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First-line chemotherapy plus immune checkpoint inhibitors or bevacizumab in advanced non-squamous non-small-cell lung cancer without EGFR mutations or ALK fusions

    Panpan Jiang‡

    Xi'an Jiaotong University Medical College First Affiliated Hospital Department of Medical Oncology, Xi'an, Shaanxi, China

    ‡These authors contributed equally to this work and should be considered co-first authors

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    ,
    Luying Geng‡

    Xi'an Jiaotong University Medical College First Affiliated Hospital Department of Medical Oncology, Xi'an, Shaanxi, China

    ‡These authors contributed equally to this work and should be considered co-first authors

    Search for more papers by this author

    ,
    Ziyang Mao

    Xi'an Jiaotong University Medical College First Affiliated Hospital Department of Medical Oncology, Xi'an, Shaanxi, China

    ,
    Qinyang Wang

    Xi'an Jiaotong University Medical College First Affiliated Hospital Department of Medical Oncology, Xi'an, Shaanxi, China

    ,
    Wenjuan Wang

    Xi'an Jiaotong University Medical College First Affiliated Hospital Department of Medical Oncology, Xi'an, Shaanxi, China

    ,
    Min Jiao

    Xi'an Jiaotong University Medical College First Affiliated Hospital Department of Medical Oncology, Xi'an, Shaanxi, China

    ,
    Yu Yao

    Xi'an Jiaotong University Medical College First Affiliated Hospital Department of Medical Oncology, Xi'an, Shaanxi, China

    ,
    Nanzheng Chen

    Department of Thoracic Surgery, Xi'an Jiaotong University Medical College First Affiliated Hospital, Xi'an, Shaanxi, China

    ,
    Jia Zhang

    Department of Thoracic Surgery, Xi'an Jiaotong University Medical College First Affiliated Hospital, Xi'an, Shaanxi, China

    ,
    Kejun Nan

    Oncology Hospital, Xi'an International Medical Center, Xi'an, Shaanxi, China

    ,
    Yuan Shen

    Department of Statistical Teaching & Research, Xi'an Jiaotong University, Xi'an, Shaanxi, China

    ,
    Hui Guo

    *Author for correspondence: Tel.: +86 135 7282 4106;

    E-mail Address: guohui@xjtufh.edu.cn

    Xi'an Jiaotong University Medical College First Affiliated Hospital Department of Medical Oncology, Xi'an, Shaanxi, China

    Key Laboratory of Environment & Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, Shaanxi, China

    Centre for Translational Medicine, Xi'an Jiaotong University Medical College First Affiliated Hospital, Xi'an, Shaanxi, China

    &
    Lili Jiang

    **Author for correspondence: Tel.: +86 135 7257 1594;

    E-mail Address: jiangli8499@163.com

    Xi'an Jiaotong University Medical College First Affiliated Hospital Department of Medical Oncology, Xi'an, Shaanxi, China

    Published Online:https://doi.org/10.2217/imt-2021-0112

    Aim: To compare the efficacy and safety of first-line chemotherapy (Chemo) plus immune checkpoint inhibitors (ICIs) or bevacizumab (Bev) in advanced non-squamous non-small-cell lung cancer without EGFR mutations or ALK fusions. Methods: A network meta-analysis was conducted to synthesize relative treatment outcomes. Results: Chemo + ICIs is superior to Chemo + Bev in both overall survival (hazard ratio: 0.92; 95% CI: 0.88–0.96) and progression-free survival (hazard ratio: 0.93; 95% CI: 0.90–0.97), with comparable severe adverse events. However, for patients with liver metastasis, Chemo + Bev has a 59.8% probability of providing better overall survival benefit. For specific regimens, pembrolizumab + Chemo showed an absolute advantage over other regimens. Conclusion: First-line Chemo + ICIs is superior to Chemo + Bev in advanced non-squamous non-small-cell lung cancer except for patients with liver metastasis.

