Research progress on PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

BAI Wenliang , LIU Lei , WANG Guige , ZHANG Jiaqi ,  LI Shanqing

Department of Thoracic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, P.R.China;

Corresponding author：

LI Shanqing, Email: lsq6768@sohu.com

Keywords：

Non-small cell lung cancer; anti-tumor immune effect; programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1); review

DOI：

10.7507/1007-4848.201908027

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) signaling pathway has been found capable of affecting anti-tumor immune effect in many malignancies in recent years. Patients who are diagnosed with advanced non-small cell lung cancer (NSCLC) have considerable responses after receving inhibitors against PD-1/PD-L1. This paper reviews the clinical progress of PD-1/PD-L1 inhibitors in the treatment of NSCLC.

Citation： BAI Wenliang, LIU Lei, WANG Guige, ZHANG Jiaqi, LI Shanqing. Research progress on PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2020, 27(8): 953-959. doi: 10.7507/1007-4848.201908027 Copy

1.	Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2.	Griffin R, Ramirez RA. Molecular targets in non-small cell lung cancer. Ochsner J, 2017, 17(4): 388-392.
3.	Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity, 2013, 39(1): 1-10.
4.	Ceeraz S, Nowak EC, Noelle RJ. B7 family checkpoint regulators in immune regulation and disease. Trends Immunol, 2013, 34(11): 556-563.
5.	Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol, 2008, 26: 677-704.
6.	Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol, 2005, 25(21): 9543-9553.
7.	Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother, 2007, 56(5): 739-745.
8.	Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, et al. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med, 2012, 209(6): 1201-1217.
9.	Patsoukis N, Brown J, Petkova V, et al. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal, 2012, 5(230): 46.
10.	Escors D, Gato-Cañas M, Zuazo M, et al. The intracellular signalosome of PD-L1 in cancer cells. Signal Transduct Target Ther, 2018, 3(1): 1-26.
11.	Rizvi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol, 2015, 16(3): 257-265.
12.	Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med, 2015, 373(2): 123-135.
13.	Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med, 2015, 373(17): 1627-1639.
14.	Horn L, Spigel DR, Vokes EE, et al. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phaseⅢtrials (checkmate 017 and checkmate 057). J Clin Oncol, 2017, 35(35): 3924-3933.
15.	Carbone DP, Reck M, Paz-Ares L, et al. First-line nivolumab in stageⅣor recurrent non-small-cell lung cancer. N Engl J Med, 2017, 376(25): 2415-2426.
16.	Hellmann MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol, 2017, 18(1): 31-41.
17.	Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med, 2018, 378(22): 2093-2104.
18.	Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med, 2015, 372(21): 2018-2028.
19.	Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet, 2016, 387(10027): 1540-1550.
20.	Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med, 2016, 375(19): 1823-1833.
21.	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(10183): 1819-1830.
22.	Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol, 2016, 17(11): 1497-1508.
23.	Borghaei H, Langer CJ, Gadgeel S, et al. 24-month overall survival from KEYNOTE-021 cohort G: Pemetrexed and carboplatin with or without pembrolizumab as first-line therapy for advanced nonsquamous non-small cell lung cancer. J Thorac Oncol, 2019, 14(1): 124-129.
24.	Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med, 2018, 378(22): 2078-2092.
25.	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(21): 2040-2051.
