Professor Sergey V. Orlov, Department of Clinical Oncology, Pavlov First Saint Petersburg State Medical University, 6-8 L'va Tolstogo St., Saint Petersburg 197022, Russia
Immune checkpoint inhibitors (ICI) are a standard in cancer therapy, but few patients respond to the treatment. The aim of the present study was the determination of immunological markers for monitoring response to ICI. The present study included 74 patients receiving ICI in subsequent [group 1; non-small cell lung cancer (NSCLC)] and first-line setting (group 2; melanoma) and 30 patients with NSCLC receiving first-line chemotherapy. In groups 1 and 2 β-2 microglobulin (B2-MG), neopterin (NPT), IL-6, IL-18,
Immune checkpoint inhibitors (ICI) demonstrate unprecedented results in the treatment of variety advanced solid tumors, such as non-small cell lung cancer (NSCLC) and melanoma (
PD-L1 expression on tumor and immune cells is a potential predictor of sensitivity to ICI and was initially approved by the FDA in 2015(
Tumors with microsatellite instability (MSI) demonstrate high sensitivity to anti-PD-1 therapy regardless of a histological type (
Clinical evaluation of predictive markers in tumors is limited by intratumoral heterogeneity and subsequent biopsies. Blood-based biomarkers are more accessible and could be used for non-invasive therapeutic monitoring of the treatment efficacy. In addition, blood could provide a holistic view on the patient's immune response, which is one of the key factors of the effectiveness of cancer immunotherapy (
Systemic inflammation causes tumor growth and progression and, as a result, is associated with poor survival in various types of cancer (
The present retrospective study included 74 patients with advanced malignant tumors who received ICI (groups 1 and 2). The present study also included 30 patients with advanced NSCLC (aNSCLC), who received initial platinum chemotherapy (group 3).
The present study was conducted from September 2018 to July 2021 at Pavlov First Saint Petersburg State Medical University. Patients eligible for the study had to be >18 years old, histologically confirmed NSCLC or cutaneous melanoma, stage IIIC-IV for cutaneous melanoma and stage IIIB-IVB for NSCLC and Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0, 1 or 2(
Radiological assessment was performed according to the criteria RECIST 1.1(
For all of the patients a measurement of immunological markers in peripheral blood was performed. All serum samples were collected by venipuncture of arm and stored as minimum of 2 ml aliquots at -80°C until analysis at Pavlov First Saint Petersburg State Medical University as previously described (
Group 1 included 45 patients with locally advanced and metastatic NSCLC which were treated with ICI in subsequent-line setting: anti-PD-1 (nivolumab, pembrolizumab) or anti-PD-L1 therapy (atezolizumab;
Group 2 included 29 patients with unresectable locally advanced (stage IIIC and IIID) or metastatic melanoma who received first-line nivolumab as monotherapy. According to the results of radiological evaluation, the group was also divided into 2 subgroups: responders (n=22), and non-responders (n=7).
PD-L1 expression was assessed in paraffin tissue sections (4-µm thick) by the Dako PD-L1 IHC clone 22C3 pharmDx (Agilent Technologies, Inc.) and the Ventana PD-L1 IHC clone SP142 (Ventana Medical Systems, Inc.) assay according to manufacturer's instructions. NLR and PLR were also calculated before and after two months the start of the treatment in groups 1 and 2. All patients participated the study had no history of autoimmune diseases before starting ICI. Among patients from groups 1 and 2 level of thyroid-stimulating hormone was within the range 0.4-4.0 mU/l before starting anti-PD-1/PD-L1 therapy.
In groups 1 and 2 peripheral blood samples were taken after two months from the start of ICI. Blood samples were taken both before the start of the next cycle of ICI, and immediately after the completion of the ICI infusion. The last sampling point was chosen in order to assess the direct effect of ICI on cytokine levels. Due to retrospective nature of the study some patients from group 1 and all patients from group 2 did not have preserved in advance baseline blood samples that were taken before the initiation of ICI. In group 1, 16 patients also had additional points of taking serum samples: before the start of ICI and six months after the start of therapy. These points were used to study the possible dynamic changes in the level of markers. In group 3, peripheral blood was taken before the start of the infusion of three or subsequent cycles of the chemotherapy.
