Clinical predictive markers of response to immune checkpoint inhibitor therapy in advanced non-small cell lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21044-e21044
Author(s):  
Raena Rhone ◽  
Katerine Dumais ◽  
Herman W. Powery ◽  
Frank Gentile ◽  
Luis E. Raez
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Overweight And Obesity ◽  
Predictive Markers ◽  
Concomitant Chemotherapy ◽  
Small Cell Lung

e21044 Background: Overweight and obesity have been associated with improved overall survival (OS) and progression-free survival (PFS) in patients treated with immune checkpoint inhibitors (ICI). EPSILoN score (EPSILoN), comprised of five clinical variables (smoking, Eastern Cooperative Oncology Group performance status, liver metastases, lactate dehydrogenase (LDH), and neutrophil-lymphocyte ratio), is a known predictive marker of response to ICI. This study aims to validate body mass index (BMI) and EPSILoN as predictive markers of response in frontline treatment of advanced non-small cell lung cancer (NSCLC) with ICI with or without concomitant chemotherapy. Methods: Patients with advanced NSCLC who received frontline ICI were identified using the electronic medical record. PFS and OS were retrospectively evaluated and stratified based on baseline BMI and EPSILoN. Due to lack of routine LDH testing, a modified EPSILoN (mEPSILoN) was used. For statistical analysis, log-rank tests were used to compare PFS and OS between groups, and Kaplan-Meier survival curves were used to report PFS and OS. Results: Thirty-six normal weight (NW) and 25 overweight and obese (OWO) patients were studied. Median PFS (mPFS) for OWO vs NW patients was 8.90 months vs 5.53 months (HR 0.54; 95% CI, 0.30-0.96; p = 0.04). mPFS at 12 months was 45% for OWO patients vs 23% for NW patients. Of the patients with PD-L1 ≥ 50%, 14 patients were NW and 11 patients were OWO. Among patients with PD-L1 ≥ 50%, mPFS for OWO was not reached (NR) vs 6.73 months in NW patients (HR 0.23; 95% CI, 0.09-0.60; p = 0.003), and the percent of patients that were PF at 12 months was 71% vs 15%. Of 56 patients with a calculable mEPSILoN, 29 patients had baseline mEPSILoN 1 and 27 patients had mEPSILoN 2-3. Median OS for patients with mEPSILoN 1 vs 2-3 was NR vs 11.13 months (HR 0.32; 95% CI, 0.14-0.76; p = 0.01) and 78% vs 49% survived at 12 months. Conclusions: OWO and lower mEPSILoN were associated with longer PFS and OS, respectively, in patients with advanced NSCLC who were treated with frontline ICI with or without concomitant chemotherapy, regardless of PD-L1 expression. These findings are consistent with recent studies that have reported these parameters as predictive markers of response in patients with NSCLC. However, this is the first study to our knowledge to evaluate these markers in frontline ICI treatment with or without chemotherapy.[Table: see text]

scholarly journals Clinically relevant prognostic and predictive markers for immune-checkpoint-inhibitor (ICI) therapy in non-small cell lung cancer (NSCLC)

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Wolfgang M. Brueckl ◽  
Joachim H. Ficker ◽  
Gloria Zeitler
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Genetic Markers ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Palliative Treatment ◽  
Small Cell ◽  
Predictive Markers ◽  
Small Cell Lung ◽  
Prognostic And Predictive Markers

Abstract Background Immune checkpoint inhibitors (ICI) either alone or in combination with chemotherapy have expanded our choice of agents for the palliative treatment of non-small cell lung cancer (NSCLC) patients. Unfortunately, not all patients will experience favorable response to treatment with ICI and may even suffer from severe side effects. Therefore, prognostic and predictive markers, beyond programmed death ligand 1 (PD-L1) expression status, are of utmost importance for decision making in the palliative treatment. This review focuses on clinical, laboratory and genetic markers, most of them easily to obtain in the daily clinical practice. Results Recently, a number of prognostic and predictive factors in association to palliative ICI therapy have been described in NSCLC. Besides biometric parameters and clinical characteristics of the tumor, there are useful markers from routine blood sampling as well as innovative soluble genetic markers which can be determined before and during ICI treatment. Additionally, the level of evidence is noted. Conclusions These factors can be helpful to predict patients’ outcome and tumor response to ICI. They should be implemented prospectively in ICI based clinical trials to develop reliable algorithms for palliative NSCLC treatment.

