scholarly journals Serum Metabolite Biomarkers Predictive of Response to PD-1 Blockade Therapy in Non-Small Cell Lung Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaoqun Nie ◽  
Liliang Xia ◽  
Fang Gao ◽  
Lixia Liu ◽  
Yi Yang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Advanced Nsclc ◽  
Validation Cohort ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Discovery Cohort ◽  
Free Survival ◽  
Metabolomic Profiling

Background: Despite remarkable success of immunotherapies with checkpoint blockade antibodies targeting programmed cell death protein 1 (PD-1), the majority of patients with non-small-cell lung cancer (NSCLC) have yet to receive durable benefits. We used the metabolomic profiling of early on-treatment serum to explore predictors of clinical outcomes of anti-PD-1 treatment in patients with advanced NSCLC.Methods: We recruited 74 Chinese patients who had stage IIIB/IV NSCLC-proven tumor progression and were treated with PD-1 inhibitor. The study was comprised of a discovery cohort of patients treated with nivolumab and two validation cohorts of patients receiving tislelizumab or nivolumab. Serum samples were collected 2–3 weeks after the first infusion of PD-1 inhibitor. Metabolomic profiling of serum was performed using ultrahigh performance lipid chromatograph-mass spectrometry. The serum metabolite biomarkers were identified using an integral workflow of nontargeted metabolomic data analysis.Results: A serum metabolite panel consisting of hypoxanthine and histidine was identified and validated as a predictor of response to PD-1 blockade treatment in patients with advanced NSCLC. High levels of both hypoxanthine and histidine in early on-treatment serum were associated with improved progression-free survival [hazard ratio (HR) = 0.078, 95% confidence interval (CI), 0.027–0.221, p < 0.001] and overall survival (HR = 0.124, 95% CI, 0.039–0.397, p < 0.001) in the discovery cohort. The serum metabolite panel showed a high sensitivity and specificity in distinguishing responders and non-responders in the validation cohorts 1 and 2, with an area under the receiver-operating characteristic curve of 0.933 and 1.000, respectively. High levels of serum hypoxanthine and histidine were correlated with improved progression-free survival in the validation cohort 1 (HR = 0.137, 95% CI, 0.040–0.467, p = 0.001) and in the validation cohort 2 (HR = 0.084, 95% CI, 0.009–0.762, p = 0.028).Conclusion: Our results revealed that hypoxanthine and histidine in early on-treatment serum are predictive biomarkers of response to PD-1 blockade therapy in patients with advanced NSCLC. The serum biomarker panel would enable early identification of NSCLC patients who may benefit from PD-1 blockade therapy.

Neutrophil to lymphocyte ratio as predictive of prolonged progression free survival (PFS) and overall survival (OS) in patients with metastatic non-small cell lung cancer (NSCLC) treated with second-line PD-1 immune checkpoint inhibitors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14530-e14530 ◽  
Author(s):  
Stephanie Labomascus ◽  
Ibtihaj Fughhi ◽  
Philip Bonomi ◽  
Mary J. Fidler ◽  
Jeffrey Allen Borgia ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Tumor Microenvironment ◽  
Small Cell Lung Cancer ◽  
Advanced Nsclc ◽  
Progression Free Survival ◽  
Small Cell ◽  
Second Line ◽  
Small Cell Lung ◽  
Free Survival

e14530 Background: Baselinehigh neutrophil to lymphocyte ratio (NLR) has been associated with inferior overall survival in patients with stage III/IV NSCLC. Inflammation and neutrophilic infiltrates in the tumor microenvironment appear to inhibit anti-tumor immune response. We suspect that NLR might reflect the level of inflammation in tumor microenvironment. The objectives of this study were to evaluate potential relationships between pretreatment NLR and and PFS and OS in advanced NSCLC patients treated with second-line nivolumab or pembrolizumab. Methods: Patients with stage IV NSCLC who received at least one cycle of nivolumab or pembrolizumab after first-line treatment with a platinum doublet between January 2015 and December 2016 were included. Patient demographics including NLR at baseline, date of starting immunotherapy, and date of progression were recorded. The association between NLR and duration of response was assessed using a Mann-Whitney-Wilcoxon test. A cutoff of NLR of 3.5 and 5.0 based on published data (ref) were analyzed for differences in median overall survival and progression free survival. Results: 113 patients were analyzed: median age 68, male/female 38.9%/61.1%, 15% never smoked. The median PFS for patients with NLR < 5 was 4.14 months vs. 2.27 months in those with NLR > 5 (p = 0.031). Overall survival was also impacted by NLR. There were a total of 29 deaths in the cohort, 24 of these occurred in patients with NLR > 3.5 and 5 were in patients with NLR < 3.5. A lower NLR at baseline was significantly associated with improved overall survival (p = 0.036). Conclusions: A low baseline NLR is associated with superior progression free survival and overall survival in metastatic non-small cell lung cancer patients treated with nivolumab or pembrolizumab. These findings suggest that evaluating mediators of inflammation might help to identify potential therapeutic targets which could enhance effectiveness of PD-1 immune check point inhibitors in advanced NSCLC.

