Association of azole antifungals with survival in patients with non-small cell lung cancer receiving immunotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18777-e18777
Author(s):  
Nikhil Sebastian ◽  
William A. Stokes ◽  
Madhusmita Behera ◽  
Renjian Jiang ◽  
David Gutman ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Checkpoint Inhibitors ◽  
Multivariable Analysis ◽  
Small Cell ◽  
Health Administration ◽  
Small Cell Lung ◽  
Ongoing Research ◽  
Significant Difference

e18777 Background: Preclinical data suggest certain azole derivatives may have antitumor efficacy and modulate responses to immune checkpoint inhibitors (ICIs). Clinical evidence of synergy can support ongoing research that is investigating the role of repurposing current FDA-approved azole medications to improve outcomes in people with non-small cell lung cancer (NSCLC). We evaluated the association of concomitant azole drugs in a population of NSCLC patients treated with ICI within the Veterans Health Administration. Methods: We conducted a retrospective cohort study of veterans diagnosed with NSCLC between 2010-2018 who were treated with ICI. Receipt of azole drugs was defined as taking a systemic azole within 90 days of ICI therapy. Overall survival (OS) was measured from the start of ICI therapy using Cox-Proportional Hazard (PH) multivariable regression. Patients whose earliest azole administration occurred more than 30 days after initiation of ICI were excluded. Results: We identified 3,413 Veterans treated with ICI; of these, 324 (9.5%) were treated with an azole, most commonly clotrimazole (3.0%) and fluconazole (2.5%). Patients had predominantly stage IV disease (40.8%) at initial diagnosis, followed by stage III (27.1%), stage I-II (19.9%), and unknown stage (12.1%). There was no significant difference in OS multivariable analysis (HR = 0.93 [0.81-1.06]; p = 0.28). Propensity score-matched analysis with 324 patients in each cohort also did not measure a significant difference in OS (HR = 0.89 [0.75-1.06]; p = 0.18) between patients who received any azole versus those who did not. When evaluating specific azole agents on multivariable analysis, there was an association of higher OS with receipt of clotrimazole (HR = 0.72 [0.56 – 0.92]; p = 0.009) and more than one azole (HR = 0.71 [0.53-0.96]; p = 0.026) when compared with no azole. There was an association of shorter OS with miconazole (HR = 1.92 [1.30-2.832]; p = 0.001) and no association with itraconazole (p = 0.08), fluconazole (p = 0.20), or ketoconazole (p = 0.87). In the matched analysis of 102 clotrimazole patients versus no azole, OS was longer in patients who received clotrimazole (HR = 0.76; 95% CI 0.55 – 1.04; p = 0.087), although this effect was not statistically significant. Conclusions: This analysis demonstrated a trend towards longer survival with concomitant clotrimazole and ICI for advanced NSCLC. This association was not seen for other azole mediations.

Peripheral blood biomarkers associated with outcome in non-small cell lung cancer patients treated with nivolumab and durvalumab monotherapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21732-e21732
Author(s):  
Lin Wu ◽  
Meilin Jiang ◽  
Wenying Peng ◽  
Xingxiang Pu ◽  
Bolin Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Peripheral Blood ◽  
Cox Regression ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Significant Difference ◽  
Nsclc Patients

