The role of immunotherapy in patients with lung cancer and brain metastases: a narrative review of the literature

Submitted: February 25, 2024
Accepted: July 15, 2024
Published: July 26, 2024
Abstract Views: 300
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Worldwide, approximately half of the patients diagnosed with lung cancer (LC) will develop, simultaneously or asynchronously, brain metastases (BMs). The existence of BMs negatively affects the quality of life and constitutes a poor prognostic factor, linked with high mortality. Locoregional therapy with surgery or radiation is, until now, the treatment of choice, especially for symptomatic patients; however, both options are linked to a high complication rate. The question arising here is whether, in asymptomatic patients, the benefit outweighs the risk and whether an alternative method can be used to treat this special category of patients. Over the last decade, immune checkpoint inhibitors (ICIs) have represented a major breakthrough in the field of oncology, and several molecules have been approved as a treatment option for LC. This review tried to analyze the tumor microenvironment of both the primary lung tumor and the BMs in order to evaluate the intracranial activity of ICIs, outline the main challenges of including these agents in the treatment of LC with BMs, highlight the available information from the main clinical trials, and mark the potential positive effect of choosing a combination therapy. In conclusion, it appears that immunotherapy has a positive effect, inhibiting the progression of BMs, but more data should be published specifically for this category of patients.

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Tanoue L, Detterbeck F. Lung cancer: a practical approach to evidence-based clinical evaluation and Management. Amsterdam, Netherlands: Elsevier; 2018.
Gavrilovic IT, Posner JB. Brain Metastases: epidemiology and pathophysiology. J Neuro-Oncol 2005;75:5-14. DOI: https://doi.org/10.1007/s11060-004-8093-6
Lamba N, Kearney RB, Catalano PJ, et al. Population-based estimates of survival among elderly patients with brain metastases. Neuro Oncol 2020;23:661-76. DOI: https://doi.org/10.1093/neuonc/noaa233
NCCN clinical practice guidelines in oncology: (NCCN Guidelines®) for small cell lung cancer. Version 2.2024. National Comprehensive Cancer Network, Inc. 2024.
Ernani V, Stinchcombe TE. Management of brain metastases in non–small-cell lung cancer. J Oncol Pract 2019;15:563-70. DOI: https://doi.org/10.1200/JOP.19.00357
Khan AJ, Dicker AP. On the merits and limitations of whole-brain radiation therapy. J Clin Oncol 2013;31:11-3. DOI: https://doi.org/10.1200/JCO.2012.46.0410
Mulvenna P, Nankivell M, Barton R, et al. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet 2016;388:2004-14. DOI: https://doi.org/10.1016/S0140-6736(16)30825-X
Boire A, Brastianos PK, Garzia L, Valiente M. Brain metastasis. Nat Rev Cancer 2019;20:4-11. DOI: https://doi.org/10.1038/s41568-019-0220-y
NCCN clinical practice guidelines in oncology: (NCCN Guidelines®) for non-small cell lung cancer. Version 2.2024. National Comprehensive Cancer Network, Inc. 2024.
