Efficacy and safety of immune checkpoint inhibitor and bevacizumab combined with chemotherapy in the first-line treatment of advanced wild-type non-squamous non-small cell lung cancer: a network meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

SONG Yang ¹ ,  ZHU Yuxi ^1,2

1. Department of Oncology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P. R. China;
2. Department of Oncology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P. R. China;

Corresponding author：

ZHU Yuxi, Email: zhuyuxi@hospital.cqmu.edu.cn

Keywords：

Immune checkpoint inhibitor; Bevacizumab; Chemotherapy; First-line treatment; Wild-type non-squamous non-small cell lung cancer

DOI：

10.7507/1672-2531.202303076

Video：

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Objective To analyze the efficacy and safety of immunotherapy and bevacizumab combined with chemotherapy (BIC), bevacizumab combined with chemotherapy (BC), chemotherapy (CT), immunotherapy combined with chemotherapy (IC), bevacizumab combined with immunotherapy (BI), bevacizumab (B) in the first-line treatment of advanced wild-type non-squamous non-small cell lung cancer. Methods The PubMed, Embase, Cochrane Library and Web of Science databases were searched to collect phase Ⅱ/Ⅲ randomized controlled trials (RCTs) related to the objectives of the study from January 2010 to December 1, 2022. After two investigators independently screened the literatures, extracted the data and evaluated the risk of bias of the included studies, a reticular meta-analysis was performed using R 3.6.1 software. Results A total of 11 RCTs were finally included, including 5 329 patients and six treatment combinations. Meta-analysis results showed that BIC was superior to CT for progression-free survival (PFS) (HR=0.34, 95% CI 0.18 to 0.69), but BIC did not show a significant advantage over the other groups for overall survival (OS). Bayesian ranking results showed that the BIC group had the greatest probability in terms of OS, PFS, and ORR. Among all programmed death ligand 1 (PD-L1) expressing subgroups, there was no significant difference in OS between BIC, BC, IC, CT, BI, and B. Compared with CT, IC was significantly improved in OS (HR=0.68, 95%CI 0.52 to 0.92), PFS (HR=0.58, 95%CI 0.45 to 0.75), and ORR (HR=0.47, 95%CI 0.33 to 0.66). Conclusion In the first-line treatment of wild-type advanced non-squamous NSCLC, immunotherapy and bevacizumab combined with chemotherapy may improve the efficacy in the short term, but do not change the long-term survival time. Immunotherapy combined with chemotherapy can significantly improve the survival time and prognosis of patients compared with chemotherapy alone. Due to the limited quantity and quality of the included studies, more high-quality studies are needed to verify the above conclusion.

Citation： SONG Yang, ZHU Yuxi. Efficacy and safety of immune checkpoint inhibitor and bevacizumab combined with chemotherapy in the first-line treatment of advanced wild-type non-squamous non-small cell lung cancer: a network meta-analysis. Chinese Journal of Evidence-Based Medicine, 2023, 23(11): 1275-1283. doi: 10.7507/1672-2531.202303076 Copy

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18.	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.
19.	Zhou C, Chen G, Huang Y, et al. Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small-cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial. Lancet Respir Med, 2021, 9(3): 305-314.
20.	Lu S, Wang J, Yu Y, et al. Tislelizumab plus chemotherapy as first-line treatment for locally advanced or metastatic nonsquamous NSCLC (RATIONALE 304): a randomized phase 3 trial. J Thorac Oncol, 2021, 16(9): 1512-1522.
21.	Sugawara S, Lee JS, Kang JH, et al. Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer. Ann Oncol, 2021, 32(9): 1137-1147.
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23.	Iwai T, Sugimoto M, Patel H, et al. Anti-VEGF antibody protects against alveolar exudate leakage caused by vascular hyperpermeability, resulting in mitigation of pneumonitis induced by immunotherapy. Mol Cancer Ther, 2021, 20(12): 2519-2526.
24.	Xue L, Gao X, Zhang H, et al. Antiangiogenic antibody BD0801 combined with immune checkpoint inhibitors achieves synergistic antitumor activity and affects the tumor microenvironment. BMC Cancer, 2021, 21(1): 1134.
25.	Bagegni NA, Park H, Kraft K, et al. Phase 1b trial of anti-VEGF/PDGFR vorolanib combined with immune checkpoint inhibitors in patients with advanced solid tumors. Cancer Chemother Pharmacol, 2022, 89(4): 487-497.
26.	Zhang W, Gu J, Bian C, et al. Immune-related adverse events associated with immune checkpoint inhibitors for advanced non-small cell lung cancer: a network meta-analysis of randomized clinical trials. Front Pharmacol, 2021, 12: 686876.

