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

Authors：

YANG Hao , ZHANG Chengcheng , ZHANG Yue , ZHANG Liwen ,  FU Maoyong

Department of Thoracic Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, Sichuan, P. R. China;

Corresponding author：

FU Maoyong, Email: fumaoyongmd@163.com

Keywords：

Resectable non-small cell lung cancer; immunotherapy; neoadjuvant therapy; review

DOI：

10.7507/1007-4848.202308029

Video：

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Abstract Full text Figures/Tables Video References Cited by

Resectable non-small cell lung cancer (NSCLC) is prone to recurrence and metastasis after simple surgery. Although patients can benefit from preoperative neoadjuvant chemotherapy and postoperative adjuvant chemotherapy, the 5-year survival rate is not significantly improved. In recent years, with the rise of immunotherapy, NSCLC immunotherapy has gradually received attention. Many explorations have been made on resectable NSCLC immunotherapy, and satisfactory results have been obtained. With the release of multiple phase 3 research results, a new chapter in resectable NSCLC immunotherapy has officially opened. However, there are still many problems in the immunotherapy of resectable NSCLC. This article reviews the current relevant research and provides reference for clinical application.

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.	Chen Q, Guo Z, Liu S, et al. The cancer incidence and mortality among children and adolescents during the period of 2010-2014 in Henan Province, China. Cancer Med, 2019, 8(2): 814-823.
3.	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.
4.	Burdett S, Pignon JP, Tierney J, et al. Adjuvant chemotherapy for resected early-stage non-small cell lung cancer. Cochrane Database Syst Rev, 2015, 2015(3): CD011430.
5.	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.
6.	Gadgeel S, Rodriguez-Abreu D, Speranza G, et al. Updated analysis from KEYNOTE-189: Pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous nonsmall cell lung cancer. J Clin Oncol, 2020, 38(14): 1505-1517.
7.	Jotte R, Cappuzzo F, Vynnychenko I, et al. Atezolizumab in combination with carboplatin and nab-paclitaxel in advanced squamous NSCLC (IMpower131): Results from a randomized phase Ⅲ trial. J Thorac Oncol, 2020, 15(8): 1351-1360.
8.	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.
9.	Heather A, Wakelee, Moishe Liberman, et al. KEYNOTE-671: Randomized, double-blind, phase 3 study of pembrolizumab or placebo plus platinum-based chemotherapy followed by resection and pembrolizumab or placebo for early stage NSCLC. 2023 ASCO Annual Meeting. Abstract #LBA100.
10.	O'Brien M, Paz-Ares L, Marreaud S, et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stageⅠB-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.	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.
12.	Lavin Y, Kobayashi S, Leader A, et al. Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses. Cell, 2017, 169(4): 750-765.
13.	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.
14.	Rosner S, Reuss JE, Zahurak M, et al. Five-year clinical outcomes after neoadjuvant nivolumab in resectable non-small cell lung cancer. Clin Cancer Res, 2023, 29(4): 705-710.
15.	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.
16.	Gao S, Li N, Gao S, et al. Neoadjuvant PD-1 inhibitor (Sintilimab) in NSCLC. J Thorac Oncol, 2020, 15(5): 816-826.
17.	Zhang F, Guo W, Zhou B, et al. Three-year follow-up of neoadjuvant programmed cell death protein-1 inhibitor (sintilimab) in NSCLC. J Thorac Oncol, 2022, 17(7): 909-920.
