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Reviews on Recent Clinical Trials

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ISSN (Print): 1574-8871
ISSN (Online): 1876-1038

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Perspective

Comparison of Clinical Trial Results of the Recently Approved Immunotherapeutic Drugs for Advanced Biliary Tract Cancers

Author(s): Samayita Das*

Volume 19, Issue 2, 2024

Published on: 29 January, 2024

Page: [81 - 90] Pages: 10

DOI: 10.2174/0115748871276666240123043710

Price: $65

Abstract

The recently approved immunotherapeutic drugs are Keytruda (pembrolizumab) and Imfinzi (durvalumab) for advanced biliary tract cancers that inhibit PD-1 receptor and PD-L1 ligand, respectively. In this perspective, the results of the two clinical trials, i.e., TOPAZ-1 (NCT03875235) and KEYNOTE-966 (NCT04003636), are critically appraised, compared, and discussed to assess the benefits of these two drugs in the context of the treatment of advanced biliary tract cancers with a focus on PD-L1 status and MIS (microsatellite instability) status and therapy responsiveness in the subgroups. Analyzing the PD-L2 status in biliary tract cancer patients can aid in assessing the prognostic value of PD-L2 expression in determining the clinical response and this may aid in appropriate patient stratification.

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[1]
Oneda E, Abu Hilal M, Zaniboni A. Biliary tract cancer: Current medical treatment strategies. Cancers 2020; 12(5): 1237.
[http://dx.doi.org/10.3390/cancers12051237] [PMID: 32423017]
[2]
Jansen H, Pape UF, Utku N. A review of systemic therapy in biliary tract carcinoma. J Gastrointest Oncol 2020; 11(4): 770-89.
[http://dx.doi.org/10.21037/jgo-20-203] [PMID: 32953160]
[3]
Tam VC, Ramjeesingh R, Burkes R, Yoshida EM, Doucette S, Lim HJ. Emerging systemic therapies in advanced unresectable biliary tract cancer: Review and canadian perspective. Curr Oncol 2022; 29(10): 7072-85.
[http://dx.doi.org/10.3390/curroncol29100555] [PMID: 36290832]
[4]
Han Y, Liu D, Li L. PD-1/PD-L1 pathway: Current researches in cancer. Am J Cancer Res 2020; 10(3): 727-42.
[PMID: 32266087]
[5]
Ahmadzadeh M, Johnson LA, Heemskerk B, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 2009; 114(8): 1537-44.
[http://dx.doi.org/10.1182/blood-2008-12-195792] [PMID: 19423728]
[6]
Loke P, Allison JP. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc Natl Acad Sci 2003; 100(9): 5336-41.
[http://dx.doi.org/10.1073/pnas.0931259100] [PMID: 12697896]
[7]
Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 2007; 8(3): 239-45.
[http://dx.doi.org/10.1038/ni1443] [PMID: 17304234]
[8]
Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med 2016; 375(18): 1767-78.
[http://dx.doi.org/10.1056/NEJMra1514296] [PMID: 27806234]
[9]
Yamaguchi H, Hsu JM, Yang WH, Hung MC. Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics. Nat Rev Clin Oncol 2022; 19(5): 287-305.
[http://dx.doi.org/10.1038/s41571-022-00601-9] [PMID: 35132224]
[10]
Wang Y, Du J, Gao Z, et al. Evolving landscape of PD-L2: bring new light to checkpoint immunotherapy. Br J Cancer 2023; 128(7): 1196-207.
[http://dx.doi.org/10.1038/s41416-022-02084-y] [PMID: 36522474]
[11]
Yaman Suleiman DC. Prognostic value of tumor-infiltrating lymphocytes (TILs) and expression of PD-L1 in cholangiocarcinoma. J Clin Oncol 2015; 33(3) (3 suppl): 294.
