Место двойной иммунологической блокады в лечении метастатического немелкоклеточного рака легкого: реальность и перспективы

Юдин Д.И., Лактионов К.К., Лактионова Л.В., Бредер В.В. Место двойной иммунологической блокады в лечении метастатического немелкоклеточного рака легкого: реальность и перспективы. Современная Онкология. 2021; 23 (3): 428–435. DOI: 10.26442/18151434.2021.3.201189

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Yudin DI, Laktionov KK, Laktionova LV, Breder VV. Dual immunological blockade in the treatment of metastatic non-small cell lung cancer: reality and perspectives. Journal of Modern Oncology. 2021; 23 (3): 428–435. DOI: 10.26442/18151434.2021.3.201189

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Аннотация

В настоящее время иммунотерапия является ключевой опцией в лекарственном лечении немелкоклеточного рака легкого. Перед онкологами в реальной клинической практике стоит непростой выбор 1-й линии терапии от моноиммунотерапии до различных комбинированных режимов, включая двойную иммунологическую блокаду PD-1/PD-L1 и CTLA-4. Цель данного обзора – попытка уточнить место двойной иммунологической блокады среди других режимов комбинированного лечения немелкоклеточного рака легкого в настоящее время и возможные перспективы. Позитивные ожидания от двойной иммунотерапии связаны с предположением, что комбинированное использование этих препаратов является синергетическим и может помочь преодолеть резистентность к терапии одним препаратом. В обзоре собрана информация из открытых источников как о текущих исследованиях с двойной иммунологической блокадой, так и о уже полученных результатах по применению комбинации ниволумаба и ипилимумаба, тремелимумаба и дурвалумаба и других препаратов для лечения пациентов с метастатическим немелкоклеточным раком легкого. Использование данного подхода представляется перспективным для возможного преодоления резистентности к моноиммунотерапии анти-PD1/PD-L1-препаратами, особенно в популяции пациентов с низким и негативным PD-L1-статусом.

Ключевые слова: двойная иммунотерапия, метастатический рак легкого, немелкоклеточный рак легкого, анти-PD1, анти-PD-L1, анти-CTLA-4, анти-PD1/CTLA-4

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Nowadays immunotherapy is a crucial option in the treatment of non-small cell lung cancer. There are a lot of actual options of the first-line therapy for the patients with metastatic lung cancer, including dual immunological blockade of PD-1/PD-L1 and CTLA-4 pathways. This review is an attempt to clarify the place of dual immunological blockade now and in the future. The scientific rationale for dual immunotherapy is a possible synergy and overcome resistance to single-drug therapy. The review collected information from open sources, both current studies with dual immunological blockade, and already obtained results of the trials for nivolumab and ipilimumab, tremelimumab and durvalumab, and other combinations for the treatment of patients with metastatic non-small cell lung cancer. This approach is promising for the possible overcoming of resistance to monoimmunotherapy with anti-PD1/PD-L1 antibodies, especially in the population with low and negative PD-L1 status.

Keywords: dual immunotherapy, metastatic lung cancer, non-small cell lung cancer, anti-PD1, anti-PD-L1, anti-CTLA-4, anti-PD1/CTLA-4