    Plain language summary

    Chemotherapy plus immune checkpoint inhibitors and chemotherapy plus bevacizumab were both superior to traditional chemotherapy and were recommended as the first-line treatment for advanced non-squamous non-small-cell lung cancer patients without EGFR mutations or ALK fusions. However, the efficacy and safety of these two treatment models have not been comprehensively discussed head-to-head in clinical trials. Therefore, a network meta-analysis was performed to compare efficacy between these two treatment models, especially according to different clinical characteristics, to guide decision making in clinical practice.

    Papers of special note have been highlighted as: • of interest

    References

    • 1. Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature 553(7689), 446–454 (2018).
    • 2. Arbour KC, Riely GJ. Systemic therapy for locally advanced and metastatic non-small cell lung cancer: a review. JAMA 322(8), 764–774 (2019).
    • 3. Reck M, Rodríguez-Abreu D, Robinson AG et al. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J. Clin. Oncol. 37(7), 537–546 (2019).
    • 4. 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. 383(14), 1328–1339 (2020).
    • 5. Holmes M, Mahar A, Lum T, Kao S, Cooper WA. Real-world programmed death-ligand 1 prevalence rates in non-small cell lung cancer: correlation with clinicopathological features and tumour mutation status. J. Clin. Pathol. 74(2), 123–128 (2021).
    • 6. 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. 14(1), 124–129 (2019).
    • 7. 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. 38(14), 1505–1517 (2020). • This was the study that led to the approval of first-line (1L) pembrolizumab plus chemotherapy for patients with metastatic non-squamous non-small-cell lung cancer regardless of PD-L1 expression.The present study found that pembrolizumab plus chemotherapy yielded better efficacy than other immune checkpoint inhibitors plus chemotherapy and chemotherapy plus bevacizumab.
    • 8. 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. 20(7), 924–937 (2019). • This study led to the approval of 1L atezolizumab plus chemotherapy for patients with advanced non-small-cell lung cancer.
    • 9. Paz-Ares L, Ciuleanu TE, Cobo M et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 22(2), 198–211 (2021).
    • 10. Huang LT, Cao R, Wang YR et al. Clinical option of pemetrexed-based versus paclitaxel-based first-line chemotherapeutic regimens in combination with bevacizumab for advanced non-squamous non-small-cell lung cancer and optimal maintenance therapy: evidence from a meta-analysis of randomized control trials. BMC Cancer 21(1), 426 (2021).
    • 11. Liu Y, Li HM, Wang R. Effectiveness and safety of adding bevacizumab to platinum-based chemotherapy as first-line treatment for advanced non-small-cell lung cancer: a meta-analysis. Front. Med. (Lausanne) 8, 616380 (2021).
    • 12. Reck M, Wehler T, Orlandi F et al. Safety and patient-reported outcomes of atezolizumab plus chemotherapy with or without bevacizumab versus bevacizumab plus chemotherapy in non-small-cell lung cancer. J. Clin. Oncol. 38(22), 2530–2542 (2020).
    • 13. Hutton B, Salanti G, Caldwell DM et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann. Intern. Med. 162(11), 777–784 (2015).
    • 14. Higgins JP, Altman DG, Gøtzsche PC et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 343, d5928 (2011).
    • 15. Cope S, Zhang J, Saletan S, Smiechowski B, Jansen JP, Schmid P. A process for assessing the feasibility of a network meta-analysis: a case study of everolimus in combination with hormonal therapy versus chemotherapy for advanced breast cancer. BMC Med. 12(1), 1–17 (2014).