[http://dx.doi.org/10.1200/jco.2015.333]
[12]
Sabbatino F, Villani V, Yearley JH, et al. PD-L1 and HLA class I antigen expression and clinical course of the disease in intrahepatic cholangiocarcinoma. Clin Cancer Res 2016; 22(2): 470-8.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-0715] [PMID: 26373575]
[13]
Fontugne J, Augustin J, Pujals A, et al. PD-L1 expression in perihilar and intrahepatic cholangiocarcinoma. Oncotarget 2017; 8(15): 24644-51.
[http://dx.doi.org/10.18632/oncotarget.15602] [PMID: 28445951]
[14]
Gani F, Nagarajan N, Kim Y, et al. Program death 1 immune checkpoint and tumor microenvironment: Implications for patients with intrahepatic cholangiocarcinoma. Ann Surg Oncol 2016; 23(8): 2610-7.
[http://dx.doi.org/10.1245/s10434-016-5101-y] [PMID: 27012989]
[15]
Jakubowski CD, Azad NS. Immune checkpoint inhibitor therapy in biliary tract cancer (cholangiocarcinoma). Chin Clin Oncol 2020; 9(1): 2.
[http://dx.doi.org/10.21037/cco.2019.12.10] [PMID: 32008328]
[16]
Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001; 2(3): 261-8.
[http://dx.doi.org/10.1038/85330] [PMID: 11224527]
[17]
Rodig N, Ryan T, Allen JA, et al. Endothelial expression of PD-L1 and PD‐L2 down‐regulates CD8 + T cell activation and cytolysis. Eur J Immunol 2003; 33(11): 3117-26.
[http://dx.doi.org/10.1002/eji.200324270] [PMID: 14579280]
[18]
Yearley JH, Gibson C, Yu N, et al. PD-L2 expression in human tumors: Relevance to anti-PD-1 therapy in cancer. Clin Cancer Res 2017; 23(12): 3158-67.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-1761] [PMID: 28619999]
[19]
Lesterhuis WJ, Punt CJA, Hato SV, et al. Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice. J Clin Invest 2011; 121(8): 3100-8.
[http://dx.doi.org/10.1172/JCI43656] [PMID: 21765211]
[20]
Lesterhuis WJ, Steer H, Lake RA. PD-L2 is predominantly expressed by Th2 cells. Mol Immunol 2011; 49(1-2): 1-3.
[http://dx.doi.org/10.1016/j.molimm.2011.09.014] [PMID: 22000002]
[21]
Messal N, Serriari NE, Pastor S, Nunès JA, Olive D. PD-L2 is expressed on activated human T cells and regulates their function. Mol Immunol 2011; 48(15-16): 2214-9.
[http://dx.doi.org/10.1016/j.molimm.2011.06.436] [PMID: 21752471]
[22]
Matsubara T, Takada K, Azuma K, et al. A clinicopathological and prognostic analysis of PD-L2 expression in surgically resected primary lung squamous cell carcinoma. Ann Surg Oncol 2019; 26(6): 1925-33.
[http://dx.doi.org/10.1245/s10434-019-07257-3] [PMID: 30815803]
[23]
Nakayama Y, Mimura K, Kua LF, et al. Immune suppression caused by PD-L2 expression on tumor cells in gastric cancer. Gastric Cancer 2020; 23(6): 961-73.
[http://dx.doi.org/10.1007/s10120-020-01079-z] [PMID: 32367440]
[24]
Jung HI, Jeong D, Ji S, et al. Overexpression of PD-L1 and PD-L2 is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Res Treat 2017; 49(1): 246-54.
[http://dx.doi.org/10.4143/crt.2016.066] [PMID: 27456947]
[25]
Shin SJ, Jeon YK, Kim PJ, et al. Clinicopathologic analysis of PD-L1 and PD-L2 expression in renal cell carcinoma: Association with oncogenic proteins status. Ann Surg Oncol 2016; 23(2): 694-702.
[http://dx.doi.org/10.1245/s10434-015-4903-7] [PMID: 26464193]
[26]
Zhang Y, Xu J, Hua J, et al. A PD-L2-based immune marker signature helps to predict survival in resected pancreatic ductal adenocarcinoma. J Immunother Cancer 2019; 7(1): 233.
[http://dx.doi.org/10.1186/s40425-019-0703-0] [PMID: 31464648]
[27]