18.	Chaft JE, Oezkan F, Kris MG, et al. Neoadjuvant atezolizumab for resectable non-small cell lung cancer: An open-label, single-arm phase Ⅱtrial. Nat Med, 2022, 28(10): 2155-2161.
19.	Lee J, Chaft J, Nicholas A, et al. PS01.05 surgical and clinical outcomes with neoadjuvant atezolizumab in resectable stageⅠB-ⅢB NSCLC: LCMC3 trial primary analysis. J Thorac Oncol, 2021, 16: S59–S61.
20.	Reuss JE, Anagnostou V, Cottrell TR, et al. Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer. J Immunother Cancer, 2020, 8(2): e001282.
21.	Betticher DC, Hsu Schmitz SF, Tötsch M, et al. Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stageⅢA pN2 non-small-cell lung cancer: A multicenter phaseⅡ trial. J Clin Oncol, 2003, 21(9): 1752-1759.
22.	Liang W, Cai K, Cao Q, et al. International expert consensus on immunotherapy for early-stage non-small cell lung cancer. Transl Lung Cancer Res, 2022, 11(9): 1742-1762.
23.	Heinhuis KM, Ros W, Kok M, et al. Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors. Ann Oncol, 2019, 30(2): 219-235.
24.	Leonetti A, Wever B, Mazzaschi G, et al. Molecular basis and rationale for combining immune checkpoint inhibitors with chemotherapy in non-small cell lung cancer. Drug Resist Updat, 2019, 46: 100644.
25.	Brown JS, Sundar R, Lopez J. Combining DNA damaging therapeutics with immunotherapy: More haste, less speed. Br J Cancer, 2018, 118(3): 312-324.
26.	Reck M, Rodríguez-Abreu D, Robinson AG, et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score≥50. J Clin Oncol, 2021, 39(21): 2339-2349.
27.	Herbst RS, Giaccone G, de Marinis F, et al. Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC. N Engl J Med, 2020, 383(14): 1328-1339.
28.	Wang C, Qiao W, Jiang Y, et al. The landscape of immune checkpoint inhibitor plus chemotherapy versus immunotherapy for advanced non-small-cell lung cancer: A systematic review and meta-analysis. J Cell Physiol, 2020, 235(5): 4913-4927.
29.	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.
30.	Provencio M, Serna-Blasco R, Nadal E, et al. Overall survival and biomarker analysis of neoadjuvant nivolumab plus chemotherapy in operable stage ⅢA non-small-cell lung cancer (NADIM phaseⅡtrial). J Clin Oncol, 2022, 40(25): 2924-2933.
31.	Sun C, Liu Y, Zhang P, et al. Interim analysis of the efficiency and safety of neoadjuvant PD-1 inhibitor (sintilimab) combined with chemotherapy (nab-paclitaxel and carboplatin) in potentially resectable stage ⅢA/ⅢB non-small cell lung cancer: A single-arm, phase 2 trial. J Cancer Res Clin Oncol, 2023, 149(2): 819-831.
32.	Liu Z, Gao Z, Zhang M, et al. Real-world effectiveness and prognostic factors analysis of stagesⅠ-Ⅲ non-small cell lung cancer following neoadjuvant chemo-immunotherapy or neoadjuvant chemotherapy. Ann Thorac Cardiovasc Surg, 2022, 28(2): 111-120.
33.	Dai F, Wu X, Wang X, et al. Neoadjuvant immunotherapy combined with chemotherapy significantly improved patients' overall survival when compared with neoadjuvant chemotherapy in non-small cell lung cancer: A cohort study. Front Oncol, 2022, 12: 1022123.
34.	Fei K, Guo G, Wang J, et al. Effectiveness of neoadjuvant immunochemotherapy compared to neoadjuvant chemotherapy in non-small cell lung cancer patients: Real-world data of a retrospective, dual-center study. Front Oncol, 2023, 13: 1145303.
35.	Lhuillier C, Rudqvist NP, Elemento O, et al. Radiation therapy and anti-tumor immunity: Exposing immunogenic mutations to the immune system. Genome Med, 2019, 11(1): 40.