e21732 Background: Selecting patients that potentially benefit from immune checkpoint inhibitors (ICIs) is critical. Programmed death ligand-1 (PD-L1) protein immunohistochemical expression on cancer cells or immune cells and Next generation sequencing based tumor mutational burden (TMB) are the hot spots in studies on ICIs, but there is still confusion in the testing methods. Due to blood samples are much easier for clinical application, many potential peripheral biomarkers have been proposed. This study identify blood parameters that associated with outcome of non-small cell lung cancer (NSCLC) patients with ICIs monotherapy. Methods: Data of 76 NSCLC patients were analyzed retrospectively. To assess the connection between survival and peripheral blood markers measured before and after treatment, we utilized COX regression model survival analysis and receiver operating characteristic (ROC) curve to assess the markers. Results: In the nivolumab cohort, the optimal cutoff for predicting 11 month overall survival (OS) were 168.13 and 43g/L in Plateletto-lymphocyte ratio (PLR) and albumin, respectively. When patients are grouped with PLR and albumin the cut-offs, a significant difference in SD-PR vursus PD rate were found between high and low groups, separately. which was not found when grouped by PD-L1 expression. Patients with high PLR ( > 168.13) or low albumin ( < = 43g/L) before ICI had a significantly raised hazard of progression, separately (for PLR, P = 0.006; for albumin, P = 0.033) and of death (for PLR, P = 0.014; for albumin, P = 0.009) compared with those patients who had low PLR or albumin level. More importantly, we found that higher PLR ( > 168.13) after the fourth cycle of ICIs was also an prognostic biomarker, which significantly correlated with shorter OS in both Nivolumab (P = 0.046) and durvalumab cohort (P = 0.028). Conclusions: PLR and albumin may help the stratification of high progression and death risk group in advanced NSCLC patients treated with nivolumab and durvalumab monotherapy.

scholarly journals Treatment of non-small-cell lung cancer after progression on nivolumab or pembrolizumab

2019 ◽  
Vol 27 (2) ◽  
Author(s):  
A.T. Freeman ◽  
M. Lesperance ◽  
E. S. Wai ◽  
N. S. Croteau ◽  
L. Fiorino ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Multivariable Analysis ◽  
Small Cell ◽  
Small Cell Lung ◽  
Eligibility Criteria ◽  
Significant Difference

Background Although PD-1 antibodies (PD1 Ab) are the standard of care for advanced non-small-cell lung cancer (ansclc), most patients will progress. We compared survival outcomes for patients with ansclc who received systemic therapy (st) after progression and for those who did not. Additionally, clinical characteristics that predicted receipt of st after PD1 Ab failure were evaluated. Methods All patients with ansclc in British Columbia initiated on nivolumab or pembrolizumab between June 2015 and November 2017, with subsequent progression, were identified. Eligibility criteria for additional st included an Eastern Cooperative Oncology Group (ecog) performance status (ps) of 3 or less and survival for more than 30 days from the last PD1 Ab treatment. Post-progression survival (pps) was assessed by landmark analysis. Baseline charac­teristics associated with pps were identified by multivariable analysis. Results Of 94 patients meeting the eligibility criteria, 33 received st after progression. In 75.6%, a PD1 Ab was received as first- or second-line treatment. The most common sts were erlotinib (36.4%) and docetaxel (27.3%). No statistically significant difference in median pps was observed between patients who did and did not receive st within 30 days of their last PD1 Ab treatment (6.9 months vs. 3.6 months, log-rank p = 0.15.) In multivariable analysis, factors associated with increased pps included an ecog ps of 0 or 1 compared with 2 or 3 [hazard ratio (hr): 0.42; 95% confidence interval (ci): 0.24 to 0.73; p = 0.002] and any response compared with no response to PD1 Ab (hr: 0.54; 95% ci: 0.33 to 0.90; p = 0.02). Conclusions In this cohort, only 35.1% of patients eligible for post–PD1 Ab therapy received st. Post-progression survival was not significantly affected by receipt of post-progression therapy. Prospective trials are needed to clarify the benefit of post–PD1 Ab treatments.

scholarly journals Impact of Maintenance Therapy Following Induction Immunochemotherapy for Untreated Advanced Non-Small Cell Lung Cancer Patients

2021 ◽  
Author(s):  
Ryota Nakamura ◽  
Tadaaki Yamada ◽  
Kenji Morimoto ◽  
Akira Nakao ◽  
Yasuhiro Goto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Maintenance Therapy ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Advanced Nsclc ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Cytotoxic Agents ◽  
Small Cell Lung ◽  
Significant Difference

