Abstract
Introduction
Single-agent immune checkpoint inhibitors (ICIs) like pembrolizumab or atezolizumab have been approved as first-line monotherapy for advanced non-small cell lung cancer (NSCLC) patients with PD-L1 ≥ 50%. However, emerging evidences have showed that ICI combinations (chemoimmunotherapy or dual-agent ICIs) argue to offer a higher response rate. In this network meta-analysis, we aimed to evaluate the efficacy and toxicity of first-line single-agent ICIs versus ICI combinations for advanced NSCLC patients with PD-L1 ≥ 50%.
Methods
PubMed, Embase, Cochrane Library and the Clinicaltrials.gov were systematically searched to extract eligible literature until December 2020. Outcomes included overall survival (OS), progression free survival (PFS), objective response rate (ORR) and treatment related adverse events (TRAEs) of grades 3–5.
Results
Fourteen studies with 3448 patients were included. The results showed that chemotherapy plus ICIs significantly improved PFS and ORR compared to chemotherapy, and sinti-chemo (HR: 0.31, 95% CI: 0.20–0.49) and pembro-chemo (OR: 4.2, 95% CI: 2.6–6.7) ranked first. In terms of OS, cemiplimab provided the best benefit versus chemotherapy (HR: 0.57, 95% CI: 0.43–0.77), followed by atezolizumab and pembro-chemo. In the subgroup analysis of histological type, pembro-chemo and sinti-chemo showed the best benefit of PFS in squamous and nonsquamous NSCLC, respectively, while there was no significant difference between ICI combinations with single-agent ICIs in OS. Moreover, the addition of chemotherapy to ICIs elevated toxicity compared to chemotherapy.
Conclusion
The study suggested that chemotherapy plus ICIs might improve PFS and ORR than single-agent ICIs for advanced NSCLC patients with PD-L1 ≥ 50%. However, it did not lead to OS benefit.
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Data availability
The authors confirm that all data and material analyzed during this study are included in this article.
References
Siegel RL, Miller KD, Fuchs HE, Jemal A (2021) Cancer statistics, 2021. CA Cancer J Clin 71:7–33. https://doi.org/10.3322/caac.21654
Planchard D, Popat S, Kerr K, Van Schil PE, Hellmann MD, Peters S et al (2019) Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 30:863–870. https://doi.org/10.1093/annonc/mdy474
Abdel KN, Kelly K (2019) role of targeted therapy and immune checkpoint blockers in advanced non-small cell lung cancer: a review. Oncologist 24:1270–1284. https://doi.org/10.1634/theoncologist.2018-0112
Arbour KC, Riely GJ (2019) Systemic therapy for locally advanced and metastatic non-small cell lung cancer: a review. JAMA 322:764–774. https://doi.org/10.1001/jama.2019.11058
Chen R, Manochakian R, James L, Zhao Y, Zhou K, Lou Y et al (2020) Emerging therapeutic agents for advanced non-small cell lung cancer. J Hematol Oncol 13:58. https://doi.org/10.1186/s13045-020-00881-7
Verma V, Shrimali RK, Ahmad S, Mkrtichyan M, Gupta S, Khleif SN et al (2019) PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1CD38 cells and anti-PD-1 resistance. Nat Immunol 20:1231–1243. https://doi.org/10.1038/s41590-019-0441-y
Liu Y, Zheng P (2020) Preserving the CTLA-4 Checkpoint for safer and more effective cancer immunotherapy. Trends Pharmacol Sci 41:4–12. https://doi.org/10.1016/j.tips.2019.11.003
Reck M, Rodriguez-Abreu D, Robinson AG, Shentu Y, Rangwala R, Brahmer JR et al (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non–small-cell lung cancer. N Engl J Med 375:1823–1833. https://doi.org/10.1056/NEJMoa1606774
Herbst RS, Giaccone G, de Marinis F, Mocci S, Jassem J, Spigel DR et al (2020) Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC. N Engl J Med 383:1328–1339. https://doi.org/10.1056/NEJMoa1917346
Hellmann MD, Paz-Ares L, Bernabe Caro RB, Kasinathan RS, Nathan FE, Ramalingam SS et al (2019) Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med 381:2020–2031. https://doi.org/10.1056/NEJMoa1910231
Paz-Ares L, Ciuleanu TE, Cobo M, Oukessou A, Yan J, Reck M et al (2021) 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 22:198–211. https://doi.org/10.1016/S1470-2045(20)30641-0
US Food and Drug Administration (2020) FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%). https:// www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-ipilimumab-first-line-mnsclc-pd-l1-tumor-expression-1
Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F et al (2018) Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378:2078–2092. https://doi.org/10.1056/NEJMoa1801005
Gadgeel S, Rodríguez-Abreu D, Speranza G, Esteban E, Felip E, Dómine M et al (2020) 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 38:1505–1517. https://doi.org/10.1200/JCO.19.03136
Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J et al (2018) Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 379:2040–2051. https://doi.org/10.1056/NEJMoa1810865
Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N et al (2018) Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378:2288–2301. https://doi.org/10.1056/NEJMoa1716948
West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ et al (2019) 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 20:924–937. https://doi.org/10.1016/S1470-2045(19)30167-6
Jotte R, Cappuzzo F, Vynnychenko I, Stroyakovskiy D, Rodríguez-Abreu D, Hussein M et al (2020) Atezolizumab in combination with carboplatin and Nab-Paclitaxel in advanced squamous NSCLC (IMpower131): results from a randomized phase III Trial. J Thorac Oncol 15:1351–1360. https://doi.org/10.1016/j.jtho.2020.03.028
Papadimitrakopoulou V, Cobo M, Bordoni R, Dubray-Longeras P, Szalai Z, Ursol G et al (2018) OA05.07 IMpower132: PFS and safety results with 1L atezolizumab + carboplatin/cisplatin + pemetrexed in stage IV non-squamous NSCLC. J Thorac Oncol 13:S332–S333. https://doi.org/10.1016/j.jtho.2018.08.262
Yang Y, Wang Z, Fang J, Yu Q, Han B, Cang S et al (2020) Efficacy and safety of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC: a randomized, double-blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol 15:1636–1646. https://doi.org/10.1016/j.jtho.2020.07.014
Zhou C, Chen G, Huang Y, Zhou J, Lin L, Feng J et al (2021) 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 9:305–314. https://doi.org/10.1016/S2213-2600(20)30365-9
NCCN clinical practice guidelines in oncology, Version 5 (2021) Non-small cell lung cancer. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450
Moher D, Liberati A, Tetzlaff J, Altman DG (2009) PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 339:b2535. https://doi.org/10.1136/bmj.b2535
Phan K, Tian DH, Cao C, Black D, Yan TD (2015) Systematic review and meta-analysis: techniques and a guide for the academic surgeon. Ann Cardiothorac Surg 4:112–122. https://doi.org/10.3978/j.issn.2225-319X.2015.02.04
Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Sterne JA (2011) Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343: d5928. https://doi.org/10.1136/bmj.d5928
Rucker G (2012) Network meta-analysis, electrical networks and graph theory. Res Synth Methods 3:312–324. https://doi.org/10.1002/jrsm.1058
Salanti G, Ades AE, Ioannidis JP (2011) Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol 64:163–171. https://doi.org/10.1016/j.jclinepi.2010.03.016
Van Valkenhoef G, Dias S, Ades AE, Welton NJ (2016) Automated generation of node-splitting models for assessment of inconsistency in network meta-analysis. Res Syn Methods 7:80–93. https://doi.org/10.1002/jrsm.1167
Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560. https://doi.org/10.1136/bmj.327.7414.557
Brahmer JR, Rodriguez-Abreu D, Robinson AG, Hui R, Csszi T, Fülp A et al (2020) LBA51 KEYNOTE-024 5-year OS update: First-line (1L) pembrolizumab (pembro) vs. platinum-based chemotherapy (chemo) in patients (pts) with metastatic NSCLC and PD-L1 tumour proportion score (TPS) ≥50%. Ann Oncol 31: S1181-S1182. https://www.sciencedirect.com/science/article/pii/S092375342042366X
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A et al (2019) 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 37:537–546. https://doi.org/10.1200/JCO.18.00149
Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ et al (2019) 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 393:1819–1830. https://doi.org/10.1016/S0140-6736(18)32409-7
Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M et al (2017) First-Line Nivolumab in Stage IV or recurrent non-small-cell lung cancer. N Engl J Med 376:2415–2426. https://doi.org/10.1056/NEJMoa1613493
Ramalingam SS, Ciuleanu TE, Pluzanski A, Lee JS, Schenker M, Caro RB et al (2021) OA03.03 Nivolumab (NIVO) + ipilimumab (IPI) Versus Platinum-Doublet Chemotherapy (Chemo) as first-line (1L) Treatment for advanced non-small cell lung cancer (aNSCLC): 3-year update from CheckMate 227 Part 1. J Thorac Oncol 16. https://www.sciencedirect.com/science/article/abs/pii/S1556086420308893
Rizvi NA, Cho BC, Reinmuth N, Lee KH, Luft A, Ahn MJ et al (2020) Durvalumab with or without tremelimumab vs standard chemotherapy in first-line treatment of metastatic non-small cell lung cancer: The MYSTIC Phase 3 randomized clinical trial. JAMA Oncol 6:661–674. https://doi.org/10.1001/jamaoncol.2020.0237
