting the vasculature of tumours: combining VEGF pathway inhibitors with radiotherapy. The British Journal of Radiology. 2019 Jan;92(1093):20180405. Epub 2018 Sep 5. PMID: 30160184; PMCID: PMC6435061.
  • Ang C, Klempner SJ, Ali SM, et al. Prevalence of established and emerging biomarkers of immune checkpoint inhibitor response in advanced hepatocellular carcinoma. Oncotarget. 2019 Jun 18;10(40):4018–4025. PMID: 31258846; PMCID: PMC6592287.
  • Topalian SL, Taube JM, Anders RA, et al. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 2016 May;16(5):275–287. Epub 2016 Apr 15. PMID: 27079802; PMCID: PMC5381938.
  • Harding JJ, Nandakumar S, Armenia J, et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-Generation sequencing for matching patients to targeted and immune therapies. Clinical Cancer Research. 2019 Apr 1;25(7):2116–2126. Epub 2018 Oct 29. PMID: 30373752; PMCID: PMC6689131.
  • Ruiz de Galarreta M, Bresnahan E, Molina-Sánchez P, et al. β-Catenin activation promotes immune escape and resistance to Anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discovery. 2019 Aug 9;9(8):1124–1141. Epub 2019 Jun 11. PMID: 31186238; PMCID: PMC6677618.
  • Macek Jilkova Z, Aspord C, Decaens T., et al. Predictive factors for response to PD-1/PD-L1 checkpoint inhibition in the field of hepatocellular carcinoma: current status and challenges. Cancers (Basel). 2019 Oct 14;11(10):1554. PMID: 31615069; PMCID: PMC6826488.
  • Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-Line treatment of metastatic nonsquamous NSCLC. New England Journal of Medicine. 2018 Jun 14;378(24):2288–2301. Epub 2018 Jun 4. PMID: 29863955.
  • He AR, Kim AY, Toskich BM, et al. A phase II study of atezolizumab (ATEZO) and bevacizumab (Bev) in combination with Y90 TARE in patients (Pts) with hepatocellular carcinoma (HCC). Journal of Clinical Oncology. 2021;39(3_suppl): TPS358–TPS358.

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