36.	Taunk NK, Rimner A, Culligan M, et al. Immunotherapy and radiation therapy for operable early stage and locally advanced non-small cell lung cancer. Transl Lung Cancer Res, 2017, 6(2): 178-185.
37.	Antonia SJ, Villegas A, Daniel D, et al. Overall Survival with durvalumab after chemoradiotherapy in stage ⅢNSCLC. N Engl J Med, 2018, 379(24): 2342-2350.
38.	Upadhaya S, Neftelino ST, Hodge JP, et al. Combinations take centre stage in PD1/PDL1 inhibitor clinical trials. Nat Rev Drug Discov, 2021, 20(3): 168-169.
39.	Dickhoff C, Senan S, Schneiders FL, et al. Ipilimumab plus nivolumab and chemoradiotherapy followed by surgery in patients with resectable and borderline resectable T3-4N0-1 non-small cell lung cancer: The INCREASE trial. BMC Cancer, 2020, 20(1): 764.
40.	Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer, 2018, 118(1): 9-16.
41.	Huang Y, Goel S, Duda DG, et al. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res, 2013, 73(10): 2943-2948.
42.	Reck M, Mok TSK, Nishio M, et al. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): Key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir Med, 2019, 7(5): 387-401.
43.	Lam TC, Tsang KC, Choi HC, et al. Combination atezolizumab, bevacizumab, pemetrexed and carboplatin for metastatic EGFR mutated NSCLC after TKI failure. Lung Cancer, 2021, 159: 18-26.
44.	Roy S. Herbst, Wu Y , et al. Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resectedEGFR-mutated (EGFRm) stageⅠB-ⅢA non-small cell lung cancer (NSCLC). 2023 ASCO, abstract LBA 3#.
45.	Pape M, Vissers PAJ, Beerepoot LV, et al. A population-based study in resected esophageal or gastroesophageal junction cancer aligned with CheckMate 577. Ther Adv Med Oncol, 2022, 14: 17588359221075495.
46.	Heymach JV, Mitsudomi T, Harpole D, et al. Design and rationale for a phaseⅢ, double-blind, placebo-controlled study of neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab for the treatment of patients with resectable stagesⅡandⅢ non-small-cell lung cancer: The AEGEAN Trial. Clin Lung Cancer, 2022, 23(3): e247-e251.
47.	Shun Lu, Lin Wu, Wei Zhang, et al. Perioperative toripalimab+platinum-doublet chemotherapy vs. chemotherapy in resectable stage Ⅱ/Ⅲ non-small cell lung cancer (NSCLC): Interim event-free survival (EFS) analysis of the phaseⅢNEOTORCH study. 2023 ASCO Annual Meeting, Abstract #8501.
48.	Akinboro O, Larkins E, Pai-Scherf LH, et al. FDA approval summary: Pembrolizumab, atezolizumab, and cemiplimab-rwlc as single agents for first-line treatment of advanced/metastatic PD-L1-high NSCLC. Clin Cancer Res, 2022, 28(11): 2221-2228.
49.	Addeo A, Friedlaender A, Banna GL, et al. TMB or not TMB as a biomarker: That is the question. Crit Rev Oncol Hematol, 2021, 163: 103374.
50.	Sesma A, Pardo J, Cruellas M, et al. From tumor mutational burden to blood T cell receptor: Looking for the best predictive biomarker in lung cancer treated with immunotherapy. Cancers (Basel), 2020, 12(10): 2974.
51.	Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: Prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol, 2020, 21(10): 1353-1365.
52.	Marcus L, Fashoyin-Aje LA, Donoghue M, et al. FDA approval summary: Pembrolizumab for the treatment of tumor mutational burden-high solid tumors. Clin Cancer Res, 2021, 27(17): 4685-4689.
53.	Paz-Ares L, Langer CJ, Novello S, et al. Pembrolizumab (Pembro) plus platinum-based chemotherapy (Chemo) for metastatic nsclc: Tissue tmb (Ttmb) and outcomes in keynote-021, 189, and 407. Ann Oncol, 2019, 30: v917-v918.
54.	Jee J, Lebow ES, Yeh R, et al. Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer. Nat Med, 2022, 28(11): 2353-2363.