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. Doroshow DB, Sanmamed MF, Hastings K, et al. Immunotherapy in non-small cell lung cancer: facts and hopes. Clin Cancer Res, 2019, 25(15): 4592-4602.
3. Fukumura D, Kloepper J, Amoozgar Z, et al. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol, 2018, 15(5): 325-340.
4. Voron T, Marcheteau E, Pernot S, et al. Control of the immune response by pro-angiogenic factors. Front Oncol, 2014, 4: 70.
5. Salanti G, Ades AE, Ioannidis JP. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol, 2011, 64(2): 163-171.
6. Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov, 2018, 8(9): 1069-1086.
7. Hack SP, Zhu AX, Wang Y. Augmenting anticancer immunity through combined targeting of angiogenic and PD-1/PD-L1 pathways: challenges and opportunities. Front Immunol, 2020, 11: 598877.
8. Lee J, Koh J, Kim HK, et al. Bevacizumab plus atezolizumab after progression on atezolizumab monotherapy in pretreated patients with NSCLC: an open-label, two-stage, phase 2 trial. J Thorac Oncol, 2022, 17(7): 900-908.
9. Kudo M. Scientific rationale for combined immunotherapy with PD-1/PD-L1 antibodies and VEGF inhibitors in advanced hepatocellular carcinoma. Cancers (Basel), 2020, 12(5): 1089.
10. Liu Y, Zhang T, Zhang L, et al. Combined application of bevacizumab and PD-1 blockade displays durable treatment effects by increasing the infiltration and cytotoxic function of CD8+ T cells in lung cancer. Immunotherapy, 2022, 14(9): 695-708.
11. 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, 16(11): 1909-1924.
12. 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.
13. Zhou C, Wu YL, Chen G, et al. BEYOND: a randomized, double-blind, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer. J Clin Oncol, 2015, 33(19): 2197-2204.
14. Niho S, Kunitoh H, Nokihara H, et al. Randomized phase II study of first-line carboplatin-paclitaxel with or without bevacizumab in Japanese patients with advanced non-squamous non-small-cell lung cancer. Lung Cancer, 2012, 76(3): 362-367.
15. Yoshida H, Kim YH, Sakamori Y, et al. A randomized phase II study of maintenance bevacizumab, pemetrexed or bevacizumab plus pemetrexed for advanced non-squamous non-small cell lung cancer. Anticancer Res, 2020, 40(5): 2981-2987.
16. 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(7): 924-937.
17. 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): 1505-1517.
18. 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.
19. Zhou C, Chen G, Huang Y, et al. Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small-cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial. Lancet Respir Med, 2021, 9(3): 305-314.
20. Lu S, Wang J, Yu Y, et al. Tislelizumab plus chemotherapy as first-line treatment for locally advanced or metastatic nonsquamous NSCLC (RATIONALE 304): a randomized phase 3 trial. J Thorac Oncol, 2021, 16(9): 1512-1522.
21. Sugawara S, Lee JS, Kang JH, et al. Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer. Ann Oncol, 2021, 32(9): 1137-1147.
22. Gu T, Jiang A, Zhou C, et al. Adverse reactions associated with immune checkpoint inhibitors and bevacizumab: a pharmacovigilance analysis. Int J Cancer, 2023, 152(3): 480-495.
23. Iwai T, Sugimoto M, Patel H, et al. Anti-VEGF antibody protects against alveolar exudate leakage caused by vascular hyperpermeability, resulting in mitigation of pneumonitis induced by immunotherapy. Mol Cancer Ther, 2021, 20(12): 2519-2526.
24. Xue L, Gao X, Zhang H, et al. Antiangiogenic antibody BD0801 combined with immune checkpoint inhibitors achieves synergistic antitumor activity and affects the tumor microenvironment. BMC Cancer, 2021, 21(1): 1134.
25. Bagegni NA, Park H, Kraft K, et al. Phase 1b trial of anti-VEGF/PDGFR vorolanib combined with immune checkpoint inhibitors in patients with advanced solid tumors. Cancer Chemother Pharmacol, 2022, 89(4): 487-497.
26. Zhang W, Gu J, Bian C, et al. Immune-related adverse events associated with immune checkpoint inhibitors for advanced non-small cell lung cancer: a network meta-analysis of randomized clinical trials. Front Pharmacol, 2021, 12: 686876.

Chinese Journal of Evidence-Based Medicine

Efficacy and safety of immune checkpoint inhibitor and bevacizumab combined with chemotherapy in the first-line treatment of advanced wild-type non-squamous non-small cell lung cancer: a network meta-analysis

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