Development in immunotherapy of lung cancer_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

LIU Jie , ZHAO Tian , LI Qinchuan ,  CHEN Guohan

Department of Thoracic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, P. R. China;

Corresponding author：

CHEN Guohan, Email: chenguohan0160@126.com

Keywords：

Lung cancer; immunotherapy; immune checkpoint inhibitors; programmed death-1 (PD-1); programmed death-ligand 1 (PD-L1); adverse events; review

DOI：

10.7507/1007-4848.202106016

Video：

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Lung cancer is the leading cause of cancer-related deaths worldwide. Although improvement has been achieved in platinum-based chemotherapy and tyrosine kinase inhibitors-based molecular targeted therapy, they still have limitations. Immunotherapy has recently emerged as a very effective new treatment, and there is now growing enthusiasm in cancer immunotherapy worldwide. We summarized the effects of immune checkpoint inhibitors in clinical trials, and the current status and progress of anti programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) agents in lung cancer treatment. Attention has been paid to finding out the factors which influence the therapeutic effect of anti-PD-1/PD-L1 therapy and reducing the occurrence of adverse events.

Citation： LIU Jie, ZHAO Tian, LI Qinchuan, CHEN Guohan. Development in immunotherapy of lung cancer. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2022, 29(11): 1517-1524. doi: 10.7507/1007-4848.202106016 Copy

1.	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2.	Postmus PE, Kerr KM, Oudkerk M, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol, 2017, 28(suppl_4): Ⅳ1-Ⅳ21.
3.	Alvarez JGB, Otterson GA. Agents to treat BRAF-mutant lung cancer. Drugs Context, 2019, 8: 212566.
4.	Burotto M, Manasanch EE, Wilkerson J, et al. Gefitinib and erlotinib in metastatic non-small cell lung cancer: A meta-analysis of toxicity and efficacy of randomized clinical trials. Oncologist, 2015, 20(4): 400-410.
5.	Sgambato A, Casaluce F, Maione P, et al. Targeted therapies in non-small cell lung cancer: A focus on ALK/ROS1 tyrosine kinase inhibitors. Expert Rev Anticancer Ther, 2018, 18(1): 71-80.
6.	Steven A, Fisher SA, Robinson BW. Immunotherapy for lung cancer. Respirology, 2016, 21(5): 821-833.
7.	Brunet JF, Denizot F, Luciani MF, et al. A new member of the immunoglobulin superfamily-CTLA-4. Nature, 1987, 328(6127): 267-270.
8.	Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science, 1996, 271(5256): 1734-1736.
9.	Fife BT, Pauken KE, Eagar TN, et al. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol, 2009, 10(11): 1185-1192.
10.	Yang B, Liu T, Qu Y, et al. Progresses and perspectives of anti-PD-1/PD-L1 antibody therapy in head and neck cancers. Front Oncol, 2018, 8: 563.
11.	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.
12.	Nivolumab gets FDA nod for bladder cancer. Cancer Discov, 2017, 7(4): OF7.
13.	Hartung T. Utility of the adverse outcome pathway concept in drug development. Expert Opin Drug Metab Toxicol, 2017, 13(1): 1-3.
14.	Yang S, Zhang Z, Wang Q. Emerging therapies for small cell lung cancer. J Hematol Oncol, 2019, 12(1): 47.
15.	Somasundaram A, Burns TF. The next generation of immunotherapy: Keeping lung cancer in check. J Hematol Oncol, 2017, 10(1): 87.
16.	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.
17.	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.
18.	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.