Kim R, Keam B, Kim S, et al. Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: therapeutic implications for immune checkpoint inhibitors. BMC Cancer 2019;19:19. DOI: https://doi.org/10.1186/s12885-018-5214-8
Yang G, Xing L, Sun X. Navigate towards the immunotherapy era: value of immune checkpoint inhibitors in non-small cell lung cancer patients with brain metastases. Front Immunol 2022;13:852811. DOI: https://doi.org/10.3389/fimmu.2022.852811
Wang Y, Chen R, Wa Y, et al. Tumor immune microenvironment and immunotherapy in brain metastasis from non-small cell lung cancer. Front Immunol 2022;13:819451. DOI: https://doi.org/10.3389/fimmu.2022.829451
Lehnardt S. Innate immunity and neuroinflammation in the CNS: the role of microglia in toll‐like receptor‐mediated neuronal injury. Glia 2009;58:253-63. DOI: https://doi.org/10.1002/glia.20928
Kudo Y, Haymaker C, Zhang J, et al. Suppressed immune microenvironment and repertoire in brain metastases from patients with resected non-small-cell lung cancer. Ann Oncol 2019;30:1521-30. DOI: https://doi.org/10.1093/annonc/mdz207
Vilariño N, Bruna J, Bosch-Barrera J, et al. Immunotherapy in NSCLC patients with brain metastases. Understanding brain tumor microenvironment and dissecting outcomes from immune checkpoint blockade in the clinic. Cancer Treat Rev 2020;89:102067. DOI: https://doi.org/10.1016/j.ctrv.2020.102067
Ikarashi D, Okimoto T, Shukuya T, et al. Comparison of tumor microenvironments between primary tumors and brain metastases in patients with NSCLC. JTO Clin Res Rep 2021;2:100230. DOI: https://doi.org/10.1016/j.jtocrr.2021.100230
Li M, Hou X, Sai K, Wu L, et al. Immune suppressive microenvironment in brain metastatic non-small cell lung cancer: comprehensive immune microenvironment profiling of brain metastases versus paired primary lung tumors (GASTO 1060). OncoImmunology 2022;11:2059874. DOI: https://doi.org/10.1080/2162402X.2022.2059874
Hofman P. New insights into the interaction of the immune system with non-small cell lung carcinomas. Transl Lung Cancer Res 2020;9:2199-213. DOI: https://doi.org/10.21037/tlcr-20-178
Tecchio C, Cassatella MA. Neutrophil-derived chemokines on the road to immunity. Semin Immunol 2016;28:119-28. DOI: https://doi.org/10.1016/j.smim.2016.04.003
Peng W, Liu C, Xu C, et al. PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines. Cancer Res 2012;72:5209-18. DOI: https://doi.org/10.1158/0008-5472.CAN-12-1187
Mansfield AS, Aubry MC, Moser JC, et al. Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer. Ann Oncol 2016;27:1953-8. DOI: https://doi.org/10.1093/annonc/mdw289
Camy F, Karpathiou G, Dumollard JM, et al. Brain metastasis PD-L1 and CD8 expression is dependent on primary tumor type and its PD-L1 and CD8 status. J Immunother Cancer 2020;8:e000597. DOI: https://doi.org/10.1136/jitc-2020-000597
Pezzuto A, Carico E. Role of HIF-1 in cancer progression: novel insights. A review. Curr Mol Med 2019;18:343-51. DOI: https://doi.org/10.2174/1566524018666181109121849
Levallet J, Biojout T, Bazille C, et al. Hypoxia-induced activation of NDR2 underlies brain metastases from non-small cell lung cancer. Cell Death Dis 2023;14:823. DOI: https://doi.org/10.1038/s41419-023-06345-3
Parakh S, Park JJ, Mendis S, et al. Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases. Br J Cancer 2017;116:1558-63. DOI: https://doi.org/10.1038/bjc.2017.142
Goldberg SB, Schalper KA, Gettinger SN, et al. Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. Lancet Oncol 2020;21:655-63. DOI: https://doi.org/10.1016/S1470-2045(20)30111-X
Mansfield AS, Herbst RS, de Castro G, et al. Outcomes with pembrolizumab monotherapy in patients with programmed death-ligand 1–positive NSCLC with brain metastases: pooled analysis of KEYNOTE-001, 010, 024, and 042. JTO Clin Res Rep 2021;2:100205. DOI: https://doi.org/10.1016/j.jtocrr.2021.100205
Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017;389:255-65. DOI: https://doi.org/10.1016/S0140-6736(16)32517-X
