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Current Cancer Drug Targets


ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Systematic Review Article

Efficacy of PD-1 or PD-L1 Inhibitors and Central Nervous System Metastases in Advanced Cancer: A Meta-Analysis

Author(s): Minyong Peng, Shan Li, Hui Xiang, Wen Huang*, Weiling Mao and Di Xu

Volume 21, Issue 9, 2021

Published on: 01 June, 2021

Page: [794 - 803] Pages: 10

DOI: 10.2174/1568009621666210601111811

Price: $65


Background: Little is known about the efficacy of programmed cell death protein-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) inhibitors in patients with central nervous system (CNS) metastases.

Objective: This study aimed to assess the difference in efficacy of PD-1 or PD-L1 inhibitors in patients with and without CNS metastases.

Methods: From inception to March 2020, PubMed and Embase were searched for randomized controlled trials (RCTs) about PD-1 or PD-L1 inhibitors. Only trails with available hazard ratios (HRs) for overall survival (OS) of patients with and without CNS metastases simultaneously would be included. Overall survival hazard ratios and their 95% confidence interval (CI) were calculated, and the efficacy difference between these two groups was assessed in the meantime.

Results: A total of 4988 patients (559 patients with CNS metastases and 4429 patients without CNS metastases) from 8 RCTs were included. In patients with CNS metastases, the pooled HR was 0.76 (95%CI, 0.62 to 0.93), while in patients without CNS metastases, the pooled HR was 0.74 (95%CI, 0.68 to 0.79). There was no significant difference in efficacy between these two groups (χ2=0.06 P=0.80).

Conclusion: With no significant heterogeneity observed between patients with or without CNS metastases, patients with CNS metastases should not be excluded in the PD-1 or PD-L1 blockade therapy. Future research should permit more patients with CNS metastases to engage in PD-1 or PDL1 blockade therapy and explore the safety of PD-1 or PD-L1 inhibitors in patients with CNS metastases.

Keywords: Central nervous system metastases, PD-1/PD-L1 inhibitors, immunotherapy, overall survival, programmed cell death, cell carcinoma.

