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Tumor mutational burden as a predictive biomarker for non-small cell lung cancer treated with immune checkpoint inhibitors of PD-1/PD-L1

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Abstract

Background

The significant clinical benefits of PD-1/PD-L1 immune checkpoint inhibitors (ICIP) in non-small cell lung cancer (NSCLC) have been widely recognized, emphasizing the urgent need for a reliable biomarker. In this study, we find the remarkable capacity of tumor mutational burden (TMB) to serve as an accessible and streamlined indicator.

Patients and methods

We designed a retrospective cohort study, consisting of 600 NSCLC patients treated with ICIP. Association between TMB and overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) has been explored.

Results

A strong positive correlation between TMB levels and OS, PFS rates, clinical benefit has been found when TMB >  = 16(TMB >  = 16 mutations/megabase (mut/Mb)). However, when TMB < 16, increasing TMB values did not exhibit a gradual stepwise increase in OS and PFS rates. The median months of OS in the TMB >  = 16 and < 16 are 35.58, and 10.71 months respectively with average 12.39 months (p < 0.0001). The median months of PFS in the TMB >  = 16 and < 16 are not-obtained, and 2.79 months respectively with an average of 3.32 months (p < 0.0001). The DCR in the TMB >  = 16 and < 16 are 71.4% and 44.2% respectively with an average of 47.7% (p < 0.0001). The ORR in the TMB >  = 16 and < 16 are 49.4% and 20.8% respectively with an average of 24.5% (p < 0.0001).

Conclusion

The TMB >  = 16 shows significantly associated with optimal ICIP treatment outcomes, including higher patient survival rates, delayed disease progression, and significant clinical benefits. These results present the potential of TMB as a promising biomarker candidate for NSCLC patients undergoing ICIP treatment.

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References

  1. Bryan DS, Donington JS. The role of surgery in management of locally advanced non-small cell lung cancer. Curr Treat Options Oncol. 2019;20(4):27.

    Article  PubMed  Google Scholar 

  2. Nagasaka M, Gadgeel SM. Role of chemotherapy and targeted therapy in early-stage non-small cell lung cancer. Expert Rev Anticancer Ther. 2018;18(1):63–70.

    Article  CAS  PubMed  Google Scholar 

  3. Brown S, Banfill K, Aznar MC, Whitehurst P, Faivre FC. The evolving role of radiotherapy in non-small cell lung cancer. Br J Radiol. 2019;92(1104):20190524.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wu SG, Shih JY. Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer. Mol Cancer. 2018;17(1):38.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Reck M, Remon J, Hellmann MD. First-line immunotherapy for non-small-cell lung cancer. J Clin Oncol. 2022;40(6):586–97.

    Article  CAS  PubMed  Google Scholar 

  6. Tan AC, Pavlakis N. Anti-angiogenic therapy in ALK rearranged non-small cell lung cancer (NSCLC). Int J Mol Sci. 2022;23(16):8863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lahiri A, Maji A, Potdar PD, Singh N, Parikh P, Bisht B, et al. Lung cancer immunotherapy: progress, pitfalls, and promises. Mol Cancer. 2023;22(1):40.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Patel SA, Weiss J. Advances in the treatment of non-small cell lung cancer: immunotherapy. Clin Chest Med. 2020;41(2):237–47.

    Article  PubMed  Google Scholar 

  9. Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, et al. 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. 2019;393(10183):1819–30.

    Article  CAS  PubMed  Google Scholar 

  10. Addeo A, Friedlaender A, Banna GL, Weiss GJ. TMB or not TMB as a biomarker: that is the question. Crit Rev Oncol Hematol. 2021;163: 103374.

    Article  PubMed  Google Scholar 

  11. Chan TA, Yarchoan M, Jaffee E, Swanton C, Quezada SA, Stenzinger A, et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol. 2019;30(1):44–56.

    Article  CAS  PubMed  Google Scholar 

  12. Giannakis M, Mu XJ, Shukla SA, Qian ZR, Cohen O, Nishihara R, et al. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 2016;15(4):857–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, 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):1353–65.