Abstract Purpose The primary objective of this study was to identify the potential predictors to assess impact of maintenance therapy after induction immunochemotherapy in the real-world setting of patients with advanced non-small cell lung cancer (NSCLC). Methods We retrospectively identified 152 patients with advanced NSCLC who received immunochemotherapy at eight hospitals in Japan between January 2019 to December 2019. Patients who received at least four cycles of induction immunochemotherapy and one cycle of maintenance therapy with immune-checkpoint inhibitors were included. We investigated the biomarkers for progression-free survival (PFS) for maintenance therapy after induction immunochemotherapy. Results Out of the 92 patients with advanced NSCLC included in the study, 42 received maintenance therapy with cytotoxic agents whereas 50 received maintenance therapy without cytotoxic agents. Among those who received maintenance therapy without cytotoxic agents, responders to prior immunochemotherapy had significantly longer PFS than non-responders (p = 0.004), except those with maintenance therapy with cytotoxic agents. In non-responders to prior immunochemotherapy, patients with maintenance therapy with cytotoxic agents had significantly longer PFS than those with maintenance therapy without cytotoxic agents (log-rank p = 0.007), whereas among responders to prior immunochemotherapy, there was no significant difference in PFS for different maintenance regimens (log-rank p = 0.31). Conclusions This retrospective study showed that response to prior immunochemotherapy was associated with clinical outcomes among patients with advanced NSCLC who received maintenance therapy.

Changes in PD-L1 tumor proportion score are associated with CD274 gene (encoding PD-L1) copy number variation in non-small cell lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9029-9029
Author(s):  
Stephanie Leigh Alden ◽  
Biagio Ricciuti ◽  
Giuseppe Lamberti ◽  
Liam Flinn Spurr ◽  
Lynette M. Sholl ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Copy Number ◽  
Checkpoint Inhibitors ◽  
Major Change ◽  
Small Cell ◽  
Categorical Variables ◽  
Small Cell Lung ◽  
Significant Difference

9029 Background: PD-L1 tumor proportion score (TPS) is often used to determine eligibility for first line therapy with immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC). However, PD-L1 expression can vary over time and between tumor sites, potentially leading to inaccurate patient stratification. Therefore, it is critical to understand the clinicopathologic and genomic factors that are associated with PD-L1 changes in NSCLC. Methods: Clinicopathologic and genomic data were collected from patients with NSCLC and quantitative PD-L1 immunohistochemistry (IHC) on at least two different biopsies. NSCLC biopsies were categorized as PD-L1 negative, low, and high if they had a PD-L1 TPS < 1%, 1-49%, and ≥50%, respectively. Intrapatient changes in PD-L1 TPS between samples (DPD-L1) were defined as follows: major decrease (decrease in PD-L1 TPS from ≥50% to < 50% or from ≥1% to < 1%), major increase (increase in PD-L1 TPS from < 1% to ≥1% or < 50% to ≥50%), and non-major change (all other cases). Next-generation sequencing (NGS) was used to evaluate copy number (CN) variations at the CD274 locus, which encodes PD-L1. Wilcoxon and Kruskal-Wallis rank sum tests were used to analyze continuous variables and Fisher’s exact test was used to analyze categorical variables. Results: Among 250 patients with NSCLC with PD-L1 IHC assays performed on at least two distinct tissue samples, PD-L1 TPS of the first biopsy was < 1% in 104 (41.6%), 1-49% in 80 (32.0%), and ≥50% in 66 (26.4%) samples, for a median PD-L1 TPS of 2% (range: 0% to 100%). When intrapatient DPD-L1 was examined, there were major decreases and major increases in PD-L1 TPS in 49 (19.6%) and 65 (26.0%) cases, respectively, and non-major changes were observed in the remaining 136 samples (54.4%), with a median DPD-L1 of 0% (range: -90% to +90%). Baseline PD-L1 TPS and DPD-L1 were not significantly affected by histology, smoking status, sex, or treatment. Among 219 NSCLC samples that underwent tissue NGS and had full CN data available, the median PD-L1 TPS differed significantly based on CD274 CN: PD-L1 TPS 1% with single copy deletion vs. 5% with copy neutral vs. 42.5% with low amplification vs. 97.5% with high amplification (p < 0.01). Among 56 patients with paired PD-L1 TPS and NGS on both samples, there was a significant difference in median DPD-L1 according to CD274 CN change: DPD-L1 TPS -49% with acquired CD274 CN loss vs. 0% with no major change in CD274 CN vs. +1.75% with acquired CD274 CN gain (p = 0.01). Conclusions: PD-L1 TPS varies within the same patient in almost half of NSCLC cases, with few clinicopathologic correlates of change in expression. Variation in PD-L1 TPS correlates with changes in CD274 CN across biopsies. These findings suggest a genomic correlate to predict PD-L1 TPS across samples, as well as a potential complementary method in determining in ICI initiation.