Gadgeel SM, Lukas RV, Goldschmidt J, et al. 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;128:105-12. DOI: https://doi.org/10.1016/j.lungcan.2018.12.017
Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N Eng J Med 2015;373:123-35. DOI: https://doi.org/10.1056/NEJMoa1504627
Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Eng J Med 2015;373:1627-39. DOI: https://doi.org/10.1056/NEJMoa1507643
Cortinovis D, Chiari R, Catino A, et al. Italian cohort of the nivolumab EAP in squamous NSCLC: efficacy and safety in patients with CNS metastases. Anticancer Res 2019;39:4265-71. DOI: https://doi.org/10.21873/anticanres.13590
Crinò L, Bronte G, Bidoli P, et al. Nivolumab and brain metastases in patients with advanced non-squamous non-small cell lung cancer. Lung Cancer 2019;129:35-40. DOI: https://doi.org/10.1016/j.lungcan.2018.12.025
Sun L, Davis CW, Hwang W-T, et al. Outcomes in patients with non–small-cell lung cancer with brain metastases treated with pembrolizumab-based therapy. Clin Lung Cancer 2021;22:58-66.e3. DOI: https://doi.org/10.1016/j.cllc.2020.10.017
Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus Ipilimumab in advanced non–small-cell lung cancer. N Eng J Med 2019;381:2020-31. DOI: https://doi.org/10.1056/NEJMoa1910231
Paz-Ares LG, Ramalingam SS, Ciuleanu T-E, et al. First-line nivolumab plus ipilimumab in advanced NSCLC: 4-year outcomes from the randomized, open-label, phase 3 CheckMate 227 part 1 trial. J Thorac Oncol 2022;17:289-308. DOI: https://doi.org/10.1016/j.jtho.2021.09.010
Borghaei H, Pluzanski A, Caro RB, et al. Abstract CT221: nivolumab (NIVO) + ipilimumab (IPI) as first-line (1L) treatment for patients with advanced non-small cell lung cancer (NSCLC) with brain metastases: Results from CheckMate 227. Cancer Res 2020;80:CT221. DOI: https://doi.org/10.1158/1538-7445.AM2020-CT221
Reck M, Ciuleanu T-E, Lee J-S, et al. Systemic and intracranial outcomes with first-line nivolumab plus ipilimumab in patients with metastatic NSCLC and baseline brain metastases from CheckMate 227 part 1. J Thorac Oncol 2023;18:1055-69. DOI: https://doi.org/10.1016/j.jtho.2023.04.021
Ready NE, Audigier-Valette C, Goldman JW, et al. First-line nivolumab plus ipilimumab for metastatic non-small cell lung cancer, including patients with ECOG performance status 2 and other special populations: CheckMate 817. J Immunother Cancer 2023;11:e006127. DOI: https://doi.org/10.1136/jitc-2022-006127
Buriolla S, Pelizzari G, Corvaja C, et al. Immunotherapy in NSCLC patients with brain metastases. Int J Mol Sci 2022;23:7068. DOI: https://doi.org/10.3390/ijms23137068
Mathew M, Enzler T, Shu CA, Rizvi NA. Combining chemotherapy with PD-1 blockade in NSCLC. Pharmacol Ther 2018;186:130-7. DOI: https://doi.org/10.1016/j.pharmthera.2018.01.003
Awad MM, Gadgeel SM, Borghaei H et al. Long-term overall survival from KEYNOTE-021 cohort G: pemetrexed and carboplatin with or without pembrolizumab as first-line therapy for advanced nonsquamous NSCLC. J Thorac Oncol 2021;16:162-8. DOI: https://doi.org/10.1016/j.jtho.2020.09.015
Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Eng J Med 2018;378:2078-92. DOI: https://doi.org/10.1056/NEJMoa1801005
Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer. N Eng J Med 2018;379:2040-51. DOI: https://doi.org/10.1056/NEJMoa1810865
Facchinetti F, Di Maio M, Perrone F, Tiseo M. First-line immunotherapy in non-small cell lung cancer patients with poor performance status: a systematic review and meta-analysis. Transl Lung Cancer Res 2021;10:2917-36. DOI: https://doi.org/10.21037/tlcr-21-15
Paz-Ares L, Ciuleanu T-E, Cobo M, Schenker M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:198-211. DOI: https://doi.org/10.1016/S1470-2045(20)30641-0
Carbone D, Ciuleanu T, Cobo M, et al. OA09.01 first-line nivolumab + ipilimumab + chemo in patients with advanced NSCLC and brain metastases: results from CheckMate 9LA. J Thorac Oncol 2021;16:S862. DOI: https://doi.org/10.1016/j.jtho.2021.08.061
