Research progress in perioperative immunotherapy for non-small cell lung cancer_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

XU Yuanyuan , MAO Feng , CHEN Xiaoke , TAN Qiang ,  LUO Qingquan

Department of Oncology Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 200030, P. R. China;

Corresponding author：

LUO Qingquan, Email: luoqingquan@hotmail.com

Keywords：

Immunotherapy; non-small cell lung cancer; perioperative stage; review

DOI：

10.7507/1007-4848.202401032

Video：

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It is very limited that the benefit of perioperative chemotherapy in early non-small cell lung cancer (NSCLC), and the 5-year survival rate is only 5% higher than surgery. Antibodies that block programmed cell death protein 1/programmed death receptor-ligand 1 significantly improve the survival of advanced NSCLC. The value of immunotherapy in early NSCLC is also being explored. This paper firstly summarized and analyzed the progress of immunotherapy in the perioperative period of NSCLC. Secondly, the safety and feasibility of surgical resection after neoadjuvant immunotherapy were discussed. Finally, the clinical value of different therapeutic efficacy prediction indicators was summarized, in order to clarify the current status of immunotherapy in the perioperative period, so as to improve the clinical benefits of early NSCLC patients.

1.	Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin, 2022, 72(1): 7-33.
2.	Uramoto H, Tanaka F. Recurrence after surgery in patients with NSCLC. Transl Lung Cancer Res, 2014, 3(4): 242-249.
3.	Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: A pooled analysis by the LACE Collaborative Group. J Clin Oncol, 2008, 26(21): 3552-3559.
4.	NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small-cell lung cancer: A systematic review and meta-analysis of individual participant data. Lancet, 2014, 383(9928): 1561-1571.
5.	Nasser NJ, Gorenberg M, Agbarya A. First line immunotherapy for non-small cell lung cancer. Pharmaceuticals (Basel), 2020, 13(11): 373.
6.	Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stageⅢnon-small-cell lung cancer. N Engl J Med, 2017, 377(20): 1919-1929.
7.	Qiu B, Guo W, Zhang F, et al. Dynamic recurrence risk and adjuvant chemotherapy benefit prediction by ctDNA in resected NSCLC. Nat Commun, 2021, 12(1): 6770.
8.	Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage ⅠB-ⅢA non-small-cell lung cancer (IMpower010): A randomised, multicentre, open-label, phase 3 trial. Lancet, 2021, 398(10308): 1344-1357.
9.	Wakelee H, Altorki N, Felip E, et al. PL03.09 IMpower010: Overall survival interim analysis of a phaseⅢ study of Atezolizumab vs. best supportive care in resected NSCLC. J Thorac Oncol, 2022, 17(9): S2.
10.	O'Brien M, Paz-Ares L, Marreaud S, et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage ⅠB-ⅢA non-small-cell lung cancer (PEARLS/KEYNOTE-091): An interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol, 2022, 23(10): 1274-1286.
11.	https://www.clinicaltrials.gov/.
12.	Sauer R, Liersch T, Merkel S, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: Results of the German CAO/ARO/AIO-94 randomized phase Ⅲtrial after a median follow-up of 11 years. J Clin Oncol, 2012, 30(16): 1926-1933.