Immune-related endocrine toxicities in non-small cell lung cancer: predictors of outcome to checkpoint inhibitors?

2019 ◽  
Author(s):  
Roberta Poli ◽  
Clement Dumont ◽  
Lisa Pietrogiovanna ◽  
Vincent Servois ◽  
Sophie Beaucaire-Danel ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Predictors Of Outcome ◽  
Small Cell Lung

scholarly journals P09.25 Role of Immune Checkpoint Inhibitors (ICPi) in KRAS-Mutated Non-Small Cell Lung Cancer (NSCLC)

2021 ◽  
Vol 16 (3) ◽  
pp. S300-S301
Author(s):  
M. Peravali ◽  
C. Gomes-Lima ◽  
E. Tefera ◽  
M. Baker ◽  
M. Sherchan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung

scholarly journals Circulating Biomarkers of Response and Toxicity of Immunotherapy in Advanced Non-Small Cell Lung Cancer (NSCLC): A Comprehensive Review

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1794
Author(s):  
Alice Indini ◽  
Erika Rijavec ◽  
Francesco Grossi
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Liquid Biopsy ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Circulating Biomarkers ◽  
Small Cell Lung ◽  
Nsclc Patients

Immune checkpoint inhibitors (ICIs) targeting the programmed cell death (PD)-1 protein and its ligand, PD-L1, and cytotoxic T-lymphocyte-associated antigen (CTLA)-4, have revolutionized the management of patients with advanced non-small cell lung cancer (NSCLC). Unfortunately, only a small portion of NSCLC patients respond to these agents. Furthermore, although immunotherapy is usually well tolerated, some patients experience severe immune-related adverse events (irAEs). Liquid biopsy is a non-invasive diagnostic procedure involving the isolation of circulating biomarkers, such as circulating tumor cells (CTC), cell-free DNA (cfDNA), and microRNAs (miRNAs). Thanks to recent advances in technologies, such as next-generation sequencing (NGS) and digital polymerase chain reaction (dPCR), liquid biopsy has become a useful tool to provide baseline information on the tumor, and to monitor response to treatments. This review highlights the potential role of liquid biomarkers in the selection of NSCLC patients who could respond to immunotherapy, and in the identification of patients who are most likely to experience irAEs, in order to guide improvements in care.

scholarly journals Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy

2021 ◽  
Vol 9 (4) ◽  
pp. e002421
Author(s):  
Alessio Cortellini ◽  
Massimo Di Maio ◽  
Olga Nigro ◽  
Alessandro Leonetti ◽  
Diego L Cortinovis ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Objective Response ◽  
Multivariable Analysis ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Metastatic Nsclc ◽  
The Impact

BackgroundSome concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate.MethodsWe present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses.Results950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, β-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); p<0.0001), and OS (HR=1.93 (95% CI 1.59 to 2.35); p<0.0001) following pembrolizumab, and shorter PFS (HR=1.30 (95% CI 1.08 to 1.56), p=0.0046) and OS (HR=1.58 (95% CI 1.29 to 1.94), p<0.0001), following chemotherapy. PPIs were associated with worse OS (HR=1.49 (95% CI 1.26 to 1.77); p<0.0001) with pembrolizumab and shorter OS (HR=1.12 (95% CI 1.02 to 1.24), p=0.0139), with chemotherapy. At the pooled analysis, there was a statistically significant interaction with treatment (pembrolizumab vs chemotherapy) for corticosteroids (p=0.0020) and PPIs (p=0.0460) with respect to OS, for corticosteroids (p<0.0001), ATB (p=0.0290), and PPIs (p=0.0487) with respect to PFS, and only corticosteroids (p=0.0033) with respect to objective response rate.ConclusionIn this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features.

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