26.	Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature, 2014, 515(7528): 563-567.
27.	Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet, 2016, 387(10030): 1837-1846.
28.	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(10066): 255-265.
29.	Peters S, Gettinger S, Johnson ML, et al. PhaseⅡtrial of atezolizumab as first-line or subsequent therapy for patients with programmed death-ligand 1-selected advanced non-small-cell lung cancer (BIRCH). J Clin Oncol, 2017, 35(24): 2781-2789.
30.	Jotte RM, Cappuzzo F, Vynnychenko I, et al. IMpower 131: primary PFS and safety analysis of a randomized phaseⅢstudy of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. ASCO annual meeting, 2018.
31.	Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med, 2018, 378(24): 2288-2301.
32.	Antonia SJ. Durvalumab after chemoradiotherapy in stageⅢnon-small-cell lung cancer. Reply. N Engl J Med, 2019, 380(10): 990.
33.	Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stageⅢNSCLC. N Engl J Med, 2018, 379(24): 2342-2350.
34.	Planchard D, Yokoi T, McCleod MJ, et al. A PhaseⅢstudy of durvalumab (MEDI4736) with or without tremelimumab for previously treated patients with advanced NSCLC: Rationale and protocol design of the ARCTIC study. Clin Lung Cancer, 2016, 17(3): 232-236.
35.	Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol, 2016, 17(3): 299-308.
36.	Mahoney KM, Atkins MB. Prognostic and predictive markers for the new immunotherapies. Oncology (Williston Park), 2014, 28(3): 39-48.
37.	Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science, 2015, 348(6230): 124-128.
38.	Hellmann MD, Nathanson T, Rizvi H, et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell, 2018, 33(5): 843-852.
39.	许莹. 肿瘤微环境中的树突状细胞. 癌症进展, 2016, 14(2): 118-120.
40.	Lou Y, Diao L, Cuentas ER, et al. Epithelial-mesenchymal transition is associated with a distinct tumor microenvironment including elevation of inflammatory signals and multiple immune checkpoints in lung adenocarcinoma. Clin Cancer Res, 2016, 22(14): 3630-3642.
41.	Akbay EA, Koyama S, Carretero J, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov, 2013, 3(12): 1355-1363.
42.	Chen N, Fang W, Zhan J, et al. Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-driven NSCLC: implication for optional immune targeted therapy for NSCLC patients with EGFR mutation. J Thorac Oncol, 2015, 10(6): 910-923.
43.	Rutledge WC, Kong J, Gao J, et al. Tumor-infiltrating lymphocytes in glioblastoma are associated with specific genomic alterations and related to transcriptional class. Clin Cancer Res, 2013, 19(18): 4951-4960.
44.	Chaudhary B, Elkord E. Regulatory T cells in the tumor microenvironment and cancer progression: role and therapeutic targeting. Vaccines (Basel), 2016, 4(3): pii: E28.
45.	Hu-Lieskovan S, Goldman JW, Han M, et al. High intratumoral T cell infiltration correlated with mutational load and response to pembrolizumab in non-small cell lung cancer. World Conference on Lung Cancer, 2015.
46.	Schalper KA, Brown J, Carvajal-Hausdorf D, et al. Objective measurement and clinical significance of TILs in non-small cell lung cancer. J Natl Cancer Inst, 2015, 107(3): dju435.
47.	Garrido F, Cabrera T, Aptsiauri N. "Hard" and "soft" lesions underlying the HLA classⅠalterations in cancer cells: implications for immunotherapy. Int J Cancer, 2010, 127(2): 249-256.
48.	Taube JM, Anders RA, Young GD, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med, 2012, 4(127): 127ra37.
49.	Grah JJ, Katalinic D, Juretic A, et al. Clinical significance of immunohistochemical expression of cancer/testis tumor-associated antigens (MAGE-A1, MAGE-A3/4, NY-ESO-1) in patients with non-small cell lung cancer. Tumori, 2014, 100(1): 60-68.