B2-microglobulin (B2-MG) was determined by an immunoturbidimetric method, using a test system manufactured by Biosystems S.A. Due to the fact that the level of B2-MG in the blood depends on the renal function, the value of serum creatinine was studied among patients from the three groups before the start and two months after treatment. The study of neopterin (NPT) was performed using enzyme-linked immunosorbent assay (ELISA) kit of IBL International GmbH (cat. no. RE59321) according to the manufacturer's instructions. The level of cytokines, IL-6 (cat. no. A8768) and IL-18 (cat. no. A8770) were determined by ELISA with test systems of the Vector-Best also according to the kit instructions.
The majority of autoantibodies were determined by ELISA using commercial test systems of Orgentec Diagnostika GmbH: antibodies to extractable nuclear antigens (cat. no. 416-5140), anticardiolipin antibodies (IgG and IgM; cat. no. 416-5150), anti-MCV antibodies (cat. no. 416-5480). Anti-thyroid peroxidase autoantibodies (anti-TPO) (cat. no. EA 1012-9601 G), antibodies to thyroid stimulating hormone receptor (cat. no. EA 1015-9601 G), antibodies to β-2-glycoprotein (cat. no. EA 1632-9601 G) were evaluated using commercial ELISA kits manufactured by Euroimmun Medizinische Labordiagnostika AG. Anti-neutrophil cytoplasmic antibodies IgG (cat. no. FA 1200-1005), antinuclear antibodies (diagnostic titer >1: 160) (cat. no. FA 1510-0010-1), anti-mitochondrial antibody, anti-liver kidney microsomal antibody and anti-smooth muscle antibody (cat. no. FA 1300-1005-8) were determined by indirect immunofluorescence using a commercial kit of Euroimmun Medizinische Labordiagnostika AG. The detection of the listed autoantibodies was carried out according to manufacturer's instructions.
Determination of allelic variant of the
Statistical data processing was performed using GraphPad Prism (version 9.3.1; GraphPad Software Inc.). Fisher's exact test was applied for the comparative analysis of qualitative characteristics. Evaluation of differences in quantitative parameters between two compared groups was performed using the Mann-Whitney U-test. Optimal cut-off values for immunological markers and the level of PD-L1 expression were determined using receiver operating characteristic curve (ROC) analysis for the subsequent study of PFS. Differences in PFS between two compared groups were analyzed using a log-rank test with hazard ratio analysis, as well as a graphical presentation using the Kaplan-Meier method. In group 1 and 2 univariate and multivariate Cox regression analysis were used to assess the effect of clinical, morphological data and immunological markers on PFS. P<0.05 was considered to indicate a statistically significant difference.
There were no significant differences between responders and non-responders in sex (P=0.891), age (P=1.0), ECOG PS (P=1.0), smoking status (P=0.068), body mass index (BMI) (P=0.719), histological type (P=0.283), PD-L1 expression levels on tumor cells (P=0.152) and the presence of EGFR/ALK mutations (P= 0.146) in group 1. No differences were observed between responders and non-responders in NLR before (P=0.546) and two months after initiation of therapy (P=0.132), as well as PLR before (P=0.244) and two months after initiation (P=0.428).