13.	Zhang X, Wu T, Cai X, et al. Neoadjuvant immunotherapy for MSI-H/dMMR locally advanced colorectal cancer: New strategies and unveiled opportunities. Front Immunol, 2022, 13: 795972.
14.	Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med, 2018, 378(21): 1976-1986.
15.	Wislez M, Mazieres J, Lavole A, et al. Neoadjuvant durvalumab for resectable non-small-cell lung cancer (NSCLC): Results from a multicenter study (IFCT-1601 IONESCO). J Immunother Cancer, 2022, 10(10): e005636.
16.	Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med, 2022, 386(21): 1973-1985.
17.	Ford PM, Spicer J, Lu S, et al. Abstract CT003: Nivolumab (NIVO)+platinum-doublet chemotherapy (chemo) vs. chemo as neoadjuvant treatment (tx) for resectable (ⅠB-ⅢA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial. Cancer Res, 2021, 81 (13_Supplement): CT003.
18.	Cascone T, William WN, Weissferdt A, et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: The phase 2 randomized NEOSTAR trial. Nat Med, 2021, 27(3): 504-514.
19.	Spicer J, Cascone T, Kar G, et al. 929MO: Platform study of neoadjuvant durvalumab (D) alone or combined with novel agents in patients (pts) with resectable, early-stage non-small cell lung cancer (NSCLC): Pharmacodynamic correlates and circulating tumor DNA (ctDNA) dynamics in the NeoCOAST study. Ann Oncol, 2022, 33(Suppl_7): S427-S437.
20.	Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): An open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol, 2020, 21(11): 1413-1422.
21.	Mariano PP, Ernest N, Jose LGL, et al. Nivolumab+chemotherapy versus chemotherapy as neoadjuvant treatment for resectable stage ⅢA NSCLC: Primary endpoint results of pathological complete response (pCR) from phaseⅡ NADIMⅡ trial. J Clin Oncol, 2020: 8501.
22.	Romero A, Serna R, Nadal E, et al. MA06.03: Pre-treatment ctDNA levels significantly predicts of OS and PFS in NADIMⅡ trial. J Thorac Oncol, 2022, 17(9): S63.
23.	Rothschild SI, Zippelius A, Eboulet EI, et al. SAKK 16/14: Durvalumab in addition to neoadjuvant chemotherapy in patients with stageⅢA(N2) non-small-cell lung cancer: A multicenter single-arm phaseⅡtrial. J Clin Oncol, 2021, 39(26): 2872-2880.
24.	Zhao J, Zhao L, Guo W, et al. Efficacy, safety, and biomarker analysis of neoadjuvant camrelizumab and apatinib in patients with resectable NSCLC: A phase 2 clinical trial. J Thorac Oncol, 2023, 18(6): 780-791.
25.	Cascone T, Awad MM, Spicer JD, et al. LBA1-CheckMate 77T: Phase Ⅲstudy comparing neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) vs. neoadjuvant placebo plus chemo followed by surgery and adjuvant NIVO or placebo for previously untreated, resectable stage Ⅱ-Ⅲb NSCLC. Ann Oncol, 2023: S1254-S1335.
26.	Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative durvalumab for resectable non-small-cell lung cancer. N Engl J Med, 2023, 389(18): 1672-1684.
27.	Yue D, Wang W, Liu H, et al. LBA58 pathological response to neoadjuvant tislelizumab (TIS) plus platinum-doublet (PtDb) chemotherapy (CT) in resectable stage Ⅱ-ⅢA NSCLC patients (pts) in the phase Ⅲ(Ph3) RATIONALE-315 trial. Ann Oncol, 2023, 34(Supplement 2): S1299.
28.	Lu S, Wu L, Zhang W, et al. Perioperative toripalimab+platinum-doublet chemotherapy vs chemotherapy in resectable stage Ⅱ/Ⅲnon-small cell lung cancer (NSCLC): Interim event-free survival (EFS) analysis of the phaseⅢ Neotorch study. J Clin Oncol, 2023: 425126.