Chervoneva I, Peck AR, Sun Y, et al. High PD-L2 predicts early recurrence of ER-positive breast cancer. JCO Precis Oncol 2023; 7(7): e2100498.
[http://dx.doi.org/10.1200/PO.21.00498] [PMID: 36652667]
[28]
Cancer Genome Atlas Research Network. Integrated genomic and molecular characterization of cervical cancer. Nature 2017; 543(7645): 378-84.
[http://dx.doi.org/10.1038/nature21386] [PMID: 28112728]
[29]
Heij L, Bednarsch J, Tan X, et al. Expression of checkpoint molecules in the tumor microenvironment of intrahepatic cholangiocarcinoma: Implications for immune checkpoint blockade therapy. Cells 2023; 12(6): 851.
[http://dx.doi.org/10.3390/cells12060851] [PMID: 36980192]
[30]
Jeffrey S. Comprehensive genomic profiling of biliary tract cancers to reveal tumor-specific differences and genomic alterations. J Clin Oncol 2015; 33(3)
[31]
Churi CR, Shroff R, Wang Y, et al. Mutation profiling in cholangiocarcinoma: Prognostic and therapeutic implications. PLoS One 2014; 9(12): e115383.
[http://dx.doi.org/10.1371/journal.pone.0115383] [PMID: 25536104]
[32]
Putra J, de Abreu FB, Peterson JD, et al. Molecular profiling of intrahepatic and extrahepatic cholangiocarcinoma using next generation sequencing. Exp Mol Pathol 2015; 99(2): 240-4.
[http://dx.doi.org/10.1016/j.yexmp.2015.07.005] [PMID: 26189129]
[33]
Mody K, Jain P, El-Refai SM, et al. Clinical, genomic, and transcriptomic data profiling of biliary tract cancer reveals subtype-specific immune signatures. JCO Precis Oncol 2022; 6(6): e2100510.
[http://dx.doi.org/10.1200/PO.21.00510] [PMID: 35675577]
[34]
Marcano-Bonilla L, Mohamed EA, Mounajjed T, Roberts LR. Biliary tract cancers: Epidemiology, molecular pathogenesis and genetic risk associations. Chin Clin Oncol 2016; 5(5): 61.
[http://dx.doi.org/10.21037/cco.2016.10.09] [PMID: 27829275]
[35]
Tamai K, Nakamura M, Mizuma M, et al. Suppressive expression of CD 274 increases tumorigenesis and cancer stem cell phenotypes in cholangiocarcinoma. Cancer Sci 2014; 105(6): 667-74.
[http://dx.doi.org/10.1111/cas.12406] [PMID: 24673799]
[36]
Yi M, Jiao D, Xu H, et al. Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors. Mol Cancer 2018; 17(1): 129.
[http://dx.doi.org/10.1186/s12943-018-0864-3] [PMID: 30139382]
[37]
Pietrantonio F, Randon G, Di Bartolomeo M, et al. Predictive role of microsatellite instability for PD-1 blockade in patients with advanced gastric cancer: A meta-analysis of randomized clinical trials. ESMO Open 2021; 6(1): 100036.
[http://dx.doi.org/10.1016/j.esmoop.2020.100036] [PMID: 33460964]
[38]
Hu H, Kang L, Zhang J, et al. Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): A single-centre, parallel-group, non-comparative, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2022; 7(1): 38-48.
[http://dx.doi.org/10.1016/S2468-1253(21)00348-4] [PMID: 34688374]
[39]
Andre T, Amonkar M, Norquist JM, et al. Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): An open-label, randomised, phase 3 trial. Lancet Oncol 2021; 22(5): 665-77.
[http://dx.doi.org/10.1016/S1470-2045(21)00064-4] [PMID: 33812497]
[40]
Diaz LA Jr, Shiu KK, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): Final analysis of a randomised, open-label, phase 3 study. Lancet Oncol 2022; 23(5): 659-70.
[http://dx.doi.org/10.1016/S1470-2045(22)00197-8] [PMID: 35427471]
[41]
Eso Y, Shimizu T, Takeda H, Takai A, Marusawa H. Microsatellite instability and immune checkpoint inhibitors: Toward precision medicine against gastrointestinal and hepatobiliary cancers. J Gastroenterol 2020; 55(1): 15-26.