Using ROC analysis optimal cut-off level of PD-L1 expression to determine efficacy of ICI was ≥50%. However, PD-L1 ≥50% was not significantly associated with longer PFS in univariate Cox regression analysis [hazard ratio (HR): 0.28, 95% confidence interval (95% CI) 0.04-0.99; P=0.091]. In univariate regression analysis, the presence of EGFR/ALK mutations (HR: 5.18, 95% CI 0.75-22.68; P=0.045) and NLR ≥5 (HR: 8.02, 95% CI 1.21-32.24, P=0.009) were associated with shorter PFS (
No differences were observed between the responders and non-responders in age (P=0.811), sex (P=0.665), ECOG PS (P=1.0), disease stage (P=1.0), category M (P=0.690), level of serum LDH and PD-L1 expression (P=0.792) in group 2. NLR ≥5 before initiation of ICI was significantly associated with progression of disease <six months (P=0.007). There were no significant differences between responders and non-responders in NLR after two months of starting ICI (P=0.068), as well as PLR before (P=0.922) and two months after initiation (P=0.546).
In melanoma optimal cut-off level of PD-L1 expression to determine efficacy of therapy was ≥5%. At the same time, the level of PD-L1 ≥5% was also not correlated with longer PFS in univariate Cox regression analysis (HR: 0.28, 95% CI 0.01-1.59; P=0.237) (
In group 1 irAEs developed in 37.8% of cases. All cases were represented by 1-2 grade and included the following diseases: Autoimmune thyroiditis (n=7), rash (n=4), hepatitis (n=3), pneumonitis (n=2), colitis (n=1). The presence of irAEs was associated with the duration of the response >6 months: 53.9% of cases (14/26) in responders compared with 15.8% (3/19) in non-responders (P=0.013). Univariate regression analysis showed that irAEs was associated with longer PFS (HR: 2.88, 95% CI 1.10-8.45; P=0.038). However, this relationship was not found in multivariate analysis (P=0.064).
In group 2 irAEs developed in 44.8% of cases and represented the following diseases: rash (n=6), autoimmune thyroiditis (n=5), hepatitis (n=1), pneumonitis (n=1). Only the case of hepatitis was represented by grade 3 of toxicity, the rest were grade 1-2. The appearance of irAEs during ICI was associated with prolonged PFS in univariate (HR: 4.72, 95% CI 1.42-21.36; P=0.020), but not in multivariate regression analysis (HR: 5.21, 95% CI 1.07-38.67; P=0.058).
Anti-TPO antibodies (according to the manufacturer's instructions the positive threshold value was >50 IU/ml) were detected in all cases of autoimmune thyroiditis (n=7) in group 1. The appearance of antibodies after two months from the start of ICI was significantly associated with a response ≥six months: in responders a presence of the marker was observed in 26.9% (7/26) of cases and in non-responders-0% (0/19) (P=0.016). Using univariate regression analysis, no association between anti-TPO antibodies and PFS was demonstrated in group 1 (P=0.118). In group 2, anti-TPO antibodies were also detected in all cases of autoimmune thyroiditis (n=5). No association was demonstrated between the appearance of anti-TPO antibodies and duration of response ≥6 months and also PFS (P>0.05).
Diagnostic titer of antinuclear antibodies and antibodies to extractable nuclear antigens was detected in all cases of immune-related hepatitis in group 1 (n=3) and in group 2 (n=1). In group 1 and 2 none of studied autoantibodies was detected in other immune-related adverse events, such as rash, pneumonitis and colitis.
In group 1 and 2 there was no statistically significant association between the duration of response to anti-PD-1/PD-L1 therapy, PFS and the presence of one of the following autoantibodies: Antinuclear antibodies, antibodies to extractable nuclear antigens, anticardiolipin antibodies, anti-MCV antibodies, antibodies to thyroid stimulating hormone receptor, antibodies to β-2-glycoprotein, anti-neutrophil cytoplasmic antibodies, anti-mitochondrial antibody, anti-liver kidney microsomal antibody and anti-smooth muscle antibody (P>0,05).
The
Among patients with aNSCLC receiving ICI, a level of B2-MG after two months was significantly lower in responders compared with non-responders in group 1: Median was 1.7 mg/l (95% CI 1.6-2.3 mg/l) compared with 2.9 mg/l (95% CI 2.5-3.3 mg/l), respectively (P<0,0001;
In 16 patients with NSCLC receiving ICI no association was observed between pretreatment level of B2-MG and PFS (P=0.805). The change in B2-MG from baseline to measurements after two months was associated with PFS. In 16 patients increased level of marker during two months of treatment >2.7 times was associated with short PFS: Median was 319 days compared with not reached, respectively (P=0.021). Also in group 1, 16 patients with NSCLC median level of the marker after two and six months were comparable (P=0.912).