29.	Wakelee H, Liberman M, Kato T, et al. Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N Engl J Med, 2023, 389(6): 491-503.
30.	Rhodin KE, Rucker AJ, Ready NE, et al. The immunotherapeutic landscape in non-small cell lung cancer and its surgical horizons. J Thorac Cardiovasc Surg, 2020, 159(4): 1616-1623.
31.	Spicer J, Wang C, Tanaka F, et al. Surgical outcomes from the phase 3 CheckMate 816 trial: Nivolumab (NIVO)+platinum-doublet chemotherapy (chemo) vs. chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). J Clin Oncol, 2021, 39(15_suppl): 8503-e.
32.	Zhang B, Xiao Q, Xiao H, et al. Perioperative outcomes of video-assisted thoracoscopic surgery versus open thoracotomy after neoadjuvant chemoimmunotherapy in resectable NSCLC. Front Oncol, 2022, 12: 858189.
33.	Guidelines Working Committee of Chinese Society of Clinical Oncology. Guidelines of Chinese Society of Clinical Oncology (CSCO). Non-Small Cell Lung Cancer. Beijing: People's Medical Publishing House.
34.	中国临床肿瘤学会血管靶向治疗专家委员会, 中国临床肿瘤学会非小细胞肺癌专家委员会. 肿瘤突变负荷应用于肺癌免疫治疗的专家共识. 中国肺癌杂志, 2021, 24(11): 743-752.
35.	Ettinger DS, Wood DE, Aisner DL, et al. Non-small cell lung cancer, version 5. 2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw, 2017, 15(4): 504-535.
36.	Deng H, Zhao Y, Cai X, et al. PD-L1 expression and Tumor mutation burden as Pathological response biomarkers of Neoadjuvant immunotherapy for early-stage non-small cell lung cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol, 2022, 170: 103582.
37.	Chaft JE, Oezkan F, Kris MG, et al. Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an open-label, single-arm phaseⅡtrial. Nat Med, 2022, 28(10): 2155-2161.
38.	吴一龙, 陆舜, 程颖, 等. 非小细胞肺癌分子残留病灶专家共识. 循证医学, 2021, 21(3): 129-135.
39.	Xia L, Mei J, Kang R, et al. Perioperative ctDNA-based molecular residual disease detection for non-small cell lung cancer: A prospective multicenter cohort study (LUNGCA-1). Clin Cancer Res, 2022, 28(15): 3308-3317.
40.	Patel SP, Othus M, Chen Y, et al. Neoadjuvant-adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N Engl J Med, 2023, 388(9): 813-823.
41.	Chaft JE, Hellmann MD, Velez MJ, et al. Initial experience with lung cancer resection after treatment with t-cell checkpoint inhibitors. Ann Thorac Surg, 2017, 104(3): e217-e218.
42.	Chiou VL, Burotto M. Pseudoprogression and immune-related response in solid tumors. J Clin Oncol, 2015, 33(31): 3541-3543.
43.	Jia XH, Xu H, Geng LY, et al. Efficacy and safety of neoadjuvant immunotherapy in resectable non-small cell lung cancer: A meta-analysis. Lung Cancer, 2020, 147: 143-153.
44.	Bott MJ, Cools-Lartigue J, Tan KS, et al. Safety and feasibility of lung resection after immunotherapy for metastatic or unresectable tumors. Ann Thorac Surg, 2018, 106(1): 178-183.
45.	Bott MJ, Yang SC, Park BJ, et al. Initial results of pulmonary resection after neoadjuvant nivolumab in patients with resectable non-small cell lung cancer. J Thorac Cardiovasc Surg, 2019, 158(1): 269-276.
46.	Ren S, Wang C, Shen J, et al. Neoadjuvant immunotherapy with resectable non-small cell lung cancer: Recent advances and future challenges. J Thorac Dis, 2020, 12(4): 1615-1620.