    • 16. Chaimani A, Higgins JP, Mavridis D, Spyridonos P, Salanti G. Graphical tools for network meta-analysis in STATA. PLoS One 8(10), e76654 (2013).
    • 17. Sutton A, Ades AE, Cooper N, Abrams K. Use of indirect and mixed treatment comparisons for technology assessment. Pharmacoeconomics 26(9), 753–767 (2008).
    • 18. 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. 64(2), 163–171 (2011).
    • 19. Spiegelhalter DJ, Best NG, Carlin BR et al. Bayesian measures of model complexity and fit. J. R. Stat. Soc. B. 64, 583–616 (2002).
    • 20. Schünemann HJ, Oxman AD, Vist GE et al. Confidence intervals. In: Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0). Higgins JGreen S (Eds). The Cochrane Collaboration, London, UK (2011). https://handbook-5-1.cochrane.org/
    • 21. Dias S, Welton NJ, Caldwell DM, Ades AE. Checking consistency in mixed treatment comparison meta-analysis. Stat. Med. 29(7-8), 932–944 (2010).
    • 22. Paz-Ares L, Ciuleanu TE, Yu X et al. Nivolumab (NIVO) 1 platinum-doublet chemotherapy (chemo) vs chemo as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (aNSCLC): CheckMate 227 – part 2 final analysis. Ann. Oncol. 30(Suppl. 11), xi67–xi68 (2019).
    • 23. Zhou C, Chen G, Huang Y et al. OA04.03 A randomized phase 3 study of camrelizumab plus chemotherapy as 1st line therapy for advanced/metastatic non-squamous non-small cell lung cancer. J. Thorac. Oncol. 14(10), S215–S216 (2019).
    • 24. Papadimitrakopoulou V, Cobo M, Bordoni R et al. IMpower132: PFS and safety results with 1L atezolizumab + carboplatin/cisplatin + pemetrexed in stage IV non-squamous NSCLC. J. Thorac. Oncol. 13(10), S332–S333 (2018).
    • 25. Reck M, von Pawel J, Zatloukal P et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann. Oncol. 21(9), 1804–1809 (2010).
    • 26. Galetta D, Cinieri S, Pisconti S et al. Cisplatin/pemetrexed followed by maintenance pemetrexed versus carboplatin/paclitaxel/bevacizumab followed by maintenance bevacizumab in advanced nonsquamous lung cancer: the GOIM (Gruppo Oncologico Italia Meridionale) ERACLE phase III randomized trial. Clin. Lung Cancer 16(4), 262–273 (2015).
    • 27. 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. 33(19), 2197–2204 (2015). • In this study, overall survival was significantly prolonged with carboplatin/paclitaxel plus bevacizumab (median 24.3 months), which is comparable with the results in KEYNOTE-189.
    • 28. Sandler A, Gray R, Perry MC et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 355(24), 2542–2550 (2006).
    • 29. 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 76(3), 362–367 (2012).
    • 30. Koyama R, Udagawa H, Sugiyama E et al. 1436P randomized phase II study comparing cisplatin + pemetrexed + bevacizumab with carboplatin + paclitaxel + bevacizumab in treatment-naive advanced non-squamous non-small-cell lung cancer (CLEAR study). Ann. Oncol. 29(Suppl. 8), viii493–viii547 (2018).
    • 31. Patel JD, Socinski MA, Garon EB et al. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J. Clin. Oncol. 31(34), 4349–4357 (2013).
    • 32. Zinner RG, Obasaju CK, Spigel DR et al. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients with advanced nonsquamous non-small-cell lung cancer. J. Thorac. Oncol. 10(1), 134–142 (2015).
    • 33. Liu T, Ding S, Dang J, Wang H, Chen J, Li G. First-line immune checkpoint inhibitors for advanced non-small cell lung cancer with wild-type epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK): a systematic review and network meta-analysis. J. Thorac. Dis. 11(7), 2899–2912 (2019).