Neutrophil to lymphocyte ratio, PD-L1 expression, and survival in patients with advanced non-small cell lung cancer receiving first-line immune checkpoint inhibitor therapy.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 46-46
Author(s):  
Mingjia Li ◽  
Songzhu Zhao ◽  
Daniel Spakowicz ◽  
Jarred Thomas Burkart ◽  
Sandip H. Patel ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Prognostic Value ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Lymphocyte Ratio

46 Background: Neutrophil to lymphocyte ratio (NLR) is known to be prognostic for patients with various types of cancer, including those who are treated with immune checkpoint inhibitors (ICI). We evaluated NLR at baseline and during early phase of treatment for patients with advanced non-small cell lung cancer (NSCLC) who received ICI to evaluate its prognostic value in first line ICI therapy and its relationship to programmed death-ligand 1 (PD-L1) expression. Methods: We retrospectively evaluated patients with advanced NSCLC who received ICI as first line therapy from 2016 to 2018. NLR was calculated as ratio of absolute neutrophil/lymphocyte counts and was consider elevated if ≥5. PD-L1 expression by immunohistochemistry was performed as standard of care with 22C3 antibody. Kaplan Meier analysis was used for survival. Wilcoxon-Mann-Whitney test was used to evaluate PD-L1 expression between groups. All Calculation was performed using SAS V9.4. Results: A total of 78 patients were included in this study; 28 received pembrolizumab monotherapy, 45 received pembrolizumab, carboplatin, and pemetrexed, and 5 received other pembrolizumab combinations. Patients with baseline NLR < 5 before initiating ICI had median estimated OS of 46.1 months (79.4% patient still alive and 95% CI not reached) compare to median OS of 10.7 months (95% CI lower limit 6.4 and upper limit not reached) for patients with NLR ≥5, P < 0.001. Similar association between NLR and OS can be seen when NLR were repeated immediate before the cycle 2 with P = 0.001. We observed an association between baseline NLR and PD-L1 expression. The median PD-L1 tumor proportion score (TPS) was 60% (Interquartile Range 1-80) for patients with baseline NLR < 5 vs 20% (IQR 0-60) for patients with NLR ≥5, P = 0.037. Conclusions: We confirmed the prognostic value of NLR for patients with advanced NSCLC at baseline and during early treatment in patients with NSCLC receiving first line ICI treatment. We also found an association between elevated NLR and lower PD-L1 expression. Future study with larger cohort is still needed to further delineate these relationships.

scholarly journals Two Complementarity Immunotherapeutics in Non-Small-Cell Lung Cancer Patients—Mechanism of Action and Future Concepts

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2836
Author(s):  
Kamila Wojas-Krawczyk ◽  
Paweł Krawczyk ◽  
Michał Gil ◽  
Maciej Strzemski
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Limited Effectiveness

Due to the limited effectiveness of immunotherapy used as first-line monotherapy in patients with non-small-cell lung cancer (NSCLC), the concepts of combining classical immunotherapy based on immune checkpoint antibodies with other treatment methods have been developed. Pembrolizumab and atezolizumab were registered in combination with chemotherapy for the treatment of metastatic NSCLC, while durvalumab found its application in consolidation therapy after successful chemoradiotherapy in patients with locally advanced NSCLC. Exceptionally attractive, due to their relatively low toxicity and high effectiveness, are treatment approaches in which a combination of two different immunotherapy methods is applied. This method is based on observations from clinical trials in which nivolumab and ipilimumab were used as first-line therapy for advanced NSCLC. It turned out that the dual blockade of immune checkpoints activated T lymphocytes in different compartments of the immune response, at the same time affecting the downregulation of immune suppressor cells (regulatory T cells). These experiments not only resulted in the registration of combination therapy with nivolumab and ipilimumab, but also initiated other clinical trials using immune checkpoint inhibitors (ICIs) in combination with other ICIs or activators of costimulatory molecules found on immune cells. There are also studies in which ICIs are associated with molecules that modify the tumour environment. This paper describes the mechanism of the synergistic effect of a combination of different immunotherapy methods in NSCLC patients.