B2-MG was also statistically significantly lower in responders than in non-responders in group 2: median was 1.8 mg/l (95% CI 1.6-2.3 mg/l) compared with 3.6 mg/l (95% CI 3.1-4.0 mg/l), respectively (P=0.0001) (
Among patients from groups 1 and 2 creatinine corresponded to the reference value both before the start and after two months of ICI. This indicates the absence of effect of renal function on the level of the marker in two groups.
Median of NPT was lower in responders compared with non-responders in group 1: 8.6 nmol/l (95 % CI 7.6-10.0 nmol/l) compared with 13.4 nmol/l (95% CI 13.0-23.0 nmol/l), respectively (P<0.0001;
In group 1 in 16 patients with NSCLC high baseline level of NPT (defined as >6.8 nmol/l) was associated with short PFS: Median was 224 days compared with not reached (P=0.0018). No association was observed between the change in NPT from baseline to measurements after two months of therapy initiation and PFS (P=0.067). Also, 16 patients demonstrated no differences in the level of the marker at two control points: after two and six months of the start of ICI (P=0.736).
There was a statistically significant difference of the level of NPT in responders and non-responders in group 2: Median was 8.7 nmol/l (95% CI 7.6-10.3 nmol/l) compared with 14.2 nmol/l (95% CI 10.9-17.0 nmol/l), respectively (P=0.0016) (
A level of IL-6 after two months of the start of ICI was lower in responders compared with non-responders in group 1: Median was 3.9 pg/ml (95% CI 2.8-5.0 pg/ml) compared with 14 pg/ml (95% CI 6.0-18.4 pg/ml), respectively (P<0.0001) (
In group 1 in 16 patients with NSCLC no significant association was observed between lower IL-6 at baseline (P=0.209), decreasing the level of the marker during first two months of ICI (P=0.091) and PFS. Also, levels of the marker were comparable after two and six months in 16 patients in group 1 (P=0.334).
A level of IL-6 after two months was lower in responders compared with non-responders in group 2: Median was 1.8 pg/ml (95% CI 1.8-5.0 pg/ml) and 6.7 pg/ml (95% CI 4.2-12.9 pg/ml), respectively (P=0.013;
The level of IL-18 in responders was significantly lower compared with non-responders in group 1: Median was 233.3 pg/ml (95% CI 198.9-271.8 pg/ml) compared with 327.4 pg/ml (95% CI 300.5-405.5 pg/ml), respectively (P=0.0003;
In 16 patients with NSCLC receiving ICI no association was observed between the baseline level of IL-18 (P=0.641), change in the level of the marker during two months of treatment (P=0.067) and PFS. As for IL-6, 16 patients had similar levels of IL-18 at two and six months after therapy initiation (P=1.0).
The level of IL-18 was significantly lower in responders compared with non-responders in group 2: Median was 206.3 pg/ml (95% CI 183.0-287.1 pg/ml) and 314.0 pg/ml (95% CI 222.0-347.7 pg/ml), respectively (P=0.032) (
In group 3 there were no differences between responders and non-responders in sex (P=1.0), age (P=0.411), ECOG PS (P=0.892), smoking status (P=0.384), body mass index (P=1.0), histological type (P=0.460) and stage of disease (P=1.0), NLR before (P=0.196) and two months after initiation of therapy (P=0.104), as well as PLR before (P=0.627) and two months after initiation (P=0.359). Also, there were no differences between two subgroups in B2-MG (P=1.0), NPT (P=0.233), IL-6 (P=0.893) and IL-18 (P=1.0). None of the studied autoantibodies was found during the treatment. For the group 3, no statistical significance was observed between any of allelic variants of the
Group 3 allowed the assessment of the specificity of changes in immunological parameters in relation to ICI in groups 1 and 2. Measurement of these markers in group 3 could help to indirectly assess the level of markers before the start of ICI among patients in group 1 who previously had received chemotherapy. Group 1 and group 3 did not statistically differ in sex (P=0.806), age (P=0.655), histology (P=1.0) and TNM stage (P=1.0).