Graphical Abstract
Topalian, S.L.; Taube, J.M.; Anders, R.A.; Pardoll, D.M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer, 2016, 16(5), 275-287.
[] [PMID: 27079802]
Wolchok, J.D.; Chiarion-Sileni, V.; Gonzalez, R.; Rutkowski, P.; Grob, J.J.; Cowey, C.L.; Lao, C.D.; Wagstaff, J.; Schadendorf, D.; Ferrucci, P.F.; Smylie, M.; Dummer, R.; Hill, A.; Hogg, D.; Haanen, J.; Carlino, M.S.; Bechter, O.; Maio, M.; Marquez-Rodas, I.; Guidoboni, M.; McArthur, G.; Lebbé, C.; Ascierto, P.A.; Long, G.V.; Cebon, J.; Sosman, J.; Postow, M.A.; Callahan, M.K.; Walker, D.; Rollin, L.; Bhore, R.; Hodi, F.S.; Larkin, J. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med., 2017, 377(14), 1345-1356.
[] [PMID: 28889792]
Antonia, S.J.; Villegas, A.; Daniel, D.; Vicente, D.; Murakami, S.; Hui, R.; Kurata, T.; Chiappori, A.; Lee, K.H.; de Wit, M.; Cho, B.C.; Bourhaba, M.; Quantin, X.; Tokito, T.; Mekhail, T.; Planchard, D.; Kim, Y.C.; Karapetis, C.S.; Hiret, S.; Ostoros, G.; Kubota, K.; Gray, J.E.; Paz-Ares, L.; de Castro Carpeño, J.; Faivre-Finn, C.; Reck, M.; Vansteenkiste, J.; Spigel, D.R.; Wadsworth, C.; Melillo, G.; Taboada, M.; Dennis, P.A.; Özgüroğlu, M. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N. Engl. J. Med., 2018, 379(24), 2342-2350.
[] [PMID: 30280658]
Motzer, R.J.; Escudier, B.; McDermott, D.F.; George, S.; Hammers, H.J.; Srinivas, S.; Tykodi, S.S.; Sosman, J.A.; Procopio, G.; Plimack, E.R.; Castellano, D.; Choueiri, T.K.; Gurney, H.; Donskov, F.; Bono, P.; Wagstaff, J.; Gauler, T.C.; Ueda, T.; Tomita, Y.; Schutz, F.A.; Kollmannsberger, C.; Larkin, J.; Ravaud, A.; Simon, J.S.; Xu, L.A.; Waxman, I.M.; Sharma, P. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med., 2015, 373(19), 1803-1813.
[] [PMID: 26406148]
Ferris, R.L.; Blumenschein, G., Jr; Fayette, J.; Guigay, J.; Colevas, A.D.; Licitra, L.; Harrington, K.; Kasper, S.; Vokes, E.E.; Even, C.; Worden, F.; Saba, N.F.; Iglesias Docampo, L.C.; Haddad, R.; Rordorf, T.; Kiyota, N.; Tahara, M.; Monga, M.; Lynch, M.; Geese, W.J.; Kopit, J.; Shaw, J.W.; Gillison, M.L. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N. Engl. J. Med., 2016, 375(19), 1856-1867.
[] [PMID: 27718784]
Cagney, D.N.; Martin, A.M.; Catalano, P.J.; Redig, A.J.; Lin, N.U.; Lee, E.Q.; Wen, P.Y.; Dunn, I.F.; Bi, W.L.; Weiss, S.E.; Haas-Kogan, D.A.; Alexander, B.M.; Aizer, A.A. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro-oncol., 2017, 19(11), 1511-1521.
[] [PMID: 28444227]
Pruitt, AA Epidemiology,treatment, and complications of central nervous system metastases. Continuum (Minneap Minn)., 2017, 23(6), 1580-1600.
Ransohoff, R.M.; Engelhardt, B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat. Rev. Immunol., 2012, 12(9), 623-635.
[] [PMID: 22903150]
Barcia, C.; Curtin, J.; Zirger, J.; Larocque, D. Immunology and the central nervous system. Clin. Dev. Immunol., 2013, 2013, 512684.
[] [PMID: 24489576]
Roth, P.; Preusser, M.; Weller, M. Immunotherapy of brain cancer. Oncol. Res. Treat., 2016, 39(6), 326-334.
[] [PMID: 27260656]
Achrol, A.S.; Rennert, R.C.; Anders, C.; Soffietti, R.; Ahluwalia, M.S.; Nayak, L.; Peters, S.; Arvold, N.D.; Harsh, G.R.; Steeg, P.S.; Chang, S.D. Brain metastases. Nat. Rev. Dis. Primers, 2019, 5(1), 5.
[] [PMID: 30655533]
