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(NLR), Platelet-To-Lymphocyte Ratio (PLR), Terms of Survival

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(NLR), Platelet-To-Lymphocyte Ratio (PLR), Terms of Survival Adv Ther https://doi.org/10.1007/s12325-020-01229-w ORIGINAL RESEARCH Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to- Lymphocyte Ratio (PLR), and Outcomes with Nivolumab in Pretreated Non-Small Cell Lung Cancer (NSCLC): A Large Retrospective Multicenter Study Alessandro Russo . Marco Russano . Tindara Franchina . Maria R. Migliorino . Giuseppe Aprile . Giovanni Mansueto . Alfredo Berruti . Alfredo Falcone . Michele Aieta . Alain Gelibter . Antonio Russo . Sandro Barni . Michele Maio . Olga Martelli . Francesco Pantano . Daniela Iacono . Lorenzo Calvetti . Silvia Quadrini . Elisa Roca . Enrico Vasile . Marco Imperatori . Mario Occhipinti . Antonio Galvano . Fausto Petrelli . Luana Calabro` . Giulia Pasquini . Salvatore Intagliata . Giuseppina R. R. Ricciardi . Giuseppe Tonini . Daniele Santini . Vincenzo Adamo Received: December 12, 2019 Ó Springer Healthcare Ltd., part of Springer Nature 2020 ABSTRACT reliable predictive biomarkers to these agents is lacking and multiple clinicopathological factors Introduction: Immune checkpoint inhibitors have been evaluated. The aim of this study was to have provided substantial benefit in non-small cell analyze the potential role of neutrophil-to-lympho- lung cancer (NSCLC) with unprecedented results in cyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), terms of survival. However, the identification of and lactate dehydrogenase (LDH) levels in patients with pretreated NSCLC receiving nivolumab. Methods: This was a retrospective multicenter Alessandro Russo and Marco Russano contributed study involving 14 Italian centers, evaluating the equally to this work. role of some laboratory results in patients with NSCLC treated with nivolumab in the second or Enhanced Digital Features To view enhanced digital features for this article go to https://doi.org/10.6084/ later lines of therapy for at least four doses and m9.figshare.11550561. with a disease re-staging. A. Russo Á T. Franchina Á G. R. R. Ricciardi Á G. Mansueto Á S. Quadrini V. Adamo (&) Medical Oncology Department, General Hospital, Medical Oncology Unit A.O. Papardo & Department Frosinone, Italy of Human Pathology, University of Messina, Messina, Italy A. Berruti Á E. Roca Á S. Intagliata e-mail: [email protected] Oncologia Medica, Azienda Ospedaliera Spedali Civili, Brescia, Italy M. Russano Á F. Pantano Á G. Tonini Á D. Santini Department of Medical Oncology, Campus Bio- A. Falcone Á E. Vasile Á G. Pasquini Medico University of Rome, Rome, Italy Unit of Medical Oncology, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy M. R. Migliorino Á D. Iacono Pulmonary Oncology Unit, St. Camillo Forlanini M. Aieta Á M. Imperatori Hospital, Rome, Italy Division of Medical Oncology, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero G. Aprile Á L. Calvetti Vulture, PZ, Italy Department of Oncology, San Bortolo General Hospital, Vicenza, Italy Adv Ther Results: A total of 187 patients with available dNLR Derived neutrophil-to-lymphocyte ratio pretreatment laboratory results were included. ECOG Eastern Cooperative Oncology Group NLR levels below 5 were associated with an HR Hazard ratio improvement in terms of both progression-free IHC Immunohistochemistry survival (PFS) (p = 0.028) and overall survival iSEND Immunotherapy, sex, ECOG PS, (OS) (p = 0.001), but not in terms of overall neutrophil-to-lymphocyte ratio, and response rate (ORR) or disease control rate (DCR). delta NLR model Moreover, PLR levels below 200 were associated LDH Lactate dehydrogenase with longer PFS (p = 0.0267) and OS (p = 0.05), as NLR Neutrophil-to-lymphocyte ratio well as higher ORR (p = 0.04) and DCR NSCLC Non-small cell lung cancer (p = 0.001). In contrast, LDH levels above the ORR Overall response rate upper normal limit (UNL) were not associated OS Overall survival with significant impact on patient outcomes. PD-1 Programmed cell death 1 Conclusions: Patients with pretreated NSCLC PD-L1 Programmed cell death ligand 1 and high pretreatment levels of NLR and PLR PD Progressive disease may experience inferior outcomes with nivolu- PFS Progression-free survival mab. Therefore, in this subgroup of patients with PLR Platelet-to-lymphocyte ratio poor prognosis the use of alternative therapeutic PR Partial response strategies may be a valuable option, especially in PS Performance status programmed cell death ligand 1 (PD-L1)-nega- Pts Patients tive patients and/or in the presence of other SD Stable disease additional poor prognostic factors. TNM Tumor, node, metastasis UNL Upper normal limit Keywords: LDH; Nivolumab; NLR; NSCLC; PD- 1; PD-L1; PLR; Prognosis Key Summary Points Abbreviations AJCC American Joint Committee on Cancer Why carry out this