scholarly journals Novel Biomarkers of Dynamic Blood PD-L1 Expression for Immune Checkpoint Inhibitors in Advanced Non-Small-Cell Lung Cancer Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Qiao Yang ◽  
Mingjing Chen ◽  
Jiaoyang Gu ◽  
Kai Niu ◽  
Xianlan Zhao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Advanced Nsclc ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients

BackgroundImmune checkpoint inhibitors (ICIs) have become a high-profile regimen for malignancy recently. However, only a small subpopulation obtains long-term clinical benefit. How to select optimal patients by reasonable biomarkers remains a hot topic.MethodsPaired tissue samples and blood samples from 51 patients with advanced malignancies were collected for correlation analysis. Dynamic changes in blood PD-L1 (bPD-L1) expression, including PD-L1 mRNA, exosomal PD-L1 (exoPD-L1) protein and soluble PD-L1 (sPD-L1), were detected after 2 months of ICIs treatment in advanced non-small-cell lung cancer (NSCLC) patients. The best cutoff values for progression-free survival (PFS) and overall survival (OS) of all three biomarkers were calculated with R software.ResultsIn 51 cases of various malignancies, those with positive tissue PD-L1 (tPD-L1) had significantly higher PD-L1 mRNA than those with negative tPD-L1. In 40 advanced NSCLC patients, those with a fold change of PD-L1 mRNA ≥ 2.04 had better PFS, OS and best objective response (bOR) rate. In addition, a fold change of exoPD-L1 ≥ 1.86 was also found to be associated with better efficacy and OS in a cohort of 21 advanced NSCLC cases. The dynamic change of sPD-L1 was not associated with efficacy and OS. Furthermore, the combination of PD-L1 mRNA and exoPD-L1 could screen better patients for potential benefit from ICIs treatment.ConclusionThere was a positive correlation between bPD-L1 and tPD-L1 expression. Increased expression of PD-L1 mRNA, exoPD-L1, or both in early stage of ICIs treatment could serve as positive biomarkers of efficacy and OS in advanced NSCLC patients.

scholarly journals Circulating predictive markers of immune checkpoint inhibitors in non-small cell lung cancer

2021 ◽  
Vol 8 (3) ◽  
pp. 34-43
Author(s):  
A. A. Musaelyan ◽  
A. L. Akopov ◽  
S. V. Lapin ◽  
V. D. Nazarov ◽  
D. I. Fillipov ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Peripheral Blood ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Predictive Markers ◽  
Small Cell Lung

Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy have become one of the key approaches in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Evaluation of level of PD-L1 (ligand of the programmed cell death receptor 1) expression on tumor cells using immunohistochemistry is the only approved option for determining the indications of ICIs in this group of patients. However, despite high level of PD-L1 expression, up to 80 % of patients do not respond to therapy due to the presence of primary or acquired resistance, which determines the limited effectiveness of ICI. In addition, 8–17 % of PD-L1-negative patients with NSCLC are also able to respond to ICIs. The limitation of this marker is that it does not allow assessing both intratumoral and systemic immune status. It is necessary to search for additional predictive markers to improve the accuracy of the selection of candidates for immunotherapy, which will avoid costs, wasted time, and a high risk of immune-related adverse events in potentially unresponsive patients. The attention of researchers is devoted to circulating markers in peripheral blood, as a non-invasive alternative to biopsy for predicting and monitoring the response. This review focuses on the most promising immunological markers in peripheral blood as potential predictors of response to ICIs in patients with advanced NSCLC.

scholarly journals Selective Histone Deacetylase Inhibitor ACY-241 (Citarinostat) Plus Nivolumab in Advanced Non-Small Cell Lung Cancer: Results From a Phase Ib Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Mark M. Awad ◽  
Yvan Le Bruchec ◽  
Brian Lu ◽  
Jason Ye ◽  
JulieAnn Miller ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Antitumor Activity ◽  
Small Cell Lung Cancer ◽  
Histone Deacetylase ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Small Cell Lung ◽  
Phase Ib