Borghaei, H.; Paz-Ares, L.; Horn, L.; Spigel, D.R.; Steins, M.; Ready, N.E.; Chow, L.Q.; Vokes, E.E.; Felip, E.; Holgado, E.; Barlesi, F.; Kohlhäufl, M.; Arrieta, O.; Burgio, M.A.; Fayette, J.; Lena, H.; Poddubskaya, E.; Gerber, D.E.; Gettinger, S.N.; Rudin, C.M.; Rizvi, N.; Crinò, L.; Blumenschein, G.R., Jr; Antonia, S.J.; Dorange, C.; Harbison, C.T.; Graf Finckenstein, F.; Brahmer, J.R. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med., 2015, 373(17), 1627-1639.
[] [PMID: 26412456]
Horn, L.; Mansfield, A.S.; Szczęsna, A.; Havel, L.; Krzakowski, M.; Hochmair, M.J.; Huemer, F.; Losonczy, G.; Johnson, M.L.; Nishio, M.; Reck, M.; Mok, T.; Lam, S.; Shames, D.S.; Liu, J.; Ding, B.; Lopez-Chavez, A.; Kabbinavar, F.; Lin, W.; Sandler, A.; Liu, S.V. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N. Engl. J. Med., 2018, 379(23), 2220-2229.
[] [PMID: 30280641]
Louveau, A.; Smirnov, I.; Keyes, T.J.; Eccles, J.D.; Rouhani, S.J.; Peske, J.D.; Derecki, N.C.; Castle, D.; Mandell, J.W.; Lee, K.S.; Harris, T.H.; Kipnis, J. Structural and functional features of central nervous system lymphatic vessels. Nature, 2015, 523(7560), 337-341.
[] [PMID: 26030524]
Louveau, A.; Herz, J.; Alme, M.N.; Salvador, A.F.; Dong, M.Q.; Viar, K.E.; Herod, S.G.; Knopp, J.; Setliff, J.C.; Lupi, A.L.; Da Mesquita, S.; Frost, E.L.; Gaultier, A.; Harris, T.H.; Cao, R.; Hu, S.; Lukens, J.R.; Smirnov, I.; Overall, C.C.; Oliver, G.; Kipnis, J. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nat. Neurosci., 2018, 21(10), 1380-1391.
[] [PMID: 30224810]
Lyle, LT; Lockman, PR; Adkins, CE; Mohammad, AS; Sechrest, E; Hua, E Alterations in pericyte subpopulations are associated with elevated blood-tumor barrier permeability in experimental brain metastasis of breast cancer. Clin. Cancer Res., 2016, 22(21), 5287-5299.
[] [PMID: 27245829]
Connell, J.J.; Chatain, G.; Cornelissen, B.; Vallis, K.A.; Hamilton, A.; Seymour, L.; Anthony, D.C.; Sibson, N.R. Selective permeabilization of the blood-brain barrier at sites of metastasis. J. Natl. Cancer Inst., 2013, 105(21), 1634-1643.
[] [PMID: 24108809]
Nduom, E.K.; Yang, C.; Merrill, M.J.; Zhuang, Z.; Lonser, R.R. Characterization of the blood-brain barrier of metastatic and primary malignant neoplasms. J. Neurosurg., 2013, 119(2), 427-433.
[] [PMID: 23621605]
Gadgeel, S.; Rodríguez-Abreu, D.; Speranza, G.; Esteban, E.; Felip, E.; Dómine, M.; Hui, R.; Hochmair, M.J.; Clingan, P.; Powell, S.F.; Cheng, S.Y.; Bischoff, H.G.; Peled, N.; Grossi, F.; Jennens, R.R.; Reck, M.; Garon, E.B.; Novello, S.; Rubio-Viqueira, B.; Boyer, M.; Kurata, T.; Gray, J.E.; Yang, J.; Bas, T.; Pietanza, M.C.; Garassino, M.C. Updated analysis From KEYNOTE-189: Pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer. J. Clin. Oncol., 2020, 38(14), 1505-1517.
[] [PMID: 32150489]
Liberati, A.; Altman, D.G.; Tetzlaff, J.; Mulrow, C.; Gøtzsche, P.C.; Ioannidis, J.P.; Clarke, M.; Devereaux, P.J.; Kleijnen, J.; Moher, D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med., 2009, 6(7), e1000100.
[] [PMID: 19621070]
Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G.; Group, P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med., 2009, 6(7), e1000097.
[] [PMID: 19621072]
Sterne, J.A.; Sutton, A.J.; Ioannidis, J.P.; Terrin, N.; Jones, D.R.; Lau, J.; Carpenter, J.; Rücker, G.; Harbord, R.M.; Schmid, C.H.; Tetzlaff, J.; Deeks, J.J.; Peters, J.; Macaskill, P.; Schwarzer, G.; Duval, S.; Altman, D.G.; Moher, D.; Higgins, J.P. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ, 2011, 343, d4002.
[] [PMID: 21784880]
