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      Modulation of peripheral blood immune cells by early use of steroids and its association with clinical outcomes in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors

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          Abstract

          Background

          Steroids are frequently used in patients with metastatic non-small cell lung cancer (mNSCLC), but they could be detrimental for patients treated with immune checkpoint inhibitors (ICIs). Here, we assessed the association between early use of steroids, clinical outcomes and peripheral immune blood cells modulation in patients with mNSCLC treated with ICIs.

          Methods

          We reviewed patients with mNSCLC treated at our institution between April 2013 and December 2017. Early use of steroids was defined as the use of a daily prednisone-equivalent dose ≥10 mg for at least 1 day within 28 days after ICI initiation. Peripheral immune blood cell counts were retrieved at baseline and at 4 and 6 weeks after ICI initiation.

          Results

          Out of 151 patients included, 35 (23%) made early use of steroids that was associated with poor disease control (OR 0.32, p=0.006), progression-free survival (HR 1.80, p=0.003) and overall survival (HR 2.60, p<0.001). Early use of steroids significantly correlated with higher median absolute neutrophil count, neutrophil to lymphocyte ratio (NLR) and derived NLR, and lower median absolute and relative eosinophil count, both at 4 and 6 weeks after ICI initiation.

          Conclusions

          In patients with mNSCLC treated with ICIs, early use of steroids was associated with worse clinical outcomes and remarkable modulation of peripheral blood immune cells, which could contribute to restraining the activation of antitumour immunity. If confirmed in prospective studies, these findings would highlight the importance of carefully evaluating and, whenever possible, avoiding steroids during early phases of ICI treatment.

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          Association of the Lung Immune Prognostic Index With Immune Checkpoint Inhibitor Outcomes in Patients With Advanced Non–Small Cell Lung Cancer

          Santiago Ponce, Laura Mezquita, Edouard Auclin … (2018)
          Question Are pretreatment derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) and lactate dehydrogenase (LDH) level associated with resistance to immunotherapy in patients with advanced non–small cell lung cancer (NSCLC)? Findings In this cohort study evaluating 466 patients with advanced NSCLC, the Lung Immune Prognostic Index (LIPI), combining baseline dNLR and LDH, was associated with the outcomes of immunotherapy but not chemotherapy. Meaning Poor baseline LIPI, combining dNLR greater than 3 and LDH greater than upper limit of normal, was correlated with worse outcomes for immune checkpoint inhibitor treatment in patients with NSCLC, but not with chemotherapy. This cohort study investigates whether the pretreatment derived neutrophils/(leukocytes minus neutrophils) ratio and lactate dehydrogenase level are associated with resistance to immunotherapy in patients with advanced non–small cell lung cancer. Importance Derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) and lactate dehydrogenase (LDH) level have been correlated with immune checkpoint inhibitor (ICI) outcomes in patients with melanoma. Objective To determine whether pretreatment dNLR and LDH are associated with resistance to ICIs in patients with advanced non–small cell lung cancer (NSCLC). Design, Setting, and Participants Multicenter retrospective study with a test (n = 161) and a validation set (n = 305) treated with programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors in 8 European centers, and a control cohort (n = 162) treated with chemotherapy only. Complete blood cell counts, LDH, and albumin levels were measured before ICI treatment. A lung immune prognostic index (LIPI) based on dNLR greater than 3 and LDH greater than upper limit of normal (ULN) was developed, characterizing 3 groups (good, 0 factors; intermediate, 1 factor; poor, 2 factors). Main Outcomes and Measures The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS) and disease control rate (DCR). Results In the pooled ICI cohort (N = 466), 301 patients (65%) were male, 422 (90%) were current or former smokers, and 401 (87%) had performance status of 1 or less; median age at diagnosis was 62 (range, 29-86) years; 270 (58%) had adenocarcinoma and 159 (34%) had squamous histologic subtype. Among 129 patients with PD-L1 data, 96 (74%) had PD-L1 of at least 1% by immunohistochemical analysis, and 33 (26%) had negative results. In the test cohort, median PFS and OS were 3 (95% CI, 2-4) and 10 (95% CI, 8-13) months, respectively. A dNLR greater than 3 and LDH greater than ULN were independently associated with OS (hazard ratio [HR] 2.22; 95% CI, 1.23-4.01 and HR, 2.51; 95% CI, 1.32-4.76, respectively). Median OS for poor, intermediate, and good LIPI was 3 months (95% CI, 1 month to not reached [NR]), 10 months (95% CI, 8 months to NR), and 34 months (95% CI, 17 months to NR), respectively, and median PFS was 2.0 (95% CI, 1.7-4.0), 3.7 (95% CI, 3.0-4.8), and 6.3 (95% CI, 5.0-8.0) months (both P  < .001). Disease control rate was also correlated with dNLR greater than 3 and LDH greater than ULN. Results were reproducible in the ICI validation cohort for OS, PFS, and DCR, but were nonsignificant in the chemotherapy cohort. Conclusions and Relevance Pretreatment LIPI, combining dNLR greater than 3 and LDH greater than ULN, was correlated with worse outcomes for ICI, but not for chemotherapy, suggesting that LIPI can serve as a potentially useful tool when selecting ICI treatment, raising the hypothesis that the LIPI might be useful for identifying patients unlikely to benefit from treatment with an ICI.
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            Baseline Biomarkers for Outcome of Melanoma Patients Treated with Pembrolizumab.

