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Neutrophil-to-Lymphocyte Ratio Is a Predictive Biomarker in Patients with Epidermal Growth Factor Receptor (EGFR) Mutated Advanced Non-Small Cell Lung Cancer (NSCLC) Treated with Tyrosine Kinase Inhibitor (TKI) Therapy

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Though patients with sensitizing epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer have been known to have rapid and durable responses to tyrosine kinase inhibitors, a subset of patients have inferior outcomes and may benefit from therapy escalation. Neutrophil-to-lymphocyte ratio (NLR) has been recognized as one indicator of poor prognosis in patients with various cancers, including non-small cell lung cancer. It is associated with cancer cachexia and treatment resistance. The aim of our study is to assess the serial predictive value of NLR and other markers of cachexia and chronic inflammation in the subset of patients with advanced non-small cell lung cancer who harbor the epidermal growth factor receptor mutation and who are undergoing treatment with tyrosine kinase inhibitor therapy.

Abstract

Background: First-line treatment for patients with non-small cell lung cancer (NSCLC) with a sensitizing epidermal growth factor receptor (EGFR) mutation is a tyrosine kinase inhibitor (TKI). Despite higher response rates and prolonged progression free survival (PFS) compared with platinum doublet chemotherapy, a subset of these patients do not receive prolonged benefit from these agents. We investigate if the neutrophil-to-lymphocyte ratio (NLR) and other markers of cachexia and chronic inflammation correlate with worse outcomes in these patients. Methods: This study is a retrospective review of 137 patients with advanced EGFR-mutated NSCLC treated with TKIs at Rush University Medical Center and University of Chicago Medicine from August 2011 to July 2019, with outcomes followed through July 2020. The predictive value of NLR and body mass index (BMI) was assessed at the start of therapy, and after 6 and 12 weeks of treatment by univariable and multivariable analyses. Results: On univariable analysis, NLR ≥ 5 or higher NLR on a continuous scale were both associated with significantly worse PFS and overall survival (OS) at treatment initiation, and after 6 or 12 weeks of treatment. On multivariable analysis, NLR ≥ 5 was associated with increased risk of death at 12 weeks of therapy (HR 3.002, 95% CI 1.282–7.029, p = 0.011), as was higher NLR on a continuous scale (HR 1.231, 95% CI 1.063–1.425, p = 0.0054). There was no difference in PFS and OS and amongst BMI categories though number of disease sites and Eastern Cooperative Oncology Group (ECOG) performance status was associated with worse PFS and OS. Conclusions: Patients with NLR ≥ 5 have a worse median PFS and median OS than patients with NLR < 5. NLR may have value as a predictive biomarker and may be useful for selecting patients for therapy intensification in the front-line setting either at diagnosis or after 12 weeks on therapy. NLR needs to be validated prospectively.

SUBMITTER: Yun N

PROVIDER: S-EPMC8003851 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeWe aimed to evaluate whether the addition of pemetrexed is effective in improving progression-free survival (PFS) in epidermal growth factor receptor (EGFR)-mutated patients with or without concomitant alterations.Materials and methodsThis multicenter clinical trial was conducted in China from June 15, 2018, to May 31, 2019. A total of 92 non-small cell lung cancer (NSCLC) patients harboring EGFR-sensitive mutations were included and divided into concomitant and non-concomitant groups. Patients in each group were randomly treated with EGFR-tyrosine kinase inhibitor (TKI) monotherapy or EGFR-TKI combined with pemetrexed in a ratio of 1:1. PFS was recorded as the primary endpoint.ResultsThe overall median PFS of this cohort was 10.1 months. There were no significant differences in PFS between patients with and without concomitant and between patients received TKI monotherapy and TKI combined with pemetrexed (p=0.210 and p=0.085, respectively). Stratification analysis indicated that patients received TKI monotherapy had a significantly longer PFS in non-concomitant group than that in concomitant group (p=0.002). In concomitant group, patients received TKI combined with pemetrexed had a significantly longer PFS than patients received TKI monotherapy (p=0.013). Molecular dynamic analysis showed rapidly emerging EGFR T790M in patients received TKI monotherapy. EGFR mutation abundance decreased in patients received TKI combined chemotherapy, which supports better efficacy for a TKI combined chemotherapy as compared to TKI monotherapy. A good correlation between therapeutic efficacy and a change in circulating tumor DNA (ctDNA) status was found in 66% of patients, supporting the guiding role of ctDNA minimal residual disease (MRD) in NSCLC treatment.ConclusionEGFR-TKI monotherapy is applicable to EGFR-sensitive patients without concomitant alterations, while a TKI combined chemotherapy is applicable to EGFR-sensitive patients with concomitant alterations. CtDNA MRD may be a potential biomarker for predicting therapeutic efficacy.

