Insurance Status is an Independent Predictor of Overall Survival in Patients With Stage III Non–small-cell Lung Cancer Treated With Curative Intent

IntroductionPopulation studies suggest an impact of insurance status on oncologic outcomes. We sought to explore this in a large single-institution cohort of patients with non–small-cell lung cancer (NSCLC).Materials and MethodsWe retrospectively analyzed 342 consecutive patients (January 2000 to December 2013) curatively treated for stage III NSCLC. Patients were categorized by insurance status as uninsured (U), Medicare/Medicaid + Veterans Affairs (M/M + VA), or Private (P). The χ² test was utilized to compare categorical variables. The Kaplan-Meier approach and the Cox proportional hazard models were used to analyze overall survival (OS) and freedom from recurrence (FFR).ResultsCompared with M/M + VA patients, P insurance patients were more likely to be younger (P < .001), married (P < .001), Caucasian (P = .001), reside in higher median income zip codes (P < .001), have higher performance status (P < .001), and undergo consolidation chemotherapy (P < .001) and trimodality therapy (P < .001). Diagnosis to treatment was delayed > 30 days in U (67.3%), M/M + VA (68.1%), and P (52.6%) patients (P = .017). Compared with the M/M + VA and U cohorts, P insurance patients had improved OS (median/5-year: 30.7 months/34.2%, 19 months/17%, and 16.9 months/3.8%; P < .001) and FFR (median/5-year: 18.4 months/27.3%, 15.2 months/23.2%, and 11.4 months/4.8%; P = .012), respectively. On multivariate analysis, insurance status was an independent predictor for OS (P = .017) but not FFR.ConclusionCompared with U or M/M + VA patients, P insurance patients with stage III NSCLC were more likely to be optimally diagnosed and treated, resulting in a doubling of median OS for P versus U patients. Improved access to affordable health insurance is critical to combat inequities in access to care and has potential for improvements in cancer outcomes.     

PTEN Loss as a Predictor of Tumor Heterogeneity and Poor Prognosis in Patients With EGFR-mutant Advanced Non–small-cell Lung Cancer Receiving Tyrosine Kinase Inhibitors

BackgroundRapid disease progression of patients with advanced epidermal growth factor receptor (EGFR)-mutant non–small-cell lung cancer (NSCLC) has been recently associated with tumor heterogeneity, which may be mirrored by coexisting concomitant alterations. The aim of this analysis was to investigate the correlation between loss of function of PTEN and the efficacy of tyrosine kinase inhibitors in this population.Materials and MethodsArchival tumor blocks from patients with EGFR-mutant NSCLC who were administered upfront tyrosine kinase inhibitors were retrospectively collected. The status of 4 genes (PTEN, TP53, c-MET, IGFR) was evaluated by immunohistochemistry, and it was correlated with overall response rate, overall survival (OS), and progression-free survival (PFS).ResultsFifty-one patients were included. In multivariate analysis, PTEN loss (hazard ratio [HR], 3.46; 95% confidence interval [CI], 1.56-7.66; P = .002), IGFR overexpression (HR, 2.22; 95% CI, 1.03-4.77; P = .04), liver metastases (HR, 3.55; 95% CI, 1.46-8.65; P = .005), and Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 1 (HR, 2.57; 95% CI, 1.04-6.34; P = .04) were significantly associated with shorter PFS. Patients with PTEN loss had a median PFS of 6 months (2-year PFS, 11.6%), whereas patients without PTEN loss had a median PFS of 18 months (2-year PFS, 43.6%) (log-rank P < .005). In the multivariate analysis, PTEN loss (HR, 5.92; 95% CI, 2.37-14.81; P < .005), liver metastases (HR, 2.63; 95% CI, 1.06-6.51; P = .037), and ECOG PS ≥ 1 (HR, 2.80; 95% CI, 1.15-6.81; P = .024) were significantly associated with shorter OS. Patients with PTEN loss had a median OS of 6 months (2-year OS, 12.2%), whereas in patients without PTEN loss, OS was not reached (2-year OS, 63.9%) (log-rank P < .0005).ConclusionsA low-cost and reproducible immunohistochemistry assay for PTEN loss analysis represents a potential tool for identifying tumor heterogeneity in patients with advanced EGFR-mutant NSCLC.     