Begg, C.B.; Mazumdar, M. Operating characteristics of a rank correlation test for publication bias. Biometrics, 1994, 50(4), 1088-101.
Gadgeel, S.M.; Lukas, R.V.; Goldschmidt, J.; Conkling, P.; Park, K.; Cortinovis, D.; de Marinis, F.; Rittmeyer, A.; Patel, J.D.; von Pawel, J.; O’Hear, C.; Lai, C.; Hu, S.; Ballinger, M.; Sandler, A.; Gandhi, M.; Fehrenbacher, L. Atezolizumab in patients with advanced non-small cell lung cancer and history of asymptomatic, treated brain metastases: Exploratory analyses of the phase III OAK study. Lung Cancer, 2019, 128, 105-112.
[] [PMID: 30642441]
Hellmann, M.D.; Paz-Ares, L.; Bernabe Caro, R.; Zurawski, B.; Kim, S.W.; Carcereny Costa, E.; Park, K.; Alexandru, A.; Lupinacci, L.; de la Mora Jimenez, E.; Sakai, H.; Albert, I.; Vergnenegre, A.; Peters, S.; Syrigos, K.; Barlesi, F.; Reck, M.; Borghaei, H.; Brahmer, J.R.; O’Byrne, K.J.; Geese, W.J.; Bhagavatheeswaran, P.; Rabindran, S.K.; Kasinathan, R.S.; Nathan, F.E.; Ramalingam, S.S. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N. Engl. J. Med., 2019, 381(21), 2020-2031.
[] [PMID: 31562796]
Paz-Ares, L.; Dvorkin, M.; Chen, Y.; Reinmuth, N.; Hotta, K.; Trukhin, D.; Statsenko, G.; Hochmair, M.J.; Özgüroğlu, M.; Ji, J.H.; Voitko, O.; Poltoratskiy, A.; Ponce, S.; Verderame, F.; Havel, L.; Bondarenko, I.; Kazarnowicz, A.; Losonczy, G.; Conev, N.V.; Armstrong, J.; Byrne, N.; Shire, N.; Jiang, H.; Goldman, J.W. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet, 2019, 394(10212), 1929-1939.
[] [PMID: 31590988]
Reck, M; Rodríguez-Abreu, D; Robinson, AG; Hui, R; Csoszi, T; Fülöp, A; Gottfried, M; Peled, N; Tafreshi, A; Cuffe, S; O'Brien, M; Rao, S; Hotta, K; Vandormael, K; Riccio, A; Yang, J; Catherine Pietanza, M; Brahmer, J.R. Updated analysis of KEYNOTE-024: Pembrolizumab versus platinum-based chemotherapy for advanced non–small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J. Clin. Oncol., 2019, 37(7), 537-546.
[] [PMID: 31786121]
Schmid, P.; Rugo, H.S.; Adams, S.; Schneeweiss, A.; Barrios, C.H.; Iwata, H.; Diéras, V.; Henschel, V.; Molinero, L.; Chui, S.Y.; Maiya, V.; Husain, A.; Winer, E.P.; Loi, S.; Emens, L.A. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol., 2020, 21(1), 44-59.
[] [PMID: 31786121]
Negi, N.; Das, B.K. CNS: Not an immunoprivilaged site anymore but a virtual secondary lymphoid organ. Int. Rev. Immunol., 2018, 37(1), 57-68.
[] [PMID: 28961037]
You, H.; Baluszek, S.; Kaminska, B. Supportive roles of brain macrophages in CNS metastases and assessment of new approaches targeting their functions. Theranostics, 2020, 10(7), 2949-2964.
[] [PMID: 32194848]
Di Giacomo, A.M.; Valente, M.; Cerase, A.; Lofiego, M.F.; Piazzini, F.; Calabrò, L.; Gambale, E.; Covre, A.; Maio, M. Immunotherapy of brain metastases: breaking a “dogma”. J. Exp. Clin. Cancer Res., 2019, 38(1), 419.
[] [PMID: 31623643]
Berghoff, A.S.; Fuchs, E.; Ricken, G.; Mlecnik, B.; Bindea, G.; Spanberger, T.; Hackl, M.; Widhalm, G.; Dieckmann, K.; Prayer, D.; Bilocq, A.; Heinzl, H.; Zielinski, C.; Bartsch, R.; Birner, P.; Galon, J.; Preusser, M. Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. OncoImmunology, 2015, 5(1), e1057388.
[] [PMID: 26942067]
Quail, D.F.; Joyce, J.A. The microenvironmental landscape of brain tumors. Cancer Cell, 2017, 31(3), 326-341.
[] [PMID: 28292436]