1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin, 2022, 72(1): 7-33.
2. Uramoto H, Tanaka F. Recurrence after surgery in patients with NSCLC. Transl Lung Cancer Res, 2014, 3(4): 242-249.
3. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: A pooled analysis by the LACE Collaborative Group. J Clin Oncol, 2008, 26(21): 3552-3559.
4. NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small-cell lung cancer: A systematic review and meta-analysis of individual participant data. Lancet, 2014, 383(9928): 1561-1571.
5. Nasser NJ, Gorenberg M, Agbarya A. First line immunotherapy for non-small cell lung cancer. Pharmaceuticals (Basel), 2020, 13(11): 373.
6. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stageⅢnon-small-cell lung cancer. N Engl J Med, 2017, 377(20): 1919-1929.
7. Qiu B, Guo W, Zhang F, et al. Dynamic recurrence risk and adjuvant chemotherapy benefit prediction by ctDNA in resected NSCLC. Nat Commun, 2021, 12(1): 6770.
8. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage ⅠB-ⅢA non-small-cell lung cancer (IMpower010): A randomised, multicentre, open-label, phase 3 trial. Lancet, 2021, 398(10308): 1344-1357.
9. Wakelee H, Altorki N, Felip E, et al. PL03.09 IMpower010: Overall survival interim analysis of a phaseⅢ study of Atezolizumab vs. best supportive care in resected NSCLC. J Thorac Oncol, 2022, 17(9): S2.
10. O'Brien M, Paz-Ares L, Marreaud S, et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage ⅠB-ⅢA non-small-cell lung cancer (PEARLS/KEYNOTE-091): An interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol, 2022, 23(10): 1274-1286.
11. https://www.clinicaltrials.gov/.
12. Sauer R, Liersch T, Merkel S, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: Results of the German CAO/ARO/AIO-94 randomized phase Ⅲtrial after a median follow-up of 11 years. J Clin Oncol, 2012, 30(16): 1926-1933.
13. Zhang X, Wu T, Cai X, et al. Neoadjuvant immunotherapy for MSI-H/dMMR locally advanced colorectal cancer: New strategies and unveiled opportunities. Front Immunol, 2022, 13: 795972.
14. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med, 2018, 378(21): 1976-1986.
15. Wislez M, Mazieres J, Lavole A, et al. Neoadjuvant durvalumab for resectable non-small-cell lung cancer (NSCLC): Results from a multicenter study (IFCT-1601 IONESCO). J Immunother Cancer, 2022, 10(10): e005636.
16. Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med, 2022, 386(21): 1973-1985.
17. Ford PM, Spicer J, Lu S, et al. Abstract CT003: Nivolumab (NIVO)+platinum-doublet chemotherapy (chemo) vs. chemo as neoadjuvant treatment (tx) for resectable (ⅠB-ⅢA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial. Cancer Res, 2021, 81 (13_Supplement): CT003.
18. Cascone T, William WN, Weissferdt A, et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: The phase 2 randomized NEOSTAR trial. Nat Med, 2021, 27(3): 504-514.
19. Spicer J, Cascone T, Kar G, et al. 929MO: Platform study of neoadjuvant durvalumab (D) alone or combined with novel agents in patients (pts) with resectable, early-stage non-small cell lung cancer (NSCLC): Pharmacodynamic correlates and circulating tumor DNA (ctDNA) dynamics in the NeoCOAST study. Ann Oncol, 2022, 33(Suppl_7): S427-S437.
20. Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): An open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol, 2020, 21(11): 1413-1422.
21. Mariano PP, Ernest N, Jose LGL, et al. Nivolumab+chemotherapy versus chemotherapy as neoadjuvant treatment for resectable stage ⅢA NSCLC: Primary endpoint results of pathological complete response (pCR) from phaseⅡ NADIMⅡ trial. J Clin Oncol, 2020: 8501.
22. Romero A, Serna R, Nadal E, et al. MA06.03: Pre-treatment ctDNA levels significantly predicts of OS and PFS in NADIMⅡ trial. J Thorac Oncol, 2022, 17(9): S63.
23. Rothschild SI, Zippelius A, Eboulet EI, et al. SAKK 16/14: Durvalumab in addition to neoadjuvant chemotherapy in patients with stageⅢA(N2) non-small-cell lung cancer: A multicenter single-arm phaseⅡtrial. J Clin Oncol, 2021, 39(26): 2872-2880.
24. Zhao J, Zhao L, Guo W, et al. Efficacy, safety, and biomarker analysis of neoadjuvant camrelizumab and apatinib in patients with resectable NSCLC: A phase 2 clinical trial. J Thorac Oncol, 2023, 18(6): 780-791.