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.	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.
21.	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.
22.	Garassino MC, Cho BC, Kim JH, et al. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): An open-label, single-arm, phase 2 study. Lancet Oncol, 2018, 19(4): 521-536.
23.	Antonia SJ. Durvalumab after chemoradiotherapy in stage Ⅲ non-small-cell lung cancer. Reply. N Engl J Med, 2019, 380(10): 990.
24.	Barlesi F, Vansteenkiste J, Spigel D, et al. Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): An open-label, randomised, phase 3 study. Lancet Oncol, 2018, 19(11): 1468-1479.
25.	Gulley JL, Rajan A, Spigel DR, et al. Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): Dose-expansion cohort of a multicentre, open-label, phase 1b trial. Lancet Oncol, 2017, 18(5): 599-610.
26.	Esposito G, Palumbo G, Carillio G, et al. Immunotherapy in small cell lung cancer. Cancers (Basel), 2020, 12(9): 2522.
27.	Takamori S, Toyokawa G, Takada K, et al. Combination therapy of radiotherapy and anti-PD-1/PD-L1 treatment in non-small-cell lung cancer: A mini-review. Clin Lung Cancer, 2018, 19(1): 12-16.
28.	Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage Ⅲ NSCLC. N Engl J Med, 2018, 379(24): 2342-2350.
29.	Theelen WS, de Jong MC, Baas P. Synergizing systemic responses by combining immunotherapy with radiotherapy in metastatic non-small cell lung cancer: The potential of the abscopal effect. Lung Cancer, 2020, 142: 106-113.
30.	Carbognin L, Pilotto S, Milella M, et al. Differential activity of Nivolumab, Pembrolizumab and MPDL3280A according to the tumor expression of programmed death-ligand-1 (PD-L1): Sensitivity analysis of trials in melanoma, lung and genitourinary cancers. PLoS One, 2015, 10(6): e0130142.
31.	Zhu J, Zhang T, Li J, et al. Association between tumor mutation burden (TMB) and outcomes of cancer patients treated with PD-1/PD-L1 inhibitions: A meta-analysis. Front Pharmacol, 2019, 10: 673.
32.	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.
33.	Hellmann MD, Callahan MK, Awad MM, et al. Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer. Cancer Cell, 2018, 33(5): 853-861.
34.	Wang L, Ma Q, Yao R, et al. Current status and development of anti-PD-1/PD-L1 immunotherapy for lung cancer. Int Immunopharmacol, 2020, 79: 106088.
35.	Oliveira AF, Bretes L, Furtado I. Review of PD-1/PD-L1 inhibitors in metastatic dMMR/MSI-H colorectal cancer. Front Oncol, 2019, 9: 396.
36.	Frigeri M, Meyer P, Banfi C, et al. Immune checkpoint inhibitor-associated myocarditis: A new challenge for cardiologists. Can J Cardiol, 2018, 34(1): 92 e1-e3.
37.	Tarrio ML, Grabie N, Bu DX, et al. PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis. J Immunol, 2012, 188(10): 4876-4884.
38.	Postow MA. Managing immune checkpoint-blocking antibody side effects. Am Soc Clin Oncol Educ Book, 2015: 76-83.
39.	O'Kane GM, Labbé C, Doherty MK, et al. Monitoring and management of immune-related adverse events associated with programmed cell death protein-1 axis inhibitors in lung cancer. Oncologist, 2017, 22(1): 70-80.
40.	Zhang X, Ran Y, Wang K, et al. Incidence and risk of hepatic toxicities with PD-1 inhibitors in cancer patients: A meta-analysis. Drug Des Devel Ther, 2016, 10: 3153-3161.
41.	Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med, 2019, 381(21): 2020-2031.
42.	Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: A comprehensive review. Eur J Cancer, 2016, 54: 139-148.