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. Chen Q, Guo Z, Liu S, et al. The cancer incidence and mortality among children and adolescents during the period of 2010-2014 in Henan Province, China. Cancer Med, 2019, 8(2): 814-823.
3. 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.
4. Burdett S, Pignon JP, Tierney J, et al. Adjuvant chemotherapy for resected early-stage non-small cell lung cancer. Cochrane Database Syst Rev, 2015, 2015(3): CD011430.
5. 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.
6. Gadgeel S, Rodriguez-Abreu D, Speranza G, et al. Updated analysis from KEYNOTE-189: Pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous nonsmall cell lung cancer. J Clin Oncol, 2020, 38(14): 1505-1517.
7. Jotte R, Cappuzzo F, Vynnychenko I, et al. Atezolizumab in combination with carboplatin and nab-paclitaxel in advanced squamous NSCLC (IMpower131): Results from a randomized phase Ⅲ trial. J Thorac Oncol, 2020, 15(8): 1351-1360.
8. 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.
9. Heather A, Wakelee, Moishe Liberman, et al. KEYNOTE-671: Randomized, double-blind, phase 3 study of pembrolizumab or placebo plus platinum-based chemotherapy followed by resection and pembrolizumab or placebo for early stage NSCLC. 2023 ASCO Annual Meeting. Abstract #LBA100.
10. O'Brien M, Paz-Ares L, Marreaud S, et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stageⅠB-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. 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.
12. Lavin Y, Kobayashi S, Leader A, et al. Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses. Cell, 2017, 169(4): 750-765.
13. 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.
14. Rosner S, Reuss JE, Zahurak M, et al. Five-year clinical outcomes after neoadjuvant nivolumab in resectable non-small cell lung cancer. Clin Cancer Res, 2023, 29(4): 705-710.
15. 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.
16. Gao S, Li N, Gao S, et al. Neoadjuvant PD-1 inhibitor (Sintilimab) in NSCLC. J Thorac Oncol, 2020, 15(5): 816-826.
17. Zhang F, Guo W, Zhou B, et al. Three-year follow-up of neoadjuvant programmed cell death protein-1 inhibitor (sintilimab) in NSCLC. J Thorac Oncol, 2022, 17(7): 909-920.
18. Chaft JE, Oezkan F, Kris MG, et al. Neoadjuvant atezolizumab for resectable non-small cell lung cancer: An open-label, single-arm phase Ⅱtrial. Nat Med, 2022, 28(10): 2155-2161.
19. Lee J, Chaft J, Nicholas A, et al. PS01.05 surgical and clinical outcomes with neoadjuvant atezolizumab in resectable stageⅠB-ⅢB NSCLC: LCMC3 trial primary analysis. J Thorac Oncol, 2021, 16: S59–S61.
20. Reuss JE, Anagnostou V, Cottrell TR, et al. Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer. J Immunother Cancer, 2020, 8(2): e001282.
21. Betticher DC, Hsu Schmitz SF, Tötsch M, et al. Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stageⅢA pN2 non-small-cell lung cancer: A multicenter phaseⅡ trial. J Clin Oncol, 2003, 21(9): 1752-1759.
22. Liang W, Cai K, Cao Q, et al. International expert consensus on immunotherapy for early-stage non-small cell lung cancer. Transl Lung Cancer Res, 2022, 11(9): 1742-1762.
23. Heinhuis KM, Ros W, Kok M, et al. Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors. Ann Oncol, 2019, 30(2): 219-235.
24. Leonetti A, Wever B, Mazzaschi G, et al. Molecular basis and rationale for combining immune checkpoint inhibitors with chemotherapy in non-small cell lung cancer. Drug Resist Updat, 2019, 46: 100644.
25. Brown JS, Sundar R, Lopez J. Combining DNA damaging therapeutics with immunotherapy: More haste, less speed. Br J Cancer, 2018, 118(3): 312-324.
26. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score≥50. J Clin Oncol, 2021, 39(21): 2339-2349.
27. Herbst RS, Giaccone G, de Marinis F, et al. Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC. N Engl J Med, 2020, 383(14): 1328-1339.
28. Wang C, Qiao W, Jiang Y, et al. The landscape of immune checkpoint inhibitor plus chemotherapy versus immunotherapy for advanced non-small-cell lung cancer: A systematic review and meta-analysis. J Cell Physiol, 2020, 235(5): 4913-4927.
29. 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.
30. Provencio M, Serna-Blasco R, Nadal E, et al. Overall survival and biomarker analysis of neoadjuvant nivolumab plus chemotherapy in operable stage ⅢA non-small-cell lung cancer (NADIM phaseⅡtrial). J Clin Oncol, 2022, 40(25): 2924-2933.
31. Sun C, Liu Y, Zhang P, et al. Interim analysis of the efficiency and safety of neoadjuvant PD-1 inhibitor (sintilimab) combined with chemotherapy (nab-paclitaxel and carboplatin) in potentially resectable stage ⅢA/ⅢB non-small cell lung cancer: A single-arm, phase 2 trial. J Cancer Res Clin Oncol, 2023, 149(2): 819-831.