Ogiya, R.; Niikura, N.; Kumaki, N.; Yasojima, H.; Iwasa, T.; Kanbayashi, C.; Oshitanai, R.; Tsuneizumi, M.; Watanabe, K.I.; Matsui, A.; Fujisawa, T.; Saji, S.; Masuda, N.; Tokuda, Y.; Iwata, H. Comparison of immune microenvironments between primary tumors and brain metastases in patients with breast cancer. Oncotarget, 2017, 8(61), 103671-103681.
[] [PMID: 29262592]
Lockman, P.R.; Mittapalli, R.K.; Taskar, K.S.; Rudraraju, V.; Gril, B.; Bohn, K.A.; Adkins, C.E.; Roberts, A.; Thorsheim, H.R.; Gaasch, J.A.; Huang, S.; Palmieri, D.; Steeg, P.S.; Smith, Q.R. Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin. Cancer Res., 2010, 16(23), 5664-5678.
[] [PMID: 20829328]
Berghoff, A.S.; Ricken, G.; Widhalm, G.; Rajky, O.; Dieckmann, K.; Birner, P.; Bartsch, R.; Höller, C.; Preusser, M. Tumour-infiltrating lymphocytes and expression of programmed death ligand 1 (PD-L1) in melanoma brain metastases. Histopathology, 2015, 66(2), 289-299.
[] [PMID: 25314639]
Ohaegbulam, K.C.; Assal, A.; Lazar-Molnar, E.; Yao, Y.; Zang, X. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol. Med., 2015, 21(1), 24-33.
[] [PMID: 25440090]
Lehrer, E.J.; Peterson, J.; Brown, P.D.; Sheehan, J.P.; Quiñones-Hinojosa, A.; Zaorsky, N.G.; Trifiletti, D.M. Treatment of brain metastases with stereotactic radiosurgery and immune checkpoint inhibitors: An international meta-analysis of individual patient data. Radiother. Oncol., 2019, 130, 104-112.
[] [PMID: 30241791]
Margolin, K.; Ernstoff, M.S.; Hamid, O.; Lawrence, D.; McDermott, D.; Puzanov, I.; Wolchok, J.D.; Clark, J.I.; Sznol, M.; Logan, T.F.; Richards, J.; Michener, T.; Balogh, A.; Heller, K.N.; Hodi, F.S. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol., 2012, 13(5), 459-465.
[] [PMID: 22456429]
Goldberg, S.B.; Gettinger, S.N.; Mahajan, A.; Chiang, A.C.; Herbst, R.S.; Sznol, M.; Tsiouris, A.J.; Cohen, J.; Vortmeyer, A.; Jilaveanu, L.; Yu, J.; Hegde, U.; Speaker, S.; Madura, M.; Ralabate, A.; Rivera, A.; Rowen, E.; Gerrish, H.; Yao, X.; Chiang, V.; Kluger, H.M. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol., 2016, 17(7), 976-983.
[] [PMID: 27267608]
Elias, R.; Giobbie-Hurder, A.; McCleary, N.J.; Ott, P.; Hodi, F.S.; Rahma, O. Efficacy of PD-1 & PD-L1 inhibitors in older adults: a meta-analysis. J. Immunother. Cancer, 2018, 6(1), 26.
[] [PMID: 29618381]
Wallis, C.J.D.; Butaney, M.; Satkunasivam, R.; Freedland, S.J.; Patel, S.P.; Hamid, O.; Pal, S.K.; Klaassen, Z. Association of patient sex with efficacy of immune checkpoint inhibitors and overall survival in advanced cancers: a systematic review and meta-analysis. JAMA Oncol., 2019, 5(4), 529-536.
[] [PMID: 30605213]
Conforti, F.; Pala, L.; Bagnardi, V.; De Pas, T.; Martinetti, M.; Viale, G.; Gelber, R.D.; Goldhirsch, A. Cancer immunotherapy efficacy and patients’ sex: a systematic review and meta-analysis. Lancet Oncol., 2018, 19(6), 737-746.
[] [PMID: 29778737]
Shen, X.; Zhao, B. Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis. BMJ, 2018, 362, k3529.
[] [PMID: 30201790]
Li, S.; Sun, S.; Xiang, H.; Yang, J.; Peng, M.; Gao, Q. Liver metastases and the efficacy of the PD-1 or PD-L1 inhibitors in cancer: a meta-analysis of randomized controlled trials. OncoImmunology, 2020, 9(1), 1746113.
[] [PMID: 32313724]
Matulonis, U.A.; Oza, A.M.; Ho, T.W.; Ledermann, J.A. Intermediate clinical endpoints: a bridge between progression-free survival and overall survival in ovarian cancer trials. Cancer, 2015, 121(11), 1737-1746.
[] [PMID: 25336142]

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