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2. Postmus PE, Kerr KM, Oudkerk M, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol, 2017, 28(suppl_4): Ⅳ1-Ⅳ21.
3. Alvarez JGB, Otterson GA. Agents to treat BRAF-mutant lung cancer. Drugs Context, 2019, 8: 212566.
4. Burotto M, Manasanch EE, Wilkerson J, et al. Gefitinib and erlotinib in metastatic non-small cell lung cancer: A meta-analysis of toxicity and efficacy of randomized clinical trials. Oncologist, 2015, 20(4): 400-410.
5. Sgambato A, Casaluce F, Maione P, et al. Targeted therapies in non-small cell lung cancer: A focus on ALK/ROS1 tyrosine kinase inhibitors. Expert Rev Anticancer Ther, 2018, 18(1): 71-80.
6. Steven A, Fisher SA, Robinson BW. Immunotherapy for lung cancer. Respirology, 2016, 21(5): 821-833.
7. Brunet JF, Denizot F, Luciani MF, et al. A new member of the immunoglobulin superfamily-CTLA-4. Nature, 1987, 328(6127): 267-270.
8. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science, 1996, 271(5256): 1734-1736.
9. Fife BT, Pauken KE, Eagar TN, et al. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol, 2009, 10(11): 1185-1192.
10. Yang B, Liu T, Qu Y, et al. Progresses and perspectives of anti-PD-1/PD-L1 antibody therapy in head and neck cancers. Front Oncol, 2018, 8: 563.
11. 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.
12. Nivolumab gets FDA nod for bladder cancer. Cancer Discov, 2017, 7(4): OF7.
13. Hartung T. Utility of the adverse outcome pathway concept in drug development. Expert Opin Drug Metab Toxicol, 2017, 13(1): 1-3.
14. Yang S, Zhang Z, Wang Q. Emerging therapies for small cell lung cancer. J Hematol Oncol, 2019, 12(1): 47.
15. Somasundaram A, Burns TF. The next generation of immunotherapy: Keeping lung cancer in check. J Hematol Oncol, 2017, 10(1): 87.
16. 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.
17. 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.
18. 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.
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. 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.
21. 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.
22. Garassino MC, Cho BC, Kim JH, et al. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): An open-label, single-arm, phase 2 study. Lancet Oncol, 2018, 19(4): 521-536.
23. Antonia SJ. Durvalumab after chemoradiotherapy in stage Ⅲ non-small-cell lung cancer. Reply. N Engl J Med, 2019, 380(10): 990.
24. Barlesi F, Vansteenkiste J, Spigel D, et al. Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): An open-label, randomised, phase 3 study. Lancet Oncol, 2018, 19(11): 1468-1479.
25. Gulley JL, Rajan A, Spigel DR, et al. Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): Dose-expansion cohort of a multicentre, open-label, phase 1b trial. Lancet Oncol, 2017, 18(5): 599-610.
26. Esposito G, Palumbo G, Carillio G, et al. Immunotherapy in small cell lung cancer. Cancers (Basel), 2020, 12(9): 2522.
27. Takamori S, Toyokawa G, Takada K, et al. Combination therapy of radiotherapy and anti-PD-1/PD-L1 treatment in non-small-cell lung cancer: A mini-review. Clin Lung Cancer, 2018, 19(1): 12-16.
28. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage Ⅲ NSCLC. N Engl J Med, 2018, 379(24): 2342-2350.
29. Theelen WS, de Jong MC, Baas P. Synergizing systemic responses by combining immunotherapy with radiotherapy in metastatic non-small cell lung cancer: The potential of the abscopal effect. Lung Cancer, 2020, 142: 106-113.
30. Carbognin L, Pilotto S, Milella M, et al. Differential activity of Nivolumab, Pembrolizumab and MPDL3280A according to the tumor expression of programmed death-ligand-1 (PD-L1): Sensitivity analysis of trials in melanoma, lung and genitourinary cancers. PLoS One, 2015, 10(6): e0130142.
31. Zhu J, Zhang T, Li J, et al. Association between tumor mutation burden (TMB) and outcomes of cancer patients treated with PD-1/PD-L1 inhibitions: A meta-analysis. Front Pharmacol, 2019, 10: 673.
32. 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.
33. Hellmann MD, Callahan MK, Awad MM, et al. Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer. Cancer Cell, 2018, 33(5): 853-861.
34. Wang L, Ma Q, Yao R, et al. Current status and development of anti-PD-1/PD-L1 immunotherapy for lung cancer. Int Immunopharmacol, 2020, 79: 106088.
35. Oliveira AF, Bretes L, Furtado I. Review of PD-1/PD-L1 inhibitors in metastatic dMMR/MSI-H colorectal cancer. Front Oncol, 2019, 9: 396.
36. Frigeri M, Meyer P, Banfi C, et al. Immune checkpoint inhibitor-associated myocarditis: A new challenge for cardiologists. Can J Cardiol, 2018, 34(1): 92 e1-e3.
37. Tarrio ML, Grabie N, Bu DX, et al. PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis. J Immunol, 2012, 188(10): 4876-4884.
38. Postow MA. Managing immune checkpoint-blocking antibody side effects. Am Soc Clin Oncol Educ Book, 2015: 76-83.
39. O'Kane GM, Labbé C, Doherty MK, et al. Monitoring and management of immune-related adverse events associated with programmed cell death protein-1 axis inhibitors in lung cancer. Oncologist, 2017, 22(1): 70-80.
40. Zhang X, Ran Y, Wang K, et al. Incidence and risk of hepatic toxicities with PD-1 inhibitors in cancer patients: A meta-analysis. Drug Des Devel Ther, 2016, 10: 3153-3161.
41. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med, 2019, 381(21): 2020-2031.
42. Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: A comprehensive review. Eur J Cancer, 2016, 54: 139-148.

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