Nadal E, Rodríguez-Abreu D, Simó M, et al. Phase II trial of atezolizumab combined with carboplatin and pemetrexed for patients with advanced nonsquamous non–small-cell lung cancer with untreated brain metastases (Atezo-Brain, GECP17/05). J Clin Oncol 2023;41:4478-85. DOI: https://doi.org/10.1200/JCO.22.02561
Weichselbaum RR, Liang H, Deng L, Fu Y-X. Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol 2017;14:365-79. DOI: https://doi.org/10.1038/nrclinonc.2016.211
Yu S, Zhang S, Xu H, et al. Organ-specific immune checkpoint inhibitor treatment in lung cancer: a systematic review and meta-analysis. BMJ Open 2023;13:e059457. DOI: https://doi.org/10.1136/bmjopen-2021-059457
Chen Z, Duan X, Qiao S, Zhu X. Radiotherapy combined with PD‐1/PD‐L1 inhibitors in NSCLC brain metastases treatment: the mechanisms, advances, opportunities, and challenges. Cancer Medicine 2022;12:995-1006. DOI: https://doi.org/10.1002/cam4.5016
Wong P, Masucci L, Florescu M, et al. Phase II multicenter trial combining nivolumab and radiosurgery for NSCLC and RCC brain metastases. Neurooncol Adv 2023;5:vdad018. DOI: https://doi.org/10.1093/noajnl/vdad018
Altan M, Wang Y, Song J, et al. Nivolumab and ipilimumab with concurrent stereotactic radiosurgery for intracranial metastases from non-small cell lung cancer: analysis of the safety cohort for non-randomized, open-label, phase I/II trial. J Immunother Cancer 2023;11:e006871. DOI: https://doi.org/10.1136/jitc-2023-006871corr1
Chen L, Douglass J, Walker AJ, et al. Concurrent immunotherapy and stereotactic radiosurgery for brain metastases is associated with a decreased incidence of new intracranial metastases. Int J Radiat Oncol Biol Phys 2015;93:E102. DOI: https://doi.org/10.1016/j.ijrobp.2015.07.807
Schapira E, Hubbeling H, Yeap BY, et al. Improved overall survival and locoregional disease control with concurrent PD-1 pathway inhibitors and stereotactic radiosurgery for lung cancer patients with brain metastases. Int J Radiat Oncol Biol Phys 2018;101:624-9. DOI: https://doi.org/10.1016/j.ijrobp.2018.02.175
Scoccianti S, Olmetto E, Pinzi V, et al. Immunotherapy in association with stereotactic radiotherapy for non-small cell lung cancer brain metastases: results from a multicentric retrospective study on behalf of AIRO. Neuro Oncol 2021;23:1750-64. DOI: https://doi.org/10.1093/neuonc/noab129
Billena C, Lobbous M, Cordova CA, et al. The role of targeted therapy and immune therapy in the management of non-small cell lung cancer brain metastases. Front Oncol 2023;13:1110440. DOI: https://doi.org/10.3389/fonc.2023.1110440
Vogelbaum MA, Brown PD, Messersmith H, et al. Treatment for brain metastases: ASCO-SNO-ASTRO guideline. J Clin Oncol 2022;40:492-516. DOI: https://doi.org/10.1200/JCO.21.02314
Zhou S, Ren F, Meng X. Efficacy of immune checkpoint inhibitor therapy in EGFR mutation-positive patients with NSCLC and brain metastases who have failed EGFR-TKI therapy. Front Immunol 2022;13:955944. DOI: https://doi.org/10.3389/fimmu.2022.955944
Sabari JK, Velcheti V, Shimizu K, et al. Activity of adagrasib (MRTX849) in brain metastases: preclinical models and clinical data from patients with KRASG12C-mutant non–small cell lung cancer. Clin Cancer Res 2022;28:3318-28. DOI: https://doi.org/10.1158/1078-0432.CCR-22-0383
Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in non–small-cell lung cancer harboring a KRASG12C mutation. N Eng J Med 2022;387:120-31. DOI: https://doi.org/10.1056/NEJMoa2204619
Jänne PA, Smit EF, de Marinis F, Laskin J, et al. LBA4 preliminary safety and efficacy of adagrasib with pembrolizumab in treatment-naïve patients with advanced non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. IOTECH 2022;16:100360. DOI: https://doi.org/10.1016/j.iotech.2022.100360
Lauko A, Kotecha R, Barnett A, et al. Impact of KRAS mutation status on the efficacy of immunotherapy in lung cancer brain metastases. Sci Rep 2021;11:18174. DOI: https://doi.org/10.1038/s41598-021-97566-z
Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Eng J Med 2018;379:2220-9. DOI: https://doi.org/10.1056/NEJMoa1809064
Paz-Ares L, Chen Y, Reinmuth N, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN. ESMO Open 2022;7:100408. DOI: https://doi.org/10.1016/j.esmoop.2022.100408
Chang J, Jing X, Hua Y, et al. Programmed cell death 1 pathway inhibitors improve the overall survival of small cell lung cancer patients with brain metastases. J Cancer Res Clin Oncol 2023;149:1825-33. DOI: https://doi.org/10.1007/s00432-022-04121-y
Planchard D, Popat S, Kerr K, et al. Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29:iv192-237. DOI: https://doi.org/10.1093/annonc/mdy275
Sholl LM. Biomarkers of response to checkpoint inhibitors beyond PD-L1 in lung cancer. Mod Pathol 2022;35:66-74. DOI: https://doi.org/10.1038/s41379-021-00932-5
Ng Kee Kwong F, Laggner U, McKinney O, et al. Expression of PD‐L1 correlates with pleomorphic morphology and histological patterns of non‐small‐cell lung carcinomas. Histopathology 2018;72:1024-32. DOI: https://doi.org/10.1111/his.13466
Heymann JJ, Bulman WA, Swinarski D, et al. PD‐L1 expression in non‐small cell lung carcinoma: Comparison among cytology, small biopsy, and surgical resection specimens. Cancer Cytopathol 2017;125:896-907. DOI: https://doi.org/10.1002/cncy.21937
Brozos-Vázquez EM, Rodríguez-López C, Cortegoso-Mosquera A, et al. Immunotherapy in patients with brain metastasis: advances and challenges for the treatment and the application of circulating biomarkers. Front Immunol 2023;14:1221113. DOI: https://doi.org/10.3389/fimmu.2023.1221113
Mino-Kenudson M, Schalper K, Cooper W, et al. Predictive biomarkers for immunotherapy in lung cancer: perspective from the International Association for the Study of Lung Cancer Pathology committee. J Thorac Oncol 2022;17:1335-54. DOI: https://doi.org/10.1016/j.jtho.2022.09.109
Miao K, Zhang X, Wang H, et al. Peripheral blood lymphocyte subsets predict the efficacy of immune checkpoint inhibitors in non–small cell lung cancer. Front Immunol 2022;13:912180. DOI: https://doi.org/10.3389/fimmu.2022.1111230
Liu S, Zhao L, Zhou G. Peripheral blood markers predict immunotherapeutic efficacy in patients with advanced non-small cell lung cancer: a multicenter study. Front Genet 2022;13:1016085. DOI: https://doi.org/10.3389/fgene.2022.1016085
Rossi E, Aieta M, Tartarone A, et al. A fully automated assay to detect the expression of pan-cytokeratins and of EML4-ALK fusion protein in circulating tumour cells (CTCs) predicts outcome of non-small cell lung cancer (NSCLC) patients. Transl Lung Cancer Res 2021;10:80-92. DOI: https://doi.org/10.21037/tlcr-20-855
Rossi G, Pezzuto A, Sini C, et al. Concomitant medications during immune checkpoint blockage in cancer patients: novel insights in this emerging clinical scenario. Crit Rev Oncol Hematol 2019;142:26-34. DOI: https://doi.org/10.1016/j.critrevonc.2019.07.005
Ricciuti B, Dahlberg SE, Adeni A, et al. Immune checkpoint inhibitor outcomes for patients with non–small-cell lung cancer receiving baseline corticosteroids for palliative versus nonpalliative indications. J Clin Oncol 2019;37:1927-34. DOI: https://doi.org/10.1200/JCO.19.00189
Jia W, Gao Q, Han A, Zhu H, Yu J. The potential mechanism, recognition and clinical significance of tumor pseudoprogression after immunotherapy. Cancer Biol Med 2019;16:655-70. DOI: https://doi.org/10.20892/j.issn.2095-3941.2019.0144
Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 2017;18:e143-52. DOI: https://doi.org/10.1016/S1470-2045(17)30074-8

How to Cite

Eleftheriadou, Eleni D., Maria Saroglou, Nikolaos Syrigos, Ellias Kotteas, and Marousa Kouvela. 2024. “The Role of Immunotherapy in Patients With Lung Cancer and Brain Metastases: A Narrative Review of the Literature”. Monaldi Archives for Chest Disease, July. https://doi.org/10.4081/monaldi.2024.2967.

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