The depth of response was associated with the progression-free survival in advanced non-small cell lung cancer patients treated with EGFR-TKI.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20509-e20509
Author(s):  
Yutao Liu ◽  
Kai Zhang ◽  
Chengcheng Li ◽  
Xingsheng Hu ◽  
Jun Jiang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Advanced Nsclc ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival ◽  
Depth Of Response ◽  
Egfr Tki

e20509 Background: Response Evaluation Criteria in Solid Tumors (RECIST) has been widely utilized to evaluate the new therapeutic strategies in cancer, however, RECIST fails to differentiate the heterogeneity of response in highly active therapies. Depth of response (DepOR), defined as maximum percent change in tumor size compared with baseline, may provide a new strategy to evaluate disease response. In the present study, we studied the association between DepOR and progression-free survival (PFS) in patients with advanced non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Methods: Advanced NSCLC patients harboring EGFR driver mutation (L858R or 19del) treated with EGFR-TKI from August 2014 to July 2017 in two sites were retrospetively collected for analysis. Patients were divided into four groups by maximal tumor shrinkage (Q1 = 1-25%, Q2 = 26-50%, Q3 = 51-75%, Q4 = 76-100%). Kaplan-Meier curves were plotted for PFS by DepOR and the hazard ratio (HR) was determined through univariable and multivariable Cox regression models. Results: In total, 265 patients were included for analysis. The number for Group Q1-Q4 was 91, 73, 65 and 36, respectively. The greater DepOR was significantly associated with a longer PFS (Log-rank P for trend < 0.0001). The DepOR vs PFS analyses HR were 0.58 (0.42-0.80) for Q2, 0.49 (0.35-0.69) for Q3 and 0.33 (0.22-0.50) for Q4 compared with Q1. In the multivariable cox regression model, abnormal LDH, brain metastasis and male were also found to be associated with poorer PFS (P < 0.05). Conclusions: Greater DepOR was significantly associated with a longer PFS in advanced NSCLC treated with EGFR-TKI, suggesting that it may be a useful clinical outcome to more efficiently evaluate the response of targeted therapy.

Hypofractionated Radiotherapy for Locally or Systemically Advanced Non-small Cell Lung Cancer

2021 ◽  
Author(s):  
Jiajia Zhang ◽  
Zi'ning Qi ◽  
Dong Han ◽  
Siying Chen ◽  
Jifeng Sun ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Advanced Nsclc ◽  
Progression Free Survival ◽  
Small Cell ◽  
Hypofractionated Radiotherapy ◽  
Small Cell Lung ◽  
Free Survival ◽  
Local Progression

Abstract Background: Palliative thoracic radiotherapy (RT) can improve local control and survival in patients with unresectable locally or systemically advanced non-small cell lung cancer (NSCLC), but the optimal RT dose has not been well-defined. We investigated the survival outcomes of patients with NSCLC who underwent hypofractionated radiotherapy (HFRT).Methods: We retrospectively investigated survival and adverse effects among 74 patients with locally or systemically advanced NSCLC who received HFRT (45 Gy/15 fractions) at our institution.Results: The median overall survival (OS) was 18.7 months, with 1- and 2-year OS rates of 65.9% and 33.9%, respectively. The median local progression-free survival (LPFS) was 7.2 months, with 1- and 2-year LPFS rates of 27.9% and 9.4%, respectively. Sixteen patients (21.6%) developed grade ≤2 pneumonitis and 14 (19%) developed grade ≤2 esophagitis; no grades ≥3 pneumonitis or esophagitis occurred.Conclusions: HFRT is safe, tolerable, and effective for patients with unresectable locally or systemically advanced NSCLC exhibiting poor prognostic factors.

A randomized discontinuation phase II trial of ridaforolimus in non-small cell lung cancer (NSCLC) patients with KRAS mutations.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7531-7531 ◽  
Author(s):  
Gregory J. Riely ◽  
Julie R. Brahmer ◽  
David Planchard ◽  
Lucio Crinò ◽  
Robert Charles Doebele ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Stable Disease ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Kras Mutations ◽  
Free Survival

7531 Background: Mutations in KRAS are present in ~25% of patients with advanced NSCLC. Preclinical data support the role of mammalian target of rapamycin (mTOR) in KRAS mediated oncogenesis. Ridaforolimus is an inhibitor of mTOR which has been shown to have efficacy in advanced endometrial cancer and soft tissue sarcoma. Everolimus, another mTOR inhibitor was previously evaluated in unselected patients with advanced NSCLC and found to have a response rate <5%. We hypothesized that by enrichment for patients with NSCLC and KRAS mutations, treatment with ridaforolimus would be associated with prolonged stable disease relative to available standard treatments for NSCLC. Methods: Patients with stage IIIB/IV non-small cell lung cancer with KRAS mutation who had received prior chemotherapy for NSCLC began treatment with oral ridaforolimus 40 mg once daily on a 5 day/week schedule. After 8 weeks, patients with >30% tumor shrinkage remained on ridaforolimus and patients with >20% tumor growth discontinued treatment. Patients with stable disease were randomized 1:1 to placebo or ridaforolimus. The primary endpoint of the study was progression-free survival (PFS) after randomization. Results: 79 patients were enrolled (40 women, median age 58 [range 28-85]). The overall response rate (CR+PR) at 8 weeks was 1/79 (1%, 95% CI 0-7%).  28 patients with stable disease at 8 weeks were randomized to ridaforolimus or placebo.  Median PFS based on investigator assessment from randomization was significantly longer with ridaforolimus (4 months) than placebo (2 months, p=0.013, HR 0.36).  Median OS from randomization was 18 months in the ridaforolimus treated arm and 5 months in the placebo treated group, (HR 0.46, p=0.09).  The most common grade ≥3 adverse events were fatigue (10%), mucositis/stomatitis (10%), pneumonia (10%), dyspnea (9%), diarrhea (6%), and hyperglycemia (6%). Conclusions: In patients with KRAS mutant NSCLC who had stable disease after 8 weeks of ridaforolimus, ridaforolimus was associated with prolonged progression-free survival.  Further evaluation of ridaforolimus in this patient population is warranted. 