Sezer A, Kilickap S, Gümüş M, Bondarenko I, Özgüroğlu M, Gogishvili M et al (2021) Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet 397:592–604. https://doi.org/10.1016/S0140-6736(21)00228-2
Bracci L, Schiavoni G, Sistigu A, Belardelli F (2014) Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ 21:15–25. https://doi.org/10.1038/cdd.2013.67
Wang Z, Till B, Gao Q (2017) Chemotherapeutic agent-mediated elimination of myeloid-derived suppressor cells. Oncoimmunology 6:e1331807. https://doi.org/10.1080/2162402X.2017.1331807
Roselli M, Cereda V, di Bari MG, Formica V, Spila A, Jochems C et al (2013) Effects of conventional therapeutic interventions on the number and function of regulatory T cells. Oncoimmunology 2:e27025. https://doi.org/10.4161/onci.27025
Lesterhuis WJ, Punt CJ, Hato SV, Eleveld-Trancikova D, Jansen BJ, Nierkens S et al (2011) Platinum-based drugs disrupt STAT6- mediated suppression of immune responses against cancer in humans and mice. J Clin Invest 121:3100–3108. https://doi.org/10.1172/JCI43656
Lisberg A, Garon EB (2019) Does platinum-based chemotherapy still have a role in first-line treatment of advanced non-small-cell lung cancer? J Clin Oncol 37:529–536. https://doi.org/10.1200/JCO.18.01534
Goldberg SB, Herbst RS (2018) Should chemotherapy plus immune check point inhibition be the standard front-line therapy for patients with metastatic non-small cell lung cancer? Cancer 124:4592–4596. https://doi.org/10.1002/cncr.31681
ClinicalTrials.gov (2020) PEmbRolizumab verSus chEmotherapy and pEmbrolizumab in Non-small-cell Lung Cancers (NSCLC) With PDL1 ≥ 50 % (PERSEE). https://clinicaltrials.gov/ct2/show/NCT04547504
Herbst RS, Lopes G, Kowalski DM, Nishio M, Wu YL, Junior G, et al (2019) Association between tissue TMB (tTMB) and clinical outcomes with pembrolizumab monotherapy (pembro) in PD-L1-positive advanced NSCLC in the KEYNOTE-010 and -042 trials. Ann Oncol 30: v916–v917. https://www.sciencedirect.com/science/article/pii/S0923753419604370
Peters S, Creelan B, Hellmann MD, Socinski MA, Carbone DP (2017) Abstract CT082: Impact of tumor mutation burden on the efficacy of first-line nivolumab in stage iv or recurrent non-small cell lung cancer: An exploratory analysis of CheckMate 026. Cancer Res 77:CT082–CT082. https://doi.org/10.1158/1538-7445.AM2017-CT082
Gandara DR, Paul SM, Kowanetz M, Schleifman E, Zou W, Li Y et al (2018) Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med 24:1441–1448. https://doi.org/10.1038/s41591-018-0134-3
Sholl LM, Hirsch FR, Hwang D, Botling FJ, Lopez-Rios FF, Lb H et al (2020) The promises and challenges of tumor mutation burden as an immunotherapy biomarker: a perspective from the International Association for the Study of Lung Cancer Pathology Committee. J Thorac Oncol 15:1409–1424. https://doi.org/10.1016/j.jtho.2020.05.019
Kim R, Keam B, Hahn S, Ock CY, Kim M, Kim TM et al (2019) First-line pembrolizumab versus pembrolizumab plus chemotherapy versus chemotherapy alone in non-small-cell lung cancer: a systematic review and network meta-analysis. Clin Lung Cancer 20:331–338. https://doi.org/10.1016/j.cllc.2019.05.009
Addeo A, Banna GL, Metro G, Di Maio M (2019) chemotherapy in combination with immune checkpoint inhibitors for the first-line treatment of patients with advanced non-small cell lung cancer: a systematic review and literature-based meta-analysis. Front Oncol 9:264. https://doi.org/10.3389/fonc.2019.00264
Hirsch FR, McElhinny A, Stanforth D, Ranger-Moore J, Jansson M, Kulangara et al (2017) PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the Blueprint PD-L1 IHC assay comparison project. J Thorac Oncol 12:208–222. https://doi.org/10.1016/j.jtho.2016.11.2228
Vennapusa B, Baker B, Kowanetz M, Boone J, Menzl I, Bruey JM et al (2019) Development of a PD-L1 complementary diagnostic immunohistochemistry assay (SP142) for atezolizumab. Appl Immunohistochem Mol Morphol 27:92–100. https://doi.org/10.1097/PAI.0000000000000594
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ZZY, MFH: protocol development; MFH and THZ: data analysis and manuscript writing; MFH, XYZ and YP: literature search; BXT and XJ: study selection; MFH, YSH, THZ: data extraction. All authors have read and agreed to the published version of the manuscript.
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He, M., Zheng, T., Zhang, X. et al. First-line treatment options for advanced non-small cell lung cancer patients with PD-L1 ≥ 50%: a systematic review and network meta-analysis. Cancer Immunol Immunother 71, 1345–1355 (2022). https://doi.org/10.1007/s00262-021-03089-x
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DOI: https://doi.org/10.1007/s00262-021-03089-x