32. Liu Z, Gao Z, Zhang M, et al. Real-world effectiveness and prognostic factors analysis of stagesⅠ-Ⅲ non-small cell lung cancer following neoadjuvant chemo-immunotherapy or neoadjuvant chemotherapy. Ann Thorac Cardiovasc Surg, 2022, 28(2): 111-120.
33. Dai F, Wu X, Wang X, et al. Neoadjuvant immunotherapy combined with chemotherapy significantly improved patients' overall survival when compared with neoadjuvant chemotherapy in non-small cell lung cancer: A cohort study. Front Oncol, 2022, 12: 1022123.
34. Fei K, Guo G, Wang J, et al. Effectiveness of neoadjuvant immunochemotherapy compared to neoadjuvant chemotherapy in non-small cell lung cancer patients: Real-world data of a retrospective, dual-center study. Front Oncol, 2023, 13: 1145303.
35. Lhuillier C, Rudqvist NP, Elemento O, et al. Radiation therapy and anti-tumor immunity: Exposing immunogenic mutations to the immune system. Genome Med, 2019, 11(1): 40.
36. Taunk NK, Rimner A, Culligan M, et al. Immunotherapy and radiation therapy for operable early stage and locally advanced non-small cell lung cancer. Transl Lung Cancer Res, 2017, 6(2): 178-185.
37. Antonia SJ, Villegas A, Daniel D, et al. Overall Survival with durvalumab after chemoradiotherapy in stage ⅢNSCLC. N Engl J Med, 2018, 379(24): 2342-2350.
38. Upadhaya S, Neftelino ST, Hodge JP, et al. Combinations take centre stage in PD1/PDL1 inhibitor clinical trials. Nat Rev Drug Discov, 2021, 20(3): 168-169.
39. Dickhoff C, Senan S, Schneiders FL, et al. Ipilimumab plus nivolumab and chemoradiotherapy followed by surgery in patients with resectable and borderline resectable T3-4N0-1 non-small cell lung cancer: The INCREASE trial. BMC Cancer, 2020, 20(1): 764.
40. Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer, 2018, 118(1): 9-16.
41. Huang Y, Goel S, Duda DG, et al. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res, 2013, 73(10): 2943-2948.
42. Reck M, Mok TSK, Nishio M, et al. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): Key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir Med, 2019, 7(5): 387-401.
43. Lam TC, Tsang KC, Choi HC, et al. Combination atezolizumab, bevacizumab, pemetrexed and carboplatin for metastatic EGFR mutated NSCLC after TKI failure. Lung Cancer, 2021, 159: 18-26.
44. Roy S. Herbst, Wu Y , et al. Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resectedEGFR-mutated (EGFRm) stageⅠB-ⅢA non-small cell lung cancer (NSCLC). 2023 ASCO, abstract LBA 3#.
45. Pape M, Vissers PAJ, Beerepoot LV, et al. A population-based study in resected esophageal or gastroesophageal junction cancer aligned with CheckMate 577. Ther Adv Med Oncol, 2022, 14: 17588359221075495.
46. Heymach JV, Mitsudomi T, Harpole D, et al. Design and rationale for a phaseⅢ, double-blind, placebo-controlled study of neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab for the treatment of patients with resectable stagesⅡandⅢ non-small-cell lung cancer: The AEGEAN Trial. Clin Lung Cancer, 2022, 23(3): e247-e251.
47. Shun Lu, Lin Wu, Wei Zhang, et al. Perioperative toripalimab+platinum-doublet chemotherapy vs. chemotherapy in resectable stage Ⅱ/Ⅲ non-small cell lung cancer (NSCLC): Interim event-free survival (EFS) analysis of the phaseⅢNEOTORCH study. 2023 ASCO Annual Meeting, Abstract #8501.
48. Akinboro O, Larkins E, Pai-Scherf LH, et al. FDA approval summary: Pembrolizumab, atezolizumab, and cemiplimab-rwlc as single agents for first-line treatment of advanced/metastatic PD-L1-high NSCLC. Clin Cancer Res, 2022, 28(11): 2221-2228.
49. Addeo A, Friedlaender A, Banna GL, et al. TMB or not TMB as a biomarker: That is the question. Crit Rev Oncol Hematol, 2021, 163: 103374.
50. Sesma A, Pardo J, Cruellas M, et al. From tumor mutational burden to blood T cell receptor: Looking for the best predictive biomarker in lung cancer treated with immunotherapy. Cancers (Basel), 2020, 12(10): 2974.
51. Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: Prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol, 2020, 21(10): 1353-1365.
52. Marcus L, Fashoyin-Aje LA, Donoghue M, et al. FDA approval summary: Pembrolizumab for the treatment of tumor mutational burden-high solid tumors. Clin Cancer Res, 2021, 27(17): 4685-4689.
53. Paz-Ares L, Langer CJ, Novello S, et al. Pembrolizumab (Pembro) plus platinum-based chemotherapy (Chemo) for metastatic nsclc: Tissue tmb (Ttmb) and outcomes in keynote-021, 189, and 407. Ann Oncol, 2019, 30: v917-v918.
54. Jee J, Lebow ES, Yeh R, et al. Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer. Nat Med, 2022, 28(11): 2353-2363.

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