[http://dx.doi.org/10.1007/s00535-019-01620-7] [PMID: 31494725]
[42]
Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017; 357(6349): 409-13.
[http://dx.doi.org/10.1126/science.aan6733] [PMID: 28596308]
[43]
Zhao P, Li L, Jiang X, Li Q. Mismatch repair deficiency/microsatellite instability-high as a predictor for anti-PD-1/PD-L1 immunotherapy efficacy. J Hematol Oncol 2019; 12(1): 54.
[http://dx.doi.org/10.1186/s13045-019-0738-1] [PMID: 31151482]
[44]
Boilève A, Hilmi M, Smolenschi C, Ducreux M, Hollebecque A, Malka D. Immunotherapy in advanced biliary tract cancers. Cancers 2021; 13(7): 1569.
[http://dx.doi.org/10.3390/cancers13071569] [PMID: 33805461]
[45]
Mody K, Starr J, Saul M, et al. Patterns and genomic correlates of PD-L1 expression in patients with biliary tract cancers. J Gastrointest Oncol 2019; 10(6): 1099-109.
[http://dx.doi.org/10.21037/jgo.2019.08.08] [PMID: 31949927]
[46]
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015; 372(26): 2509-20.
[http://dx.doi.org/10.1056/NEJMoa1500596] [PMID: 26028255]
[47]
Le DT. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. N Engl J Med 2022; 43(8): 1803-12.
[http://dx.doi.org/10.1111/liv.15641]
[48]
Kelley RK, Ueno M, Yoo C, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2023; 401(10391): 1853-65.
[http://dx.doi.org/10.1016/S0140-6736(23)00727-4] [PMID: 37075781]
[49]
Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010; 362(14): 1273-81.
[http://dx.doi.org/10.1056/NEJMoa0908721] [PMID: 20375404]
[50]
Ioka T, Kanai M, Kobayashi S, et al. Randomized phase III study of gemcitabine, cisplatin plus S‐1 versus gemcitabine, cisplatin for advanced biliary tract cancer (KHBO1401 ‐ MITSUBA). J Hepatobiliary Pancreat Sci 2023; 30(1): 102-10.
[http://dx.doi.org/10.1002/jhbp.1219] [PMID: 35900311]
[51]
Piha-Paul SA, Oh DY, Ueno M, et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE ‐158 and KEYNOTE ‐028 studies. Int J Cancer 2020; 147(8): 2190-8.
[http://dx.doi.org/10.1002/ijc.33013] [PMID: 32359091]
[52]
Kim RD, Chung V, Alese OB, et al. A phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer. JAMA Oncol 2020; 6(6): 888-94.
[http://dx.doi.org/10.1001/jamaoncol.2020.0930] [PMID: 32352498]
[53]
de Biasi AR, Villena-Vargas J, Adusumilli PS. Cisplatin-induced antitumor immunomodulation: A review of preclinical and clinical evidence. Clin Cancer Res 2014; 20(21): 5384-91.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-1298] [PMID: 25204552]
[54]
Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G. Mechanism of action of conventional and targeted anticancer therapies: Reinstating immunosurveillance. Immunity 2013; 39(1): 74-88.
[http://dx.doi.org/10.1016/j.immuni.2013.06.014] [PMID: 23890065]
[55]
Wang YJ, Fletcher R, Yu J, Zhang L. Immunogenic effects of chemotherapy-induced tumor cell death. Genes Dis 2018; 5(3): 194-203.
[http://dx.doi.org/10.1016/j.gendis.2018.05.003] [PMID: 30320184]
[56]
Solari JIG, Filippi-Chiela E, Pilar ES, et al. Damage-associated molecular patterns (DAMPs) related to immunogenic cell death are differentially triggered by clinically relevant chemotherapeutics in lung adenocarcinoma cells. BMC Cancer 2020; 20(1): 474.
[http://dx.doi.org/10.1186/s12885-020-06964-5] [PMID: 32456685]
[57]
Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006; 313(5795): 1960-4.