    Article  CAS  PubMed  Google Scholar 

  14. Kim ES, Velcheti V, Mekhail T, et al. Blood-based tumor mutational burden as a biomarker for atezolizumab in non-small cell lung cancer: the phase 2 B-F1RST trial. Nat Med. 2022;28(5):939–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Valero C, Lee M, Hoen D, Weiss K, Kelly DW, Adusumilli PS, et al. Pretreatment neutrophil-to-lymphocyte ratio and mutational burden as biomarkers of tumor response to immune checkpoint inhibitors. Nat Commun. 2021;12(1):729.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.

    Article  CAS  PubMed  Google Scholar 

  17. Zhang M, Fan Y, Nie L, Wang G, Sun K, Cheng Y. Clinical outcomes of immune checkpoint inhibitor therapy in patients with advanced non-small cell lung cancer and preexisting interstitial lung diseases: a systematic review and meta-analysis. Chest. 2022;161(6):1675–86.

    Article  CAS  PubMed  Google Scholar 

  18. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27(4):450–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim SW, Carcereny Costa E, et al. Nivolumab plus Ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019;381(21):2020–31.

    Article  CAS  PubMed  Google Scholar 

  20. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018–28.

    Article  PubMed  Google Scholar 

  21. Felip E, Altorki N, Zhou C, Csőszi T, Vynnychenko I, Goloborodko O, 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):1344–57.

    Article  CAS  PubMed  Google Scholar 

  22. Spigel DR, Faivre-Finn C, Gray JE, Vicente D, Planchard D, Paz-Ares L, et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. J Clin Oncol. 2022;40(12):1301–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540–50.

    Article  CAS  PubMed  Google Scholar 

  24. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823–33.

    Article  CAS  PubMed  Google Scholar 

  25. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Govindan R, Ding L, Griffith M, Subramanian J, Dees ND, Kanchi KL, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell. 2012;150(6):1121–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bodor JN, Boumber Y, Borghaei H. Biomarkers for immune checkpoint inhibition in non-small cell lung cancer (NSCLC). Cancer. 2020;126(2):260–70.

    Article  CAS  PubMed  Google Scholar 

  28. Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14(4):847–56.

    Article  CAS  PubMed  Google Scholar 

  29. Rizvi H, Sanchez-Vega F, La K, Chatila W, Jonsson P, Halpenny D, et al. Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol. 2018;36(7):633–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hellmann MD, Nathanson T, Rizvi H, Creelan BC, Sanchez-Vega F, Ahuja A, et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell. 2018;33(5):843–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yarchoan M, Albacker LA, Hopkins AC, Montesion M, Murugesan K, Vithayathil TT, et al. PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers. JCI Insight. 2019;4(6): e126908.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Lamberti G, Spurr LF, Li Y, Ricciuti B, Recondo G, Umeton R, et al. Clinicopathological and genomic correlates of programmed cell death ligand 1 (PD-L1) expression in nonsquamous non-small-cell lung cancer. Ann Oncol. 2020;31(6):807–14.

    Article  CAS  PubMed  Google Scholar 

  33. Ricciuti B, Wang X, Alessi JV, Rizvi H, Mahadevan NR, Li YY, et al. Association of high tumor mutation burden in non-small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels. JAMA Oncol. 2022;8(8):1160–8.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Affiliated Cixi Hospital, Wenzhou Medical University, Cixi, China

    Min-min Shao, Yue-ping Xu, Jin-jing Zhang, Mao Mao & Meng-chuan Wang

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Correspondence to Meng-chuan Wang.

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No human subjects were directly involved in this study. All the data used in this study were derived from existing biological samples from prior studies.

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Shao, Mm., Xu, Yp., Zhang, Jj. et al. Tumor mutational burden as a predictive biomarker for non-small cell lung cancer treated with immune checkpoint inhibitors of PD-1/PD-L1. Clin Transl Oncol 26, 1446–1458 (2024). https://doi.org/10.1007/s12094-023-03370-8

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