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Efficacy and safety of PD-L1 inhibitors versus PD-1 inhibitors in first-line treatment with chemotherapy for extensive-stage small-cell lung cancer

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Abstract

Objectives

Programmed cell death-ligand 1 inhibitors plus chemotherapy (PD-L1 + Chemo) have achieved substantial progress in extensive-stage small-cell lung cancer (ES-SCLC). However, evidence about programmed cell death 1 inhibitors plus chemotherapy (PD-1 + Chemo) in SCLC is relatively lacking. Whether PD-1 inhibitors differ from PD-L1 inhibitors in their clinical outcomes remains controversial.

Materials and methods

We performed a meta-analysis to compare efficacy and safety of PD-L1 + Chemo vs PD-1 + Chemo in ES-SCLC by searching PubMed, Embase, the Cochrane Library, and major oncology conferences. We examined overall survival (OS) as the primary outcome. Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (AEs).

Results

We included four randomized trials (IMpower133, CASPIAN, KEYNOTE-604, and EA5161) with a total of 1553 patients. Direct comparison showed that PD-L1 + Chemo (PFS: hazard ratio [HR] 0.79; OS: HR 0.75) and PD-1 + Chemo (PFS: HR 0.72; OS: HR 0.77) significantly prolonged survival time compared with chemotherapy alone. But PD-L1 + Chemo (relative risk [RR]: 1.07) and PD-1 + Chemo (RR: 1.13) were not superior to chemotherapy alone in terms of ORR. Indirect comparison showed no significant difference in clinical efficacy between PD-L1 + Chemo and PD-1 + Chemo (OS: HR 0.99; PFS: HR 1.10; ORR: RR 0.95). We further stratified patients according to subgroups in terms of OS. In the subgroup of patients with brain metastasis, PD-L1 + Chemo tended to prolong OS (HR: 0.61, 0.28 to 1.32). There were no significant differences between PD-L1 + Chemo and PD-1 + Chemo regarding safety analyses. However, PD-L1 + Chemo exhibited a better safety profile in reducing the risk of treatment discontinuation due to AEs (RR: 0.43, 0.19 to 0.95) and pneumonia (pneumonia of any grade, RR: 0.59, 0.24 to 1.42; pneumonia of grade ≥ 3, RR: 0.37, 0.10 to 1.39).

Conclusions

PD-L1 + Chemo and PD-1 + Chemo provided a significant survival benefit relative to chemotherapy alone for ES-SCLC. The efficacy and safety of PD-L1 + Chemo and PD-1 + Chemo were similar based on current evidence.

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Data availability

All data generated or analyzed during this study are included in the published article.

Abbreviations

AEs:

Adverse events

BBB:

Blood-brain barrier

Chemo:

Chemotherapy

CI:

Confidence interval

DCs:

Dendritic cells

ECOG:

Eastern Cooperative Oncology Group

ESMO:

European Society of Medical Oncology

HRs:

Hazard ratios

IC:

Immune cell

ICIs:

Immune checkpoint inhibitors

irAEs:

Immune-related adverse events

NCCN:

National Comprehensive Cancer Network

NSCLC:

Non-small-cell lung carcinoma

ORR:

Objective response rate

OS:

Overall survival

PD-1:

Programmed cell death 1

PD-L1:

Programmed cell death-ligand 1

PFS:

Progression-free survival

RR:

Relative risk

SE:

Standard error

SCLC:

Small-cell lung cancer

TC:

Tumor cell

TMB:

Tumor mutational burden

References

  1. Oronsky B, Reid T, Oronsky A, Carter C (2017) What’s new in SCLC? a review. Neoplasia (New York, NY) 19(10):842–847

    Article  CAS  Google Scholar 

  2. Lally B, Urbanic J, Blackstock A, Miller A, Perry M (2007) Small cell lung cancer: have we made any progress over the last 25 years? Oncologist 12(9):1096–1104

    Article  Google Scholar 

  3. Stahel R, Thatcher N, Früh M, Le Péchoux C, Postmus P, Sorensen J, Felip E (2011) 1st ESMO consensus conference in lung cancer; lugano 2010: small-cell lung cancer. Ann Oncol: Off J Eur Soc Med Oncol 22(9):1973–1980

    Article  CAS  Google Scholar 

  4. Früh M, De Ruysscher D, Popat S, Crinò L, Peters S, Felip E (2013) Small-cell lung cancer (SCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol : Off J Eur Soc Med Oncol 24:vi99–vi105

    Article  Google Scholar 

  5. Kalemkerian G, Loo B, Akerley W, Attia A, Bassetti M, Boumber Y, Decker R, Dobelbower M, Dowlati A, Downey R et al (2018) NCCN guidelines insights: small cell lung cancer, version 2.2018. J Natl Compr Cancer Netw : JNCCN 16(10):1171–1182

    Article  Google Scholar 

  6. Farago A, Keane F (2018) Current standards for clinical management of small cell lung cancer. Transl Lung Cancer Res 7(1):69–79

    Article  Google Scholar 

  7. Liu S, Reck M, Mansfield A, Mok T, Scherpereel A, Reinmuth N, Garassino M, De Castro CJ, Califano R, Nishio M et al (2021) Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J Clin Oncol : Off J Am Soc Clin Oncol 39(6):619–630

    Article  CAS  Google Scholar 

  8. Paz-Ares L, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, Statsenko G, Hochmair M, Özgüroğlu M, Ji J et al (2019) Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet (London, England) 394(10212):1929–1939

    Article  CAS  Google Scholar 

  9. Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair M, Powell S et al (2018) Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378(22):2078–2092

    Article  CAS  Google Scholar 

  10. Langer C, Gadgeel S, Borghaei H, Papadimitrakopoulou V, Patnaik A, Powell S, Gentzler R, Martins R, Stevenson J, Jalal S et al (2016) 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 17(11):1497–1508