    • 34. Peng TR, Lin HH, Tsai FP, Wu TW. Immune checkpoint inhibitors for first-line treatment of advanced non-small-cell lung cancer: a systematic review and network meta-analysis. Thorac. Cancer 12(21), 2873–2885 (2021).
    • 35. Garcia J, Hurwitz HI, Sandler AB et al. Bevacizumab (Avastin®) in cancer treatment: a review of 15 years of clinical experience and future outlook. Cancer Treat. Rev. 86, 102017 (2020).
    • 36. Frentzas S, Simoneau E, Bridgeman VL et al. Vessel co-option mediates resistance to antiangiogenic therapy in liver metastases. Nat. Med. 22(11), 1294–1302 (2016).
    • 37. Coelho AL, Gomes MP, Catarino RJ et al. Angiogenesis in NSCLC: is vessel co-option the trunk that sustains the branches? Oncotarget 8(24), 39795–398042 (2017).
    • 38. Cantelmo AR, Dejos C, Kocher F et al. Angiogenesis inhibition in non-small cell lung cancer: a critical appraisal, basic concepts and updates from American Society for Clinical Oncology 2019. Curr. Opin. Oncol. 32(1), 44–53 (2020).
    • 39. Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint inhibitors therapy. Cancer Discov. 8(9), 1069–1086 (2018).
    • 40. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39(1), 1–10 (2013).
    • 41. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann. Oncol. 27(8), 1492–1504 (2016).
    • 42. Chen L, Han X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J. Clin. Invest. 125(9), 3384–3391 (2015).
    • 43. Lickliter JD, Gan HK, Voskoboynik M et al. A first-in-human dose finding study of camrelizumab in patients with advanced or metastatic cancer in Australia. Drug Des. Devel. Ther. 14, 1177–1189 (2020).
    • 44. Shimizu T, Seto T, Hirai F et al. Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced solid tumors. Invest. New Drugs 34(3), 347–354 (2016).
    • 45. Wang C, Thudium KB, Han M et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol. Res. 2(9), 846–856 (2014).
    • 46. Fu J, Wang F, Dong L-H et al. Preclinical evaluation of the efficacy, pharmacokinetics and immunogenicity of JS-001, a programmed cell death protein-1 (PD-1) monoclonal antibody. Acta Pharmacol. Sin. 38(5), 710–718 (2017).
    • 47. Scagliotti G, Brodowicz T, Shepherd FA et al. Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer. J. Thorac. Oncol. 6(1), 64–70 (2011).
    • 48. Cavazzoni A, Digiacomo G, Alfieri R et al. Pemetrexed enhances membrane PD-L1 expression and potentiates T cell-mediated cytotoxicity by anti-PD-L1 antibody therapy in non-small-cell lung cancer. Cancers (Basel) 12(3), 666 (2020).
    • 49. Schmid S, Diem S, Li Q et al. Organ-specific response to nivolumab in patients with non-small cell lung cancer (NSCLC). Cancer Immunol. Immunother. 67(12), 1825–1832 (2018).
    • 50. Tumeh PC, Hellmann MD, Hamid O et al. Liver metastasis and treatment outcome with anti-PD-1 monoclonal antibody in patients with melanoma and NSCLC. Cancer Immunol. Res. 5(5), 417–424 (2017).
    • 51. Voron T, Marcheteau E, Pernot S et al. Control of the immune response by pro-angiogenic factors. Front. Oncol. 4, 70 (2014).
    • 52. Fukumura D, Kloepper J, Amoozgar Z et al. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat. Rev. Clin. Oncol. 15(5), 325–340 (2018).
    • 53. Reinmuth N, Jauch A, Xu EC et al. Correlation of EGFR mutations with chromosomal alterations and expression of EGFR, ErbB3 and VEGF in tumor samples of lung adenocarcinoma patients. Lung Cancer 62(2), 193–201 (2008).
    • 54. Tanaka I, Morise M, Miyazawa A et al. Potential benefits of bevacizumab combined with platinum-based chemotherapy in advanced non-small-cell lung cancer patients with EGFR mutation. Clin. Lung Cancer 21(3), 273–280.e4 (2020).