Project description:BACKGROUND:HER2 expression and amplification are observed in ~15% of tumour biopsies from patients with a sensitising EGFR mutation who develop EGFR TKI resistance. It is unknown whether HER2 targeting in this setting can result in tumour responses. METHODS:A single arm phase II study was performed to study the safety and efficacy of trastuzumab and paclitaxel treatment in patients with a sensitising EGFR mutation who show HER2 expression in a tumour biopsy (IHC???1) after progression on EGFR TKI treatment. Trastuzumab (first dose 4?mg/kg, thereafter 2?mg/kg) and paclitaxel (60?mg/m2) were dosed weekly until disease progression or unacceptable toxicity. The primary end-point was tumour response rate according to RECIST v1.1. RESULTS:Twenty-four patients were enrolled. Nine patients were exon 21 L858R positive and fifteen exon 19 del positive. Median HER2 IHC was 2+ (range 1-3). For 21 patients, gene copy number by in situ hybridisation could be calculated: 5 copies/nucleus (n?=?9), 5-10 copies (n?=?8), and >10 copies (n?=?4). An objective response was observed in 11/24 (46%) patients. Highest response rates were seen for patients with 3+ HER2 IHC (12 patients, ORR 67%) or HER2 copy number ?10 (4 patients, ORR 100%). Median tumour change in size was 42% decrease (range -100% to +53%). Median duration of response was 5.6 (95% confidence interval [CI], 3.8 to 7.3) months. Treatment toxicity was mild with four patients experiencing grade ?3 toxicity, including fatigue, neuropathy, neutropaenia, urinary tract infection, and pneumonitis. CONCLUSIONS:Trastuzumab-paclitaxel induces objective tumour responses in 46% of EGFR TKI pretreated patients with an activating EGFR mutation and HER2 expression. The treatment was well tolerated. The relation between response rate and HER2 expression level and copy number suggests effective HER2 targeting by trastuzumab, although the combination with paclitaxel does not allow to determine the relative contribution of the individual drugs in terms of treatment efficacy.

Project description:BackgroundIn the global FLAURA study, first-line osimertinib, a third-generation irreversible tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), significantly improved progression-free survival (PFS) and overall survival (OS) versus comparator EGFR TKIs in patients with EGFR mutation-positive (EGFRm) advanced non-small-cell lung cancer (NSCLC).ObjectiveThe FLAURA China study assessed first-line osimertinib in Chinese patients with EGFRm advanced NSCLC (NCT02296125).MethodsFLAURA China was a double-blind, randomized, phase III study. Adults from mainland China with previously untreated EGFRm (Exon 19 deletion or L858R) advanced NSCLC were enrolled in the global study or a China-only study under the same protocol; 136 patients were randomized to osimertinib (80 mg once daily [od]; n = 71) or comparator EGFR TKI (gefitinib or erlotinib; all sites selected gefitinib 250 mg od; n = 65). Patients were randomized and allocated to treatment groups by a central computer system. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed PFS; OS was a secondary endpoint.ResultsAll 136 randomized patients were analyzed. Osimertinib extended median PFS by 8.0 months versus comparator EGFR TKI (17.8 vs. 9.8 months; hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.37-0.85). Median OS was 33.1 months in the osimertinib group versus 25.7 months in the comparator group (HR 0.85; 95% CI 0.56-1.29). At 3 years, 20% of patients on osimertinib and 8% on the comparator remained on randomized treatment. Grade 3 or higher adverse events (AEs) were reported in 54 and 28% of patients in the osimertinib and comparator groups, respectively, driven by increased local reporting of laboratory- and disease-related AEs. No new safety signals were identified.ConclusionsFirst-line osimertinib treatment resulted in a clinically meaningful PFS and OS benefit versus comparator EGFR TKI in Chinese patients with EGFRm advanced NSCLC. Safety data were consistent with the known safety profile of osimertinib.Clinical trial registrationClinicalTrials.gov NCT02296125, registered 20 November 2014.

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Neutrophil-to-Lymphocyte Ratio Is a Predictive Biomarker in Patients with Epidermal Growth Factor Receptor (EGFR) Mutated Advanced Non-Small Cell Lung Cancer (NSCLC) Treated with Tyrosine Kinase Inhibitor (TKI) Therapy

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