25. Cascone T, Awad MM, Spicer JD, et al. LBA1-CheckMate 77T: Phase Ⅲstudy comparing neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) vs. neoadjuvant placebo plus chemo followed by surgery and adjuvant NIVO or placebo for previously untreated, resectable stage Ⅱ-Ⅲb NSCLC. Ann Oncol, 2023: S1254-S1335.
26. Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative durvalumab for resectable non-small-cell lung cancer. N Engl J Med, 2023, 389(18): 1672-1684.
27. Yue D, Wang W, Liu H, et al. LBA58 pathological response to neoadjuvant tislelizumab (TIS) plus platinum-doublet (PtDb) chemotherapy (CT) in resectable stage Ⅱ-ⅢA NSCLC patients (pts) in the phase Ⅲ(Ph3) RATIONALE-315 trial. Ann Oncol, 2023, 34(Supplement 2): S1299.
28. Lu S, Wu L, Zhang W, et al. Perioperative toripalimab+platinum-doublet chemotherapy vs chemotherapy in resectable stage Ⅱ/Ⅲnon-small cell lung cancer (NSCLC): Interim event-free survival (EFS) analysis of the phaseⅢ Neotorch study. J Clin Oncol, 2023: 425126.
29. Wakelee H, Liberman M, Kato T, et al. Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N Engl J Med, 2023, 389(6): 491-503.
30. Rhodin KE, Rucker AJ, Ready NE, et al. The immunotherapeutic landscape in non-small cell lung cancer and its surgical horizons. J Thorac Cardiovasc Surg, 2020, 159(4): 1616-1623.
31. Spicer J, Wang C, Tanaka F, et al. Surgical outcomes from the phase 3 CheckMate 816 trial: Nivolumab (NIVO)+platinum-doublet chemotherapy (chemo) vs. chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). J Clin Oncol, 2021, 39(15_suppl): 8503-e.
32. Zhang B, Xiao Q, Xiao H, et al. Perioperative outcomes of video-assisted thoracoscopic surgery versus open thoracotomy after neoadjuvant chemoimmunotherapy in resectable NSCLC. Front Oncol, 2022, 12: 858189.
33. Guidelines Working Committee of Chinese Society of Clinical Oncology. Guidelines of Chinese Society of Clinical Oncology (CSCO). Non-Small Cell Lung Cancer. Beijing: People's Medical Publishing House.
34. 中国临床肿瘤学会血管靶向治疗专家委员会, 中国临床肿瘤学会非小细胞肺癌专家委员会. 肿瘤突变负荷应用于肺癌免疫治疗的专家共识. 中国肺癌杂志, 2021, 24(11): 743-752.
35. Ettinger DS, Wood DE, Aisner DL, et al. Non-small cell lung cancer, version 5. 2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw, 2017, 15(4): 504-535.
36. Deng H, Zhao Y, Cai X, et al. PD-L1 expression and Tumor mutation burden as Pathological response biomarkers of Neoadjuvant immunotherapy for early-stage non-small cell lung cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol, 2022, 170: 103582.
37. Chaft JE, Oezkan F, Kris MG, et al. Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an open-label, single-arm phaseⅡtrial. Nat Med, 2022, 28(10): 2155-2161.
38. 吴一龙, 陆舜, 程颖, 等. 非小细胞肺癌分子残留病灶专家共识. 循证医学, 2021, 21(3): 129-135.
39. Xia L, Mei J, Kang R, et al. Perioperative ctDNA-based molecular residual disease detection for non-small cell lung cancer: A prospective multicenter cohort study (LUNGCA-1). Clin Cancer Res, 2022, 28(15): 3308-3317.
40. Patel SP, Othus M, Chen Y, et al. Neoadjuvant-adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N Engl J Med, 2023, 388(9): 813-823.
41. Chaft JE, Hellmann MD, Velez MJ, et al. Initial experience with lung cancer resection after treatment with t-cell checkpoint inhibitors. Ann Thorac Surg, 2017, 104(3): e217-e218.
42. Chiou VL, Burotto M. Pseudoprogression and immune-related response in solid tumors. J Clin Oncol, 2015, 33(31): 3541-3543.
43. Jia XH, Xu H, Geng LY, et al. Efficacy and safety of neoadjuvant immunotherapy in resectable non-small cell lung cancer: A meta-analysis. Lung Cancer, 2020, 147: 143-153.
44. Bott MJ, Cools-Lartigue J, Tan KS, et al. Safety and feasibility of lung resection after immunotherapy for metastatic or unresectable tumors. Ann Thorac Surg, 2018, 106(1): 178-183.
45. Bott MJ, Yang SC, Park BJ, et al. Initial results of pulmonary resection after neoadjuvant nivolumab in patients with resectable non-small cell lung cancer. J Thorac Cardiovasc Surg, 2019, 158(1): 269-276.
46. Ren S, Wang C, Shen J, et al. Neoadjuvant immunotherapy with resectable non-small cell lung cancer: Recent advances and future challenges. J Thorac Dis, 2020, 12(4): 1615-1620.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

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