EL, SR, RB and ALC contributed conception and design of the study; AL, GM, VC, IF, LZ and SG organized the data; EL, SR, LC and MR performed the statistical analysis; EL, VC and AL wrote the first draft of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.
Conflicts of interest
All authors declare that there are no conflicts of interest.
Ethical approval
The study was approved by the local Ethics Committee (ID of the study 2019-146). All procedures were performed by the ethics standards of our institutional research committee and with those of the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Consent to participate
Written informed consent was obtained from all subjects before the study.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49. [DOI] [PubMed]
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D.Global cancer statistics. CA Cancer J Clin. 2011;61:69–90. [DOI] [PubMed]
Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WEE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med.2015;373:123–35. [DOI] [PubMed] [PMC]
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med.2015;373:1627–39. [DOI] [PubMed] [PMC]
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;387:1540–50. [DOI]
Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet.2017;389:255–65. [DOI]
Gandhi L, Rodrí guez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med.2018;22:2078–92. [DOI] [PubMed]
Paz-Ares L, Vicente D, Tafreshi A, Robinson A, Soto Parra H, Mazières J, et al. A randomized, placebo-controlled trial of pembrolizumab plus chemotherapy in patients with metastatic squamous NSCLC: protocol-specified final analysis of KEYNOTE-407. J Thorac Oncol. 2020;15:1657–69. [DOI] [PubMed]
Associazione Italiana di Oncologia Medica [Internet]. Milano: The Association; [cited 2021 Mar 16]. Available from: https://www.aiom.it/linee-guida-aiom/
Mok TS, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, et al. Final analysis of the phase III KEYNOTE-042 study: pembrolizumab (Pembro) versus platinum-based chemotherapy (Chemo) as first-line therapy for patients (Pts) with PD-L1-positive locally advanced/metastatic NSCLC. Ann Oncol.2019;30:i38. [DOI]
Dall’Olio FG, Maggio I, Massucci M, Mollica V, Fragomeno B, Ardizzoni A.ECOG performance status ≥ 2 as a prognostic factor in patients with advanced non small cell lung cancer treated with immune checkpoint inhibitors—a systematic review and meta-analysis of real world data. Lung Cancer. 2020;145:95–104. [DOI] [PubMed]
Diem S, Schmid S, Krapf M, Flatz L, Born D, Jochum W, et al. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Lung Cancer. 2017;111:176–81. [DOI] [PubMed]
Xie X, Liu J, Yang H, Chen H, Zhou S, Lin H, et al. Prognostic value of baseline neutrophil-to-lymphocyte ratio in outcome of immune checkpoint inhibitors. Cancer Invest. 2019;37:265–74. [DOI] [PubMed]
Lenci E, Cantini L, Pecci F, Cognigni V, Agostinelli V, Mentrasti G, et al. The gustave roussy immune (GRIm)-score variation is an early-on-treatment biomarker of outcome in advanced non-small cell lung cancer (NSCLC) patients treated with first-line pembrolizumab. J Clin Med.2021;10:1005. [DOI] [PubMed] [PMC]
Cortellini A, Tiseo M, Banna GL, Cappuzzo F, Aerts JGJV, Barbieri F, et al. Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ≥ 50%. Cancer Immunol Immunother.2020;69:2209–21. [DOI] [PubMed]
Cózar B, Greppi M, Carpentier S, Narni-Mancinelli E, Chiossone L, Vivier E.Tumor-infiltrating natural killer cells. Cancer Discov.2021;11:34–44. [DOI] [PubMed]
Li XD, Ji M, Zheng X, Ning ZH, Wu J, Lu B, et al. Evaluation of tumor response to cytokine-induced killer cells therapy in malignant solid tumors. J Transl Med.2014;12:215. [DOI] [PubMed] [PMC]
Maleki Vareki S, Garrigós C, Duran I.Biomarkers of response to PD-1/PD-L1 inhibition. Crit Rev Oncol/Hematol. 2017;116:116–24. [DOI] [PubMed]
Chardin D, Paquet M, Schiappa R, Darcourt J, Bailleux C, Poudenx M, et al. Baseline metabolic tumor volume as a strong predictive and prognostic biomarker in patients with non-small cell lung cancer treated with PD1 inhibitors: a prospective study. J Immunother cancer.2020;8:e000645. [DOI] [PubMed] [PMC]
Cortellini A, Ricciuti B, Tiseo M, Bria E, Banna GL, Aerts JGJV, et al. Baseline BMI and BMI variation during first line pembrolizumab in NSCLC patients with a PD-L1 expression ≥ 50%: a multicenter study with external validation. J Immunother Cancer.2020;8:e001403. [DOI] [PubMed] [PMC]
Cortellini A, De Giglio A, Cannita K, Cortinovis DL, Cornelissen R, Baldesarri C, et al. Smoking status during first-line immunotherapy and chemotherapy in NSCLC patients: a case-control matched analysis from a large multicenter study. Thorac Cancer. 2021;12:880–9. [DOI] [PubMed] [PMC]
Cantini L, Pecci F, Hurkmans DP, Belderbos RA, Lanese A, Copparoni C, et al. High-intensity statins are associated with improved clinical activity of PD-1 inhibitors in malignant pleural mesothelioma and advanced non-small cell lung cancer patients. Eur J Cancer. 2021;144:41–8. [DOI] [PubMed]
Riihimäki M, Hemminki A, Fallah M, Thomsen H, Sundquist K, Sundquist J, et al. Metastatic sites and survival in lung cancer. Lung Cancer. 2014;86:78–84. [DOI] [PubMed]
Badawy AA, Khedr G, Omar A, Bae S, Arafat W, Grant S.Site of metastases as prognostic factors in unselected population of stage IV non-small cell lung cancer. Asian Pacific J Cancer Prev. 2018;19:1907–10.