Prognostic value of peripheral naive CD8+ T cells in oligometastatic non-small-cell lung cancer

2021 ◽  
Author(s):  
Xin Zhao ◽  
Yan Zhang ◽  
Zhenlin Gao ◽  
Yaguang Han
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Immune Cells ◽  
Prognostic Value ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival

Aim: This study aimed to investigate the prognostic value of peripheral naive and memory CD8+ and CD4+ T cells and other immune cells in patients with oligometastatic non-small-cell lung cancer (NSCLC) undergoing radiotherapy (RT). Methods: A total of 142 patients with oligometastatic NSCLC treated with RT were enrolled, and their blood samples were collected within 3 days before RT. Immune cells were identified by flow cytometry. Results: Patients with high levels of naive CD8+ T cells had longer overall survival (p = 0.004) and progression-free survival (p = 0.001) than those with low levels of naive CD8+ T cells. Multivariate analyses revealed that naive CD8+ T cells were independently correlated with overall survival (p = 0.019) and progression-free survival (p = 0.024). Conclusion: The results suggest that peripheral naive CD8+ T cells may be an independent prognostic indicator for patients with oligometastatic NSCLC undergoing RT.

A phase II study of anlotinib plus whole brain radiation therapy (WBRT) for advanced non-small cell lung cancer with multiple brain metastases.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21063-e21063
Author(s):  
Xiangzhi Zhu ◽  
Hua Tao ◽  
Ming Jiang ◽  
Meiqi Shi ◽  
Cheng Kong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Radiation Therapy ◽  
Brain Metastases ◽  
Advanced Nsclc ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival ◽  
Multiple Brain Metastases ◽  
Common Grade

e21063 Background: The prognosis of non-small-cell lung cancer (NSCLC) patients(pts) with multiple brain metastases is poor. WBRT is the main treatment for the pts, but QUARTZ study showed that the efficacy of WBRT is unsatisfactory. The synergistic effect of the antiangiogenic therapy with radiation therapy has been well established. Anlotinib, an antiangiogenic multi-target TKI, had significantly improved progression-free survival (PFS) of advanced NSCLC with Brain Metastases. This study aimed to evaluate the efficacy and safety of anlotinib combined with WBRT in pts with brain metastases ( > 3) from advanced NSCLC. Methods: Advanced NSCLC pts with brain metastases ( > 3) who were histologically confirmed to be driver gene wild type or positive and pts who had received two or more previous treatments were eligible. Pts with meningeal metastasis were excluded. All pts were treated with anlotinib (12 mg, QD, day 1 to 14 of a 21-day cycle) combined with WBRT (DT 30Gy/12f), followed by maintenance therapy with anlotinib until disease progression or treatment intolerance. The primary endpoint was intracranial progression-free survival (iPFS). Secondary endpoints were extracranial PFS (ePFS), OS and toxicity. Results: As of 25 Jan 2021, 28 pts were enrolled. The median age was 57.5 years with 46.4% male. 89.3% of pts with adenocarcinoma. 21.4% pts harbored EGFR mutation. A total of 25 pts were included in efficacy analysis. In intracranial evaluation, ORR was 64.0%, DCR was 88.0%, median iPFS was 11.1 months (95% CI 5.9 to 12.1). In extracranial evaluation, ORR was 12.0%, DCR was 84.0%, median ePFS was 6.0months (95% CI 3.2 to 8.8). Most common grade 1-2 adverse events (AEs) were hypertension (67.8%), fatigue (64.2%)，anorexia (46.4%) and hand and foot skin reaction (37.5%). The most common grade 3-4 AEs were hypertension (12.5%), hand and foot skin reaction (10.7%) and fatigue (7.2%). No intracranial hemorrhage occurred during treatment. Dose adjustment due to AE occurred in 21.4% patients. Conclusions: This prospective study shows that the combination of anlotinib and WBRT for patients with multiple brain metastases after standard treatment resistance exhibited an effective therapeutic approach and manageable AEs. For further investigation, large sample and additional clinical trials are warranted. Clinical trial information: ChiCTR1900022093.

Sign in / Sign up

Export Citation Format

Share Document