Polymorphisms in the Von Hippel–Lindau Gene Are Associated With Overall Survival in Metastatic Clear-Cell Renal-Cell Carcinoma Patients Treated With VEGFR Tyrosine Kinase Inhibitors

Background

Clear-cell renal-cell carcinoma (ccRCC) is characterized by loss of a functional Von Hippel–Lindau (VHL) protein. We investigated the potential of 3 single nucleotide polymorphisms (SNPs) in VHL as biomarkers in metastatic ccRCC (m-ccRCC) patients treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs).

The Impact of Beta Blockers on Survival Outcomes in Patients With Non–small-cell Lung Cancer Treated With Immune Checkpoint Inhibitors

BackgroundBeta blockers have been associated with anti-tumorigenic effects, potentially by reducing adrenergic-mediated stress responses. Preclinical studies have additionally shown that beta blockade may enhance the efficacy of cancer immunotherapy. We investigated patients with lung cancer who concomitantly used beta blockers and immune checkpoint inhibitors (ICIs), with the hypothesis that beta blockade would positively impact clinical outcomes.Patients and MethodsWe retrospectively reviewed the health records of 109 patients who were treated at Northwestern University from January 2014 through August 2018 with ICIs for non–small-cell lung cancer (NSCLC). Comparisons of overall survival and progression-free survival (PFS) were performed using Kaplan-Meier analysis with log-rank test, and a univariate regression analysis was performed with a Cox proportional hazards model.ResultsAmong 109 patients treated with ICIs for NSCLC, 28 of them were concomitantly prescribed beta blockers. Use of beta blockers was associated with increased PFS, with a hazard ratio of 0.58 and 95% confidence interval of 0.36 to 0.93. There was not a significant increase in overall survival among patients who took beta blockers (hazard ratio, 0.66; 95% confidence interval, 0.38-1.17). In a regression model, beta blockers were identified as predictive of PFS, as were non-squamous histology, tumor programmed death-ligand 1 positivity, and lower line of treatment.ConclusionsOur data suggests beta blocker use may be associated with improved PFS among patients treated with ICIs for NSCLC. This was a small study, and these findings should be further validated in prospective clinical studies.     

Association of Tumor Mutational Burden With DNA Repair Mutations and Response to Anti–PD-1/PD-L1 Therapy in Non–Small-Cell Lung Cancer

PurposeTo examine clinical predictors of tumor mutational burden (TMB), to explore the association between TMB and DNA repair mutations, and to analyze TMB as a biomarker for response to immune checkpoint blockade in non–small-cell lung cancer.Patients and MethodsTMB scores were determined retrospectively for 72 consecutive patients at our institution with next-generation sequencing comprehensive genomic profiling testing by Foundation Medicine. TMB scores were correlated with a number of clinical variables and presence of DNA repair mutations. Thirty-four patients were treated with anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) therapies, and survival analyses based on TMB score were performed. In addition, tissue immunohistochemical analysis was performed for a subset of patients.ResultsHistory of smoking, but not other clinical variables, including prior treatment lines, stage of disease, and number of metastatic sites, predicted higher TMB score. Higher TMB score was significantly associated with greater number of DNA repair mutations. In the subset of patients treated with immune checkpoint blockade, higher TMB score significantly predicted overall survival, but not progression-free survival (hazard ratio = 0.10, P = .003; hazard ratio 1.1, P = .84, respectively). In a small subset of patients, PD-1/PD-L1 staining did not independently predict progression-free survival or overall survival.ConclusionTissue TMB was significantly associated with smoking history and number of DNA repair mutations. TMB is a promising biomarker for response to anti–PD-1/PD-L1 therapy, with higher TMB score predicting longer overall survival.     

Impact of Clinicopathologic Features on the Efficacy of PD-1/PD-L1 Inhibitors in Patients With Previously Treated Non–small-cell Lung Cancer

Background

The current study aimed to comprehensively investigate the impact of various clinicopathologic