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2. Griffin R, Ramirez RA. Molecular targets in non-small cell lung cancer. Ochsner J, 2017, 17(4): 388-392.
3. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity, 2013, 39(1): 1-10.
4. Ceeraz S, Nowak EC, Noelle RJ. B7 family checkpoint regulators in immune regulation and disease. Trends Immunol, 2013, 34(11): 556-563.
5. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol, 2008, 26: 677-704.
6. Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol, 2005, 25(21): 9543-9553.
7. Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother, 2007, 56(5): 739-745.
8. Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, et al. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med, 2012, 209(6): 1201-1217.
9. Patsoukis N, Brown J, Petkova V, et al. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal, 2012, 5(230): 46.
10. Escors D, Gato-Cañas M, Zuazo M, et al. The intracellular signalosome of PD-L1 in cancer cells. Signal Transduct Target Ther, 2018, 3(1): 1-26.
11. Rizvi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol, 2015, 16(3): 257-265.
12. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med, 2015, 373(2): 123-135.
13. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med, 2015, 373(17): 1627-1639.
14. Horn L, Spigel DR, Vokes EE, et al. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phaseⅢtrials (checkmate 017 and checkmate 057). J Clin Oncol, 2017, 35(35): 3924-3933.
15. Carbone DP, Reck M, Paz-Ares L, et al. First-line nivolumab in stageⅣor recurrent non-small-cell lung cancer. N Engl J Med, 2017, 376(25): 2415-2426.
16. Hellmann MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol, 2017, 18(1): 31-41.
17. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med, 2018, 378(22): 2093-2104.
18. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med, 2015, 372(21): 2018-2028.
19. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet, 2016, 387(10027): 1540-1550.
20. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med, 2016, 375(19): 1823-1833.
21. 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(10183): 1819-1830.
22. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol, 2016, 17(11): 1497-1508.
23. Borghaei H, Langer CJ, Gadgeel S, et al. 24-month overall survival from KEYNOTE-021 cohort G: Pemetrexed and carboplatin with or without pembrolizumab as first-line therapy for advanced nonsquamous non-small cell lung cancer. J Thorac Oncol, 2019, 14(1): 124-129.
24. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med, 2018, 378(22): 2078-2092.
25. 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(21): 2040-2051.
26. Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature, 2014, 515(7528): 563-567.
27. Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet, 2016, 387(10030): 1837-1846.
28. 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(10066): 255-265.
29. Peters S, Gettinger S, Johnson ML, et al. PhaseⅡtrial of atezolizumab as first-line or subsequent therapy for patients with programmed death-ligand 1-selected advanced non-small-cell lung cancer (BIRCH). J Clin Oncol, 2017, 35(24): 2781-2789.
30. Jotte RM, Cappuzzo F, Vynnychenko I, et al. IMpower 131: primary PFS and safety analysis of a randomized phaseⅢstudy of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. ASCO annual meeting, 2018.
31. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med, 2018, 378(24): 2288-2301.
32. Antonia SJ. Durvalumab after chemoradiotherapy in stageⅢnon-small-cell lung cancer. Reply. N Engl J Med, 2019, 380(10): 990.
33. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stageⅢNSCLC. N Engl J Med, 2018, 379(24): 2342-2350.
34. Planchard D, Yokoi T, McCleod MJ, et al. A PhaseⅢstudy of durvalumab (MEDI4736) with or without tremelimumab for previously treated patients with advanced NSCLC: Rationale and protocol design of the ARCTIC study. Clin Lung Cancer, 2016, 17(3): 232-236.
35. Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol, 2016, 17(3): 299-308.
36. Mahoney KM, Atkins MB. Prognostic and predictive markers for the new immunotherapies. Oncology (Williston Park), 2014, 28(3): 39-48.
37. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science, 2015, 348(6230): 124-128.
38. Hellmann MD, Nathanson T, Rizvi H, et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell, 2018, 33(5): 843-852.
39. 许莹. 肿瘤微环境中的树突状细胞. 癌症进展, 2016, 14(2): 118-120.
40. Lou Y, Diao L, Cuentas ER, et al. Epithelial-mesenchymal transition is associated with a distinct tumor microenvironment including elevation of inflammatory signals and multiple immune checkpoints in lung adenocarcinoma. Clin Cancer Res, 2016, 22(14): 3630-3642.
41. Akbay EA, Koyama S, Carretero J, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov, 2013, 3(12): 1355-1363.
42. Chen N, Fang W, Zhan J, et al. Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-driven NSCLC: implication for optional immune targeted therapy for NSCLC patients with EGFR mutation. J Thorac Oncol, 2015, 10(6): 910-923.
43. Rutledge WC, Kong J, Gao J, et al. Tumor-infiltrating lymphocytes in glioblastoma are associated with specific genomic alterations and related to transcriptional class. Clin Cancer Res, 2013, 19(18): 4951-4960.
44. Chaudhary B, Elkord E. Regulatory T cells in the tumor microenvironment and cancer progression: role and therapeutic targeting. Vaccines (Basel), 2016, 4(3): pii: E28.
45. Hu-Lieskovan S, Goldman JW, Han M, et al. High intratumoral T cell infiltration correlated with mutational load and response to pembrolizumab in non-small cell lung cancer. World Conference on Lung Cancer, 2015.
46. Schalper KA, Brown J, Carvajal-Hausdorf D, et al. Objective measurement and clinical significance of TILs in non-small cell lung cancer. J Natl Cancer Inst, 2015, 107(3): dju435.
47. Garrido F, Cabrera T, Aptsiauri N. "Hard" and "soft" lesions underlying the HLA classⅠalterations in cancer cells: implications for immunotherapy. Int J Cancer, 2010, 127(2): 249-256.
48. Taube JM, Anders RA, Young GD, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med, 2012, 4(127): 127ra37.
49. Grah JJ, Katalinic D, Juretic A, et al. Clinical significance of immunohistochemical expression of cancer/testis tumor-associated antigens (MAGE-A1, MAGE-A3/4, NY-ESO-1) in patients with non-small cell lung cancer. Tumori, 2014, 100(1): 60-68.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Research progress on PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content