Among patients from group 1, previously treated with platinum-containing chemotherapy, a level of B2-MG after the initiation of ICI was significantly higher compared with patients from group 3 who received chemotherapy: Median was 2.1 mg/l (95% CI 2.0-2.5 mg/l) compared with 1.1 mg/l (95% CI 1.0-1.2 mg/l), respectively (P<0.0001). During the study of another inflammatory marker NPT, a significant difference was also demonstrated among patients from group 1 and group 3: median was 9.8 nmol/l (95% CI 10.4-14.3 nmol/l) and 6.2 nmol/l (95% CI 5.7-7.5 nmol/l), respectively (P<0.0001). A statistically significant difference in the level of IL-6 and IL-18 was observed among patients with aNSCLC, receiving ICI and chemotherapy (P<0.0001).
For 16 patients from group 1, median level of B2-MG and NPT evaluated before the start of ICI was 1.2 mg/l (95% CI 1.0-1.4 mg/l) and 5.9 nmol/l (95% CI 5.2-6.9 nmol/l), respectively. These values were comparable to the same in group 3. In 16 patients median of IL-6 before the start of ICI was similar to level of the marker in the comparison group receiving platinum-based chemotherapy in group 1: 1.9 pg/ml (95% CI 1.4-2.6) and 2.0 pg/ml (95% CI 1.7-3.0), respectively. Similar values of IL-18 were shown in two groups: ICI (group 1)-158.4 pg/ml (95% CI 141.3-169.8 pg/ml), chemotherapy (group 3)-165.5 pg/ml (95% CI 142.9-181.3 pg/ml).
The present study demonstrated a predictive role of some markers of chronic inflammation in NSCLC and cutaneous melanoma for the first time, to the best of the authors' knowledge. It has shown that NLR, B2-MG, NPT, IL-6 and IL-18 were associated with response to ICI. An association between autoimmune reactions and the effectiveness of ICI was also demonstrated.
According to the study of potential predictive tumor markers, only the presence of EGFR/ALK mutations was an independent predictor of shorter PFS among patients with NSCLC. In the present study, no relationship was found between PD-L1 expression and response to therapy in NSCLC and melanoma.
ICI suppresses negative co-stimulatory signals of T cells, thereby enhancing the antitumor response (
Another autoimmune marker of ICI efficacy is poorly studied allelic variants of gene HLA class II
Among patients with aNSCLC receiving ICI,
NLR is a convenient blood marker of systemic inflammation that reflects the balance of the antitumor immune response (
B2-MG is a non-glycosylated protein that is a component of HLA class I (
NPT is a marker of macrophage activation (
Cytokines are potential markers of response to ICI. IL-6 is one of the most promising predictive cytokine markers. A high level of IL-6 production is associated with the formation of an immunosuppressive tumor microenvironment due to myeloid-derived suppressor cells, M2 macrophage cells and Treg cells (
A similar association was shown between a high level of IL-18 during ICI and early disease progression among patients with NSCLC and melanoma who received ICI. However, no association was shown between a high level of the marker and PFS in both groups of patients. Although preclinical and some clinical studies suggest that IL-18 has antitumor activity, other studies shown that IL-18 plays a dual role in tumors, as it can exhibit pro-invasive and pro-angiogenic activity in various tumors (
A limitation of the present study was the absence of an index that included some of the studied markers, which allows the most accurate determination of patients who will respond to immunotherapy. Different combination of predictive markers before initiation of treatment and also during immunotherapy did not show greater statistically significance by univariate Cox regression analysis than using single markers.