study? CR Complete response To identify potential prognostic and DCR Disease control rate predictive biomarkers for nivolumab in unselected patients with pretreated non- A. Gelibter Á M. Occhipinti small cell lung cancer (NSCLC). Division of Oncology, Department of Radiological, Oncological and Pathological Science, Policlinico What was learned from the study? Umberto I, ‘‘Sapienza’’ University of Rome, Rome, Italy This study showed that pretreatment levels of some easy to determine serum A. Russo Á A. Galvano biomarkers, such as neutrophil-to- Department of Surgical, Oncological and Oral lymphocyte ratio (NLR) and platelet-to- Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy lymphocyte ratio (PLR), are associated with outcome in patients with NSCLC S. Barni Á F. Petrelli treated with nivolumab. Medical Oncology Unit, ASST Bergamo Ovest, Treviglio, BG, Italy High NLR levels (C 5) at baseline are M. Maio Á L. Calabro` associated with shorter progression-free Medical Oncology and Immunotherapy, Center for survival (PFS) and overall survival (OS). Immuno-oncology, University Hospital of Siena, Siena, Italy High PLR levels (C 200) at baseline are associated with shorter PFS and OS, as well O. Martelli Medical Oncology Unit, San Giovanni Addolorata as lower overall response rate and disease Hospital, Rome, Italy control rate. Adv Ther INTRODUCTION Herein, we analyzed the potential role of neutrophil-to-lymphocyte ratio (NLR), platelet- to-lymphocyte ratio (PLR), and LDH levels in a The therapeutic landscape of advanced/meta- large, retrospective, multi-institutional study static non-small cell lung cancer (NSCLC) has conducted in 14 Italian oncology centers in been recently revolutionized with the clinical patients with advanced pretreated NSCLC introduction of immune checkpoint inhibitors receiving nivolumab as second or subsequent (ICIs) targeting the programmed cell death 1 line of therapy for at least four administrations. (PD-1)/programmed cell death 1 ligand (PD-L1) axis with unprecedented results in terms of overall survival in different clinical settings METHODS [1, 2]. Nivolumab is a therapeutic option in patients with NSCLC progressing after plat- This was a retrospective multicenter study inum-based chemotherapy in both squamous involving 14 Italian oncology centers, evaluat- and non-squamous histology, independently of ing the role of clinicopathological, laboratory, PD-L1 expression [3, 4]. Immunotherapy has and radiological characteristics of patients with the notorious ability to induce highly durable NSCLC treated with nivolumab in second or tumor responses [5] and NSCLC is not an later lines of therapy. All patients consented to exception, with reported 3-year survival rates of an institutional review board-approved proto- 17% in the two pivotal trials with nivolumab in col. The trial protocol was previously approved pretreated NSCLCs [6]. Therefore, the identifi- by the Ethics Committee of the coordinating cation of predictive biomarkers is crucial for the center (Campus Bio-Medico University of optimal selection of patient candidates for sec- Rome) on 2 March 2018 (approval no. 23/18 ond-line therapy. However, there are no cur- OSS ComEt CBM) and all the patients provided rently approved predictive biomarkers for written informed consent before enrollment. nivolumab in NSCLC and the role of immuno- The study was conducted in accordance with histochemical (IHC) expression of PD-L1, used the Declaration of Helsinki. as selection criteria for pembrolizumab in both Inclusion criteria were as follows: age over first- and second-line therapy [7, 8], is contro- 18 years; cytological and/or pathological con- versial. Hence, there is still a high unmet med- firmed NSCLC; stage IIIB or IV (recurrent or ical need and novel additional clinical and metastatic) according to TNM (tumor, node, biomolecular parameters allowing proper metastasis) American Joint Committee on patient selection are eagerly awaited. Cancer (AJCC) version VIII; treatment with Inflammation is an established hallmark of nivolumab as monotherapy after at least one cancer and has a central role in tumor promo- previous line of therapy for advanced disease; at tion and progression [9]. Multiple markers of least four doses of therapy and a disease re- systemic inflammation have been correlated staging. Radiographic assessment was made with poor outcome in multiple solid tumors, locally according to the RECIST 1.1 criteria and including NSCLC, and recently some authors only patients with measurable disease were have suggested a possible predictive role of included. All patients were treated with nivo- peripheral markers of inflammation in patients lumab at the dose of 3 mg/kg i.v. every 2 weeks with NSCLC treated with nivolumab [10–16]. until disease progression or unacceptable toxic- Furthermore, some studies have also reported
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