Li J, Zhu H, Sun L, Xu W, Wang X.Prognostic value of site-specific metastases in lung cancer: a population based study. J Cancer. 2019;10:3079–86. [DOI] [PubMed] [PMC]
Iacovelli R, Lanoy E, Albiges L, Escudier B.Tumour burden is an independent prognostic factor in metastatic renal cell carcinoma. BJU Int. 2012;110:1747–53. [DOI] [PubMed]
Seban RD, Mezquita L, Berenbaum A, Dercle L, Botticella A, Le Pechoux C, et al. Baseline metabolic tumor burden on FDG PET/CT scans predicts outcome in advanced NSCLC patients treated with immune checkpoint inhibitors. Eur J Nucl Med Mol Imaging.2020;47:1147–57. [DOI] [PubMed]
Sasaki K, Morioka D, Conci S, Margonis GA, Sawada Y, Ruzzenente A, et al. The tumor burden score: a new “metro-ticket” prognostic tool for colorectal liver metastases based on tumor size and number of tumors. Ann Surg. 2018;267:132–141. [DOI] [PubMed]
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol.2017;18:e143–52. [DOI]
Katsurada M, Nagano T, Tachihara M, Kiriu T, Furukawa K, Koyama K, et al. Baseline tumor size as a predictive and prognostic factor of immune checkpoint inhibitor therapy for non-small cell lung cancer. Anticancer Res. 2019;39:815–25. [DOI] [PubMed]
Fagerland MW, Hosmer DW, Bofin AM.Multinomial goodness-of-fit tests for logistic regression models. Stat Med. 2008;27:4238–53. [DOI] [PubMed]
Frelaut M, Le Tourneau C, Borcoman E.Hyperprogression under immunotherapy. Int J Mol Sci.2019;20:2674. [DOI] [PubMed] [PMC]
Gomez D, Morris-Stiff G, Toogood GJ, Lodge JPA, Prasad KR.Interaction of tumour biology and tumour burden in determining outcome after hepatic resection for colorectal metastases. HPB. 2010;12:84–93. [DOI] [PubMed] [PMC]
Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016;315:1600–9. [DOI] [PubMed]
Capietto AH, Faccio R.Immune regulation of bone metastasis. Bonekey Rep. 2014;3:600. [DOI] [PubMed] [PMC]
Kawachi H, Tamiya M, Tamiya A, Ishii S, Hirano K, Matsumoto H, et al. Association between metastatic sites and first-line pembrolizumab treatment outcome for advanced non-small cell lung cancer with high PD-L1 expression: a retrospective multicenter cohort study. Invest New Drugs.2020;38:211–8. [DOI] [PubMed]
Tamiya M, Tamiya A, Inoue T, Kimura M, Kunimasa K, Nakahama K, et al. Metastatic site as a predictor of nivolumab efficacy in patients with advanced non-small cell lung cancer: a retrospective multicenter trial. PLoS One. 2018;13:e0192227. [DOI] [PubMed] [PMC]
Peters S, Cappuzzo F, Horn L, Paz-Ares L, Borghaei H, Barlesi F, et al. OA03.05 analysis of early survival in patients with advanced non-squamous NSCLC treated with nivolumab vs. socetaxel in CheckMate 057. J Thorac Oncol. 2017;12:S253. [DOI]