[http://dx.doi.org/10.1126/science.1129139] [PMID: 17008531]
[58]
Jiang X, Wang J, Deng X, et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer 2019; 18(1): 10.
[http://dx.doi.org/10.1186/s12943-018-0928-4] [PMID: 30646912]
[59]
Yi M, Niu M, Xu L, Luo S, Wu K. Regulation of PD-L1 expression in the tumor microenvironment. J Hematol Oncol 2021; 14(1): 10.
[http://dx.doi.org/10.1186/s13045-020-01027-5] [PMID: 33413496]
[60]
Solinas C, Aiello M, Rozali E, Lambertini M, Willard-Gallo K, Migliori E. Programmed cell death-ligand 2: A neglected but important target in the immune response to cancer? Transl Oncol 2020; 13(10): 100811.
[http://dx.doi.org/10.1016/j.tranon.2020.100811] [PMID: 32622310]
[61]
Xue C, Zhu D, Chen L, et al. Expression and prognostic value of PD-L1 and PD-L2 in ovarian cancer. Transl Cancer Res 2019; 8(1): 111-9.
[http://dx.doi.org/10.21037/tcr.2019.01.09] [PMID: 35116740]
[62]
Wang H, Yao H, Li C, et al. PD-L2 expression in colorectal cancer: Independent prognostic effect and targetability by deglycosylation. OncoImmunology 2017; 6(7): e1327494.
[http://dx.doi.org/10.1080/2162402X.2017.1327494] [PMID: 28811964]
[63]
Gao Y, Li S, Xu D, et al. Prognostic value of programmed death-1, programmed death-ligand 1, programmed death-ligand 2 expression, and CD8(+) T cell density in primary tumors and metastatic lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma. Chin J Cancer 2017; 36(1): 61.
[http://dx.doi.org/10.1186/s40880-017-0226-3] [PMID: 28754154]
[64]
Tanaka K, Miyata H, Sugimura K, et al. Negative influence of programmed death‐1‐ligands on the survival of esophageal cancer patients treated with chemotherapy. Cancer Sci 2016; 107(6): 726-33.
[http://dx.doi.org/10.1111/cas.12938] [PMID: 27015293]
[65]
Takamori S, Takada K, Azuma K, et al. Prognostic impact of programmed death-ligand 2 expression in primary lung adenocarcinoma patients. Ann Surg Oncol 2019; 26(6): 1916-24.
[http://dx.doi.org/10.1245/s10434-019-07231-z] [PMID: 30815801]
[66]
Wang Z, Li G, Wang Q, et al. PD-L2 expression is correlated with the molecular and clinical features of glioma, and acts as an unfavorable prognostic factor. OncoImmunology 2019; 8(2): e1541535.
[http://dx.doi.org/10.1080/2162402X.2018.1541535] [PMID: 30713802]
[67]
Shin SJ, Jeon YK, Cho YM, et al. The association between PD-L1 expression and the clinical outcomes to vascular endothelial growth factor-targeted therapy in patients with metastatic clear cell renal cell carcinoma. Oncologist 2015; 20(11): 1253-60.
[http://dx.doi.org/10.1634/theoncologist.2015-0151] [PMID: 26424759]
[68]
Baptista MZ, Sarian LO, Derchain SFM, Pinto GA, Vassallo J. Prognostic significance of PD-L1 and PD-L2 in breast cancer. Hum Pathol 2016; 47(1): 78-84.
[http://dx.doi.org/10.1016/j.humpath.2015.09.006] [PMID: 26541326]
[69]
Derks S, Nason KS, Liao X, et al. Epithelial PD-L2 expression marks barrett’s esophagus and esophageal adenocarcinoma. Cancer Immunol Res 2015; 3(10): 1123-9.
[http://dx.doi.org/10.1158/2326-6066.CIR-15-0046] [PMID: 26081225]
[70]
Oh CR, Kim JE, Hong YS, et al. Phase II study of durvalumab monotherapy in patients with previously treated microsatellite instability‐high/mismatch repair‐deficient orPOLE ‐mutated metastatic or unresectable colorectal cancer. Int J Cancer 2022; 150(12): 2038-45.
[http://dx.doi.org/10.1002/ijc.33966] [PMID: 35179785]

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