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1. Rotte A, D'Orazi G, Bhandaru M. Nobel committee honors tumor immunologists. J Exp Clin Cancer Res. 2018;37(1):262. DOI:10.1186/s13046-018-0937-6
2. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823-33. DOI:10.1056/NEJMoa1606774
3. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378:2078-92. DOI:10.1056/NEJMoa1801005
4. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379:2040-51. DOI:10.1056/NEJMoa1810865
5. Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393:1819-30. DOI:10.1016/S0140-6736(18)32409-7
6. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for firstline treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378:2288-301.
DOI:10.1056/NEJMoa1716948
7. West H, McCleod M, Hussein M, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20:924-37. DOI:10.1016/S1470-2045(19)30167-6
8. Spigel D, de Marinis F, Giaccone G, et al. IMPOWER110: interim overall survival (OS) analysis of a phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (TX) in PD-L1-selected NSCLC. European Society for Medical Oncology 2019 Congress; Barcelona, Spain; Sept 27 – Oct 1, 2019 (Abstr 6256).
9. Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214-8. DOI:10.1038/nature12213
10. Praest P, Liaci AM, Forster F, Wiertz E. New insights into the structure of the MHC class I peptide-loading complex and mechanisms of TAP inhibition by viral immune evasion proteins. Mol Immunol. 2019;113:103-14.
DOI:10.1016/j.molimm.2018.03.020
11. Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014;515(7528):577-81. DOI:10.1038/nature13988
12. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-64. DOI:10.1038/nrc3239
13. Keir ME, Butte MJ, Freeman GJ, et al. Pd-1 and its ligands in tolerance and Immunity. Annu Rev Immunol. 2008;26:677-704. DOI:10.1146/annurev.immunol.26.021607.090331
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DOI:10.1111/j.1600-065X.2008.00662.x
15. Stamper CC, Zhang Y, Tobin JF, et al. Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses. Nature. 2001;410(6828):608-11. DOI:10.1038/35069118
16. Chambers CA, Sullivan TJ, Allison JP. Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity. 1997;7(6):885-95. DOI:10.1016/s1074-7613(00)80406-9
17. Tivol EA, Borriello F, Schweitzer AN, et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3(5):541-7.
DOI:10.1016/1074-7613(95)90125-6
18. Nishimura H, Honjo T. PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol. 2001;22(5):265-8. DOI:10.1016/s1471-4906(01)01888-9
19. Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33(17):1974-82. DOI:10.1200/JCO.2014.59.4358
20. Centanni M, Moes D, Troconiz IF, et al. Clinical pharmacokinetics and pharmacodynamics of immune checkpoint inhibitors. Clin Pharmacokinet. 2019;58(7):835-57. DOI:10.1007/s40262-019-00748-2
21. Wang E, Kang D, Bae KS, et al. Population pharmacokinetic and pharmacodynamic analysis of tremelimumab in patients with metastatic melanoma. J Clin Pharmacol. 2014;54(10):1108-16. DOI:10.1002/jcph.309
22. Peng J, Hamanishi J, Matsumura N, et al. Chemotherapy induces programmed cell death-ligand 1 overexpression via the nuclear factor-kappaB to foster an immunosuppressive tumor microenvironment in ovarian cancer. Cancer Res. 2015;75:5034-45. DOI:10.1158/0008-5472.CAN-14-3098
23. Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 2014;21:15-25. DOI:10.1038/cdd.2013.67
24. Reck M, Ciuleanu T-E, Cobo M, et al. First-line nivolumab (NIVO) plus ipilimumab (IPI) plus two cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients with advanced non-small cell lung cancer (NSCLC): Two-year update from CheckMate 9LA. J Clin Oncol. 2021;39(15):9000. DOI:10.1200/JCO.2021.39.15_suppl.9000
25. Reck M, Ciuleanu T-E, Dols M, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. J Clin Oncol. 2020;38:9501. DOI:10.1200/JCO.2020.38.15_suppl.9501
26. Paz-Ares L, Ciuleanu T-E, Cobo 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(2):198-211. DOI:10.1016/S1470-2045(20)30641-0
27. Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. 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):1505-17. DOI:10.1200/JCO.19.03136
28. Paz-Ares L, Vicente D, Tafreshi A, et al. A randomized, placebo-controlled trial of pembrolizumab plus chemotherapy in patients with metastatic squamous NSCLC: protocol-specified final analysis of KEYNOTE-407. J Thorac Oncol. 2020;15(10):1657-69. DOI:10.1016/j.jtho.2020.06.015
29. Socinski MA, Nishio M, Jotte RM, et al. IMpower150 final overall survival analyses for atezolizumab plus bevacizumab and chemotherapy in first-line metastatic nonsquamous NSCLC. J Thorac Oncol. 2021:S1556-0864(21)02322-4. DOI:10.1016/j.jtho.2021.07.009
30. Jassem J, de Marinis F, Giaccone G, et al. Updated overall survival analysis from impower110: atezolizumab versus platinum-based chemotherapy in treatment-naive programmed death-ligand 1-selected NSCLC. J Thorac Oncol. 2021:S1556‑0864(21)02286-3. DOI:10.1016/j.jtho.2021.06.019
31. Mariamidze E, Mezquita L. ESMO20 YO for YO: highlights on metastatic NSCLC-Keynote 024 update. ESMO Open. 2021;6(1):100022.
DOI:10.1016/j.esmoop.2020.100022
32. Reck M, Rodríguez-Abreu D, Robinson AG, et al. 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):537-46. DOI:10.1200/JCO.18.00149
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Авторы

Д.И. Юдин*1, К.К. Лактионов1,2, Л.В. Лактионова3, В.В. Бредер1

1 ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России, Москва, Россия;
2 ФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России, Москва, Россия;
3 ЗАО «МЦК», Москва, Россия
*yudinden@mail.ru

________________________________________________

Denis I. Yudin*1, Konstantin K. Laktionov1,2, Liudmila V. Laktionova3, Valeriy V. Breder1

1 Blokhin National Medical Research Center of Oncology, Moscow, Russia;
2 Pirogov Russian National Research Medical University, Moscow, Russia;
3 Medical Center on Kolomenskaya, Moscow, Russia
*yudinden@mail.ru

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