BackgroundHistone deacetylase (HDAC) overexpression has been documented in various cancers and may be associated with worse outcomes. Data from early-phase studies of advanced non-small cell lung cancer (NSCLC) suggest encouraging antitumor activity with the combination of an HDAC inhibitor and either platinum-based chemotherapy or an EGFR inhibitor; however, toxicity is a limiting factor in the use of pan-HDAC inhibitors. Selective inhibition of HDAC6 may represent a potential therapeutic target and preclinical studies revealed immunomodulatory effects with HDAC6 inhibition, suggesting the potential for combination with immune checkpoint inhibitors. This phase Ib, multicenter, single-arm, open-label, dose-escalation study investigated the HDAC6 inhibitor ACY-241 (citarinostat) plus nivolumab in patients with previously treated advanced NSCLC who had not received a prior HDAC or immune checkpoint inhibitor.MethodsThe orally administered ACY-241 dose was escalated (180, 360, or 480 mg once daily). Nivolumab was administered at 240 mg (day 15 of cycle 1, then every 2 weeks thereafter). The primary endpoint was to determine the maximum tolerated dose (MTD) of ACY-241 plus nivolumab. Secondary endpoints included safety, tolerability, and preliminary antitumor activity. Pharmacodynamics was an exploratory endpoint.ResultsA total of 18 patients were enrolled, with 17 patients treated. No dose-limiting toxicities (DLTs) occurred with ACY-241 at 180 or 360 mg; 2 DLTs occurred at 480 mg. The MTD of ACY-241 was 360 mg. The most common grade ≥ 3 treatment-emergent adverse events were dyspnea (n = 3; 18%) and pneumonia (n = 3; 18%). At the 180-mg dose, 1 complete response and 2 partial responses (PRs) were observed. At the 360-mg dose, 3 PRs were observed; 1 patient achieved stable disease (SD) and 1 experienced progressive disease (PD). At the 480-mg dose, no responses were observed; 1 patient achieved SD and 3 experienced PD. Acetylation analyses revealed transient increases in histone and tubulin acetylation levels following treatment. An increase in infiltrating total CD3+ T cells was observed following treatment.ConclusionsThe study identified an MTD for ACY-241 plus nivolumab and the data suggest that the combination may be feasible in patients with advanced NSCLC. Responses were observed in patients with advanced NSCLC. Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT02635061 (identifier, NCT02635061).

scholarly journals Splenic Volume as a Surrogate Marker of Immune Checkpoint Inhibitor Efficacy in Metastatic Non Small Cell Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3020
Author(s):  
Loïck Galland ◽  
Julie Lecuelle ◽  
Laure Favier ◽  
Cléa Fraisse ◽  
Aurélie Lagrange ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Small Cell Lung ◽  
Prognostic Role ◽  
Splenic Volume

Monoclonal antibodies targeting PD1/PD-L1 are game changers in advanced non-small cell lung cancer (NSCLC), but biomarkers are lacking. We previously reported the prognostic role of splenic volume in digestive cancer and its correlation with the presence of immunosuppressive cells. The aim of this study was to evaluate the prognostic role of splenic volume in NSCLC patients treated with immune checkpoint inhibitors (ICIs). We conducted a retrospective study of 276 patients receiving ICIs for advanced NSCLC in the Georges François Leclerc Cancer Center. The association between splenic volume at baseline and at two months of therapy and progression-free survival (PFS) during ICI treatment or overall survival (OS) from ICI initiation was evaluated using univariate and multivariable Cox analyses. Splenic volume during treatment and the change in splenic volume were associated with poor PFS (respectively p = 0.02 and p = 0.001) and with OS (respectively p < 1.10−3 and p < 1.10−3). Baseline splenic volume at the first evaluation was also associated with poor OS (p = 0.001). LDH rate and dNLR were positively correlated with splenic volume, as well as with its evolution. After the adjustment of clinical variables, splenic volumes remained a predictive marker of immunotherapy efficacy. Splenic volume is a prognostic biomarker in patients with advanced NSCLC treated with ICIs.

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