    Article  CAS  Google Scholar 

  11. Rudin C, Awad M, Navarro A, Gottfried M, Peters S, Csőszi T, Cheema P, Rodriguez-Abreu D, Wollner M, Yang J et al (2020) Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer: randomized, double-blind, phase III KEYNOTE-604 study. J Clin Oncol : Off J Am Soc Clin Oncol 38(21):2369–2379

    Article  CAS  Google Scholar 

  12. Randomized phase II clinical trial of cisplatin/carboplatin and etoposide (CE) alone or in combination with nivolumab as frontline therapy for extensive-stage small cell lung cancer (ES-SCLC): ECOG-ACRIN EA5161 [https://ascopubs.org/doi/abs/https://doi.org/10.1200/JCO.2020.38.15_suppl.9000]

  13. Bucher H, Guyatt G, Griffith L, Walter S (1997) The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol 50(6):683–691

    Article  CAS  Google Scholar 

  14. Duan J, Cui L, Zhao X, Bai H, Cai S, Wang G, Zhao Z, Zhao J, Chen S, Song J et al (2020) Use of immunotherapy with programmed cell death 1 vs programmed cell death ligand 1 inhibitors in patients with cancer: a systematic review and meta-analysis. JAMA Oncol 6(3):375–384

    Article  Google Scholar 

  15. Chen L, Han X (2015) Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Investig 125(9):3384–3391

    Article  Google Scholar 

  16. Ando K, Manabe R, Kishino Y, Kusumoto S, Yamaoka T, Tanaka A, Ohmori T, Ohnishi T, Sagara H (2021) Comparative efficacy and safety of immunotherapeutic regimens with PD-1/PD-L1 inhibitors for previously untreated extensive-stage small cell lung cancer: a systematic review and network meta-analysis. Curr Oncol (Toronto, Ont) 28(2):1094–1113

    Article  Google Scholar 

  17. Iams W, Porter J, Horn L (2020) Immunotherapeutic approaches for small-cell lung cancer. Nat Rev Clin Oncol 17(5):300–312

    Article  Google Scholar 

  18. Mayoux M, Roller A, Pulko V, Sammicheli S, Chen S, Sum E, Jost C, Fransen M, Buser R, Kowanetz M et al (2020) Dendritic cells dictate responses to PD-L1 blockade cancer immunotherapy. Sci Transl Med 12(534):eaav7431

    Article  CAS  Google Scholar 

  19. Kowanetz M, Zou W, Gettinger S, Koeppen H, Kockx M, Schmid P, Kadel E, Wistuba I, Chaft J, Rizvi N et al (2018) Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1). Proc Natl Acad Sci USA 115(43):E10119–E10126

    Article  CAS  Google Scholar 

  20. Xu C, Chen Y, Du X, Liu J, Huang C, Chen L, Zhou G, Li W, Mao Y, Hsu C et al (2018) Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis. BMJ (Clinical research ed) 363:k4226

    Article  Google Scholar 

  21. Khunger M, Rakshit S, Pasupuleti V, Hernandez A, Mazzone P, Stevenson J, Pennell N, Velcheti V (2017) Incidence of pneumonitis with use of programmed death 1 and programmed death-ligand 1 inhibitors in non-small cell lung cancer: a systematic review and meta-analysis of trials. Chest 152(2):271–281

    Article  Google Scholar 

Download references

Funding

This study was funded by grants 81903176 from the National Natural Science Funds of China; 2019A1515011596 from the Science and Technology Program of Guangdong Province. C2019110 from Medical Scientific Research Foundation of Guangdong Province. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Author notes

  1. Hui Yu, Ping Chen and Xiuyu Cai have contributed equally.

Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Guangzhou, China

    Hui Yu, Ping Chen, Xiuyu Cai, Chen Chen, Xuanye Zhang, Lina He, Yixin Zhou, Shaodong Hong & Bei Zhang

  2. Collaborative Innovation Center for Cancer Medicine, Guangzhou, China

    Hui Yu, Ping Chen, Xiuyu Cai, Chen Chen, Xuanye Zhang, Lina He, Yixin Zhou, Shaodong Hong & Bei Zhang

  3. Department of VIP Region, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, China

    Hui Yu, Ping Chen, Xiuyu Cai, Yixin Zhou & Bei Zhang

  4. Department of Radiotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, China

    Chen Chen

  5. Department of Medical Oncology, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, China

    Xuanye Zhang, Lina He & Shaodong Hong

Authors
  1. Hui Yu
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  4. Chen Chen
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Contributions

H.Y., P.C., and XY.C. contributed to data acquisition, data interpretation, and statistical analysis and drafting of the manuscript. C.C., XY.Z., and LN.H. contributed to data acquisition, data interpretation, and statistical analysis. YX.Z., SD.H., and B.Z. contributed to the study design, data acquisition, data interpretation, and statistical analysis. All the authors contributed to critical revision of the manuscript.

Corresponding authors

Correspondence to Yixin Zhou, Shaodong Hong or Bei Zhang.

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Précis: Our work confirmed that PD-L1+Chemo was not superior to PD-1+Chemo in terms of OS, PFS and ORR. However, PD-L1+Chemo tended to prolong OS for patients with brain metastases and exhibited a better safety profile relative to PD-1+Chemo.

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Yu, H., Chen, P., Cai, X. et al. Efficacy and safety of PD-L1 inhibitors versus PD-1 inhibitors in first-line treatment with chemotherapy for extensive-stage small-cell lung cancer. Cancer Immunol Immunother 71, 637–644 (2022). https://doi.org/10.1007/s00262-021-03017-z

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  • DOI: https://doi.org/10.1007/s00262-021-03017-z

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