Despite the fact that the dynamic changes in B2-MG, NPT, IL-6 and IL-18 were not assessed among all patients who received ICI before the start and two months after initiation of the treatment, these markers significantly change only during immunotherapy. It was shown that levels of B2-MG, NPT, IL-6 and IL-18 were higher among patients with aNSCLC who received ICI (regardless of response or progression) than among patients with the same disease who received chemotherapy. Moreover, the levels of these markers in 16 patients with aNSCLC before initiating ICI were similar to those among patients receiving chemotherapy. Thus, a platinum-based chemotherapy does not affect the level of the inflammation markers. Also, 16 patients showed no significant changes in differences of B2-MG, NPT, IL-6, IL-18 after two and six months of starting ICI.
The use of immunological markers, such as NLR, B2-MG, NPT, IL-6, IL-18,
Not applicable.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
AAM was responsible for development of research design, review of publications on the topic of the article, analysis of the data obtained, design of illustrative material, statistical analysis and article writing. SVL was responsible for development of research design, methodology and analysis of the data obtained. MAU, SVOd, IVC and AMU were involved in curation of patients, performed experiments and curated data. ALA and SVOr were responsible for idea and design development, scientific editing, and research management. AAM and SVOr confirm the authenticity of all the raw data. All authors read and approved the final manuscript.
The present study was approved by the ethics committee of the Pavlov First Saint Petersburg State Medical University (approval no. 246-2021). All participants signed informed consent forms.
Not applicable.
The authors declare that they have no competing interests.
Graphical abstract. In advanced NSCLC and melanoma the following immunological and genetic features could predict response to immunotherapy: low level of NLR, presence of irAEs, high level of β-2 microglobulin, neopterin, IL-6 and IL-18. Absence of EGFR/ALK mutation, presence of anti-TPO autoantibodies and HLA-DRB1*03 are also predictors of response to anti-PD-(L)1 therapy in NSCLC. NLR, neutrophil-to-lymphocyte ratio; irAE, immune-related adverse event; anti-TPO-anti-thyroid peroxidase antibodies; IL-interleukin.
PFS depending on the presence of the
B2-MG among patients with advanced non-small cell lung cancer and melanoma received immune checkpoint inhibitors. (A-C) Median of B2-MG in responders and non-responders in (A) group 1 and in (B) group 2. PFS depending on the level of B2-MG in (C) group 1 and (D) group 2. B2-MG, β-2 microglobulin; PFS, progression-free survival; ***P<0.001.
NPT among patients with advanced non-small cell lung cancer and melanoma received immune checkpoint inhibitors. Median of NPT in responders and non-responders in (A) group 1 and (B) group 2. (C) PFS depending on the level of NPT in group 1. NPT, neopterin; PFS, progression-free survival; ***P<0.001.
Median level of IL-6 in responders and non-responders in (A) group 1 and (B) group 2. (C) PFS depending on the level of IL-6 after two months in group 2. PFS, progression-free survival; *P<0.05; ***P<0.001.
Median level of IL-18 in responders and non-responders in in (A) group 1 and (B) group 2; *P<0.05; ***P<0.001.
Clinical and epidemiological data of patients included in three groups.