            Benjamin Weide, Alexander Martens, Jessica C. Hassel … (2016)
            Biomarkers for outcome after immune-checkpoint blockade are strongly needed as these may influence individual treatment selection or sequence. We aimed to identify baseline factors associated with overall survival (OS) after pembrolizumab treatment in melanoma patients.
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              Safety of Programmed Death–1 Pathway Inhibitors Among Patients With Non–Small-Cell Lung Cancer and Preexisting Autoimmune Disorders

              Mehmet Altan, Justin Gainor, Matthew Hellmann … (2018)
              Purpose Although programmed death (PD)-1 pathway inhibitors are now used in nearly all patients with advanced non–small-cell lung cancer (NSCLC), the large number of patients with NSCLC and concurrent autoimmune disease (AID) have been universally excluded from immunotherapy clinical trials. Therefore, the safety of PD-1 and PD-ligand 1 (PD-L1) inhibitors in patients with NSCLC and underlying AID is currently unknown. Methods As part of a multi-institutional effort, we retrospectively collected clinicopathologic data from patients with NSCLC and a history of AID who received monotherapy with either a PD-1 or a PD-L1 (herein referred to as PD-[L]1) inhibitor. Qualifying AIDs included but were not limited to: rheumatologic, neurologic, endocrine, GI, and dermatologic conditions. Results We identified 56 patients with NSCLC and an AID who received a PD-(L)1 inhibitor. At the time of treatment initiation, 18% of patients had active AID symptoms and 20% were receiving immunomodulatory agents for their AID. A total of 55% of patients developed an AID flare and/or an immune-related adverse event (irAE). Exacerbation of the AID occurred in 13 patients (23% of the whole cohort), four of whom required systemic corticosteroids. Immune-related adverse events occurred in 21 patients (38%). Among irAEs, 74% were grade 1 or 2 and 26% were grade 3 or 4; eight patients required corticosteroids for irAE management. PD-(L)1 therapy was permanently discontinued in eight patients (14%) because of irAEs. The overall response rate to immunotherapy in this population was 22%. Conclusion In patients with NSCLC with AID treated with a PD-(L)1 inhibitor, exacerbation of AID occurred in a minority of patients. The incidence of irAEs was similar to reported rates in clinical trials where patients with AID were excluded. Adverse events were generally manageable and infrequently led to permanent discontinuation of immunotherapy.
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                Author and article information

                Journal
                Journal ID (nlm-ta): ESMO Open
                Journal ID (iso-abbrev): ESMO Open
                Journal ID (hwp): esmoopen
                Journal ID (publisher-id): esmoopen
                Title: ESMO Open
                Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                ISSN (Electronic): 2059-7029
                Publication date Collection: 2019
                Publication date (Electronic): 27 February 2019
                Volume: 4
                Issue: 1
                Electronic Location Identifier: e000457
                Affiliations
                [1 ] departmentMedical Oncology Department , Fondazione IRCCS Istituto Nazionale dei Tumori di Milano , Milan, Italy
                [2 ] departmentDepartment of Pharmaceutical Sciences , Università degli Studi del Piemonte Orientale 'Amedeo Avogadro' , Novara, Italy
                [3 ] departmentDepartment of Oncology and Hematology , Humanitas Clinical and Research Center , Rozzano, Italy
                [4 ] departmentLaboratory of Methodology for Biomedical Research , IRCCS Mario Negri Institute for Pharmacological Research , Milan, Italy
                [5 ] departmentDepartment of Experimental Oncology and Molecular Medicine , Fondazione IRCCS Istituto Nazionale dei Tumori di Milano , Milan, Italy
                [6 ] Fondazione Istituto FIRC di Oncologia Molecolare (IFOM) , Milan, Italy
                [7 ] departmentDipartimento di Scienze Biomediche per la Salute , University of Milan , Milan, Italy
                [8 ] departmentDepartment of Oncology and Hemato-oncology , University of Milan , Milan, Italy
                Author notes
                [Correspondence to ] Dr Marina Chiara Garassino; marina.garassino@ 123456istitutotumori.mi.it

                GF and GG are joint first authors.

                Author information
                http://orcid.org/0000-0002-1560-2253
                Article
                Publisher ID: esmoopen-2018-000457
                DOI: 10.1136/esmoopen-2018-000457
                PMC ID: 6435242
                PubMed ID: 30964126
                SO-VID: 714bbb47-48ab-4681-9247-f23d17be0fdd
                Copyright © © Author (s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.
                License:

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, any changes made are indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Date received : 11 October 2018
                Date revision received : 09 November 2018
                Date accepted : 26 December 2018
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                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100003196, Ministero della Salute;
                Award ID: CUP: B43C17000350001
                Categories
                Subject: Original Research
                Subject: 1506
                Custom metadata
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                Keywords: non-small cell lung cancer,immune checkpoint inhibitors,steroids
                Data availability:
                Keywords: non-small cell lung cancer, immune checkpoint inhibitors, steroids

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