Characteristics | Group 1 (n=45) | Group 2 (n=29) | Group 3 (n=30) |
---|---|---|---|
Sex, n (%) | |||
Male | 30 (66.7) | 16 (55.2) | 21 (70.0) |
Female | 15 (33.3) | 13 (44.8) | 9 (30.0) |
Age, median (IQR), n (%) | 62 (59-69) | 57 (53-62) | 64 (59-70) |
<60 | 25 (55.6) | 14 (48.3) | 12 (40.0) |
>60 | 30 (44.4) | 15 (51.7) | 18 (60.0) |
Histology, n (%) | |||
Squamous cell lung cancer | 27(60) | 0 (0.0) | 18 (60.0) |
Adenocarcinoma of the lung | 18(40) | 0 (0.0) | 12 (40.0) |
Cutaneous melanoma | - | 29(100) | - |
Stage, n (%) | |||
Locally advanced | 9(20) | 2 (6.9) | 6 (20.0) |
Metastatic | 36(80) | 27 (93.1) | 24 (80.0) |
Disease progression within the first six months, n (%) | |||
Yes | 19 (42.2) | 7 (24.1) | 17 (56.7) |
No | 26 (57.8) | 22 (75.9) | 13 (43.3) |
Immunotherapy, n (%) | |||
Nivolumab | 12 (26,6) | 29 (100.0) | - |
Pembrolizumab | 30 (66,7) | 0 (0.0) | - |
Atezolizumab | 3 (6,7) | 0 (0.0) | - |
Systemic therapy, n (%) | |||
First-line | 0 (0,0) | 29 (100.0) | - |
Second-line | 36(80) | 0 (0.0) | - |
Third-line | 9(20) | 0 (0.0) | - |
First-line therapy, n (%) | |||
Chemotherapy | 0 (0,0) | 30 (100.0) | |
ALK inhibitors | 36(80) | 0 (0.0) | |
EGFR inhibitors | 9(20) | 0 (0.0) | |
Mutational status, n (%) | |||
EGFR+ | 2 (4,4) | 0 (0.0) | 0 (0.0) |
ALK+ | 3 (6,7) | 0 (0.0) | 0 (0.0) |
EGFR/ALK- | 21 (46,7) | 0 (0.0) | 5 (16.7) |
No data | 19 (42,2 | 29 (100.0) | 25 (83.3) |
PD-L1 expression, n (%) | |||
<1% | 16 (35,6) | 9 (31.1) | 7 (23.3) |
1-49% | 20 (44,4) | 13 (44.8) | 3 (10.0) |
>50% | 9(20) | 0 (0.0) | 0 (0.0) |
No data | 0 (0,0) | 7 (24.1) | 20 (66.7) |
IQR, interquartile range; ALK, anaplastic lymphoma kinase.
Univariate and multivariate regression analysis of clinical, morphological and immunological parameters associated with PFS in NSCLC.
Univariate analysis | Multivariate analysis | |||
---|---|---|---|---|
Characteristic | HR (95% CI) | P-value | HR (95% CI) | P-value |
Age (≥75 vs. <75 years) | 1.41 (0.49-3.20) | 0.332 | - | - |
Sex (male vs. female) | 1.03 (0.36-2.65) | 0.914 | - | - |
ECOG PS (0/1 vs. 2) | 1.11 (0.56-2.49) | 0.834 | - | - |
Smoking status (former/current vs. never) | 1.53 (0.43-4.25) | 0.452 | - | - |
BMI (≥25 vs. <25 kg/m2) | 0.85 (0.60-1.45) | 0.623 | - | - |
Histology (non-squamous vs. squamous) | 0.45 (0.16-1.17) | 0.110 | - | - |
None vs. presence EGFR/ALK mutation | 5.18 (0.75-22.68) | 8.13 (1.13-64.97) | ||
Level of PD-L1 expression (<50 vs. ≥50) | 0.28 (0.04-0.99) | 0.091 | - | - |
irAEs (presence vs. none) | 2.88 (1.10-8.45) | 3.46 (1.01-14.78) | 0.064 | |
NLR before initiation of therapy (<5 vs. ≥5) | 8.02 (1.21-32.24) | 8.36 (0.78-91.11) | 0.068 | |
B2-MG (≥2.5 vs. <2.5) | 0.27 (0.09-0.69) | 0.13 (0.03-0.40) | ||
Neopterin (≥12 vs. <12) | 0.23 (0.07-0.64) | 0.35 (0.13-0.87) | ||
IL-6 (≥10 vs. <10) | 0.46 (0.18-1.16) | 0.091 | - | - |
IL-18 (≥273 vs. <273) | 0.23 (0.05-1.06) | 0.056 | - | - |
Anti-TPO (none vs. presence) | 0.31 (0.05-1.09) | 0.118 | - | - |
Values in bold are significant. PFS, progression-free survival; NSCLC, non-small cell lung cancer; ECOG PS, Eastern Cooperative Oncology Group Performance Status; BMI, body mass index; irAEs, immune-related adverse events; NLR, neutrophil-lymphocyte ratio; B2-MG, β-2 microglobulin; anti-TPO, antibodies to thyroperoxidase; HR, hazard ratio; 95%CI, 95% confidence interval.
Univariate and multivariate regression analysis of clinical, morphological and immunological parameters associated with PFS in melanoma.
Univariate analysis | Multivariate analysis | |||
---|---|---|---|---|
Characteristic | HR (95% CI) | P-value | HR (95% CI) | P-value |
Melanoma (group 2) | ||||
Age (≥65 vs. <65) | 0.78 (0.11-4.78) | 0.792 | - | - |
Sex (male vs. female) | 0.82 (0.04-9.58) | 0.873 | - | - |
ECOG PS (0/1 vs. 2) | 2.60 (0.51-11.36) | 0.209 | - | - |
Disease stage (III vs. IV) | 0.87 (0.11-5.68) | 0.882 | - | - |
Category M (M1a-b vs. M1c) | 0.43 (0.02-2.72) | 0.443 | - | - |
Serum LDH (elevated vs. normal) | 1.95 (0.55-9.43) | 0.343 | - | - |
Level of PD-L1 expression (≤5 vs. >5) | 0.28 (0.01-1.59) | 0.237 | - | - |
irAEs (presence vs. none) | 4.72 (1.42-21.36) | 5.21 (1.07-38.67) | 0.058 | |
NLR before initiation of therapy (<5 vs. ≥5) | 8.95 (2.45-32.67) | 7.93 (1.80-40.91) | ||
B2-MG (≥2.5 vs. <2.5) | 0.10 (0.02-0.39) | 0.09 (0.01-0.44) | ||
NPT (≥12 vs. <12) | 0.62 (0.14-1.21) | 0.184 | - | - |
IL-6 (≥10 vs. <10) | 0.25 (0.07-0.84) | 0.57 (0.31-1.67) | 0.516 | |
IL-18 (≥273 vs. <273) | 1.69 (0.47-8.31) | 0.459 | - | - |
Anti-TPO (none vs. presence) | 0.21 (0.01-1,07) | 0.133 | - | - |
Values in bold are significant. PFS, progression-free survival; NSCLC, non-small cell lung cancer; ECOG PS, Eastern Cooperative Oncology Group Performance Status; BMI, body mass index; irAEs, immune-related adverse events; NLR, neutrophil-lymphocyte ratio; B2-MG, β-2 microglobulin; NPT, neopterin; anti-TPO, antibodies to thyroperoxidase; HR, hazard ratio; 95%CI, 95% confidence interval.
Univariate regression analysis of clinical, morphological and immunological markers associated with PFS.
Univariate analysis | ||
---|---|---|
Characteristics | HR (95% CI) | P-value |
Age (≥75 vs. <75) | 0.83 (0.48-1.66) | 0.485 |
Sex (male vs. female) | 0.97 (0.92-1.18) | 0.672 |
ECOG PS (0/1 vs. 2) | 1.32 (0.83-1.92) | 0.213 |
Smoking status (former/current vs. never) | 1.24 (0.91-1.71) | 0.153 |
Histology (non-squamous vs. squamous) | 0.91 (0.85-1.83) | 0.532 |
NLR before initiation of therapy (<3 vs. ≥3) | 1.26 (0.85-1.93) | 0.196 |
NPT (≥10 vs. <10) | 0.61 (0.42-1.19) | 0.145 |
PFS, progression-free survival; ECOG PS, Eastern Cooperative Oncology Group Performance Status; NLR, neutrophil-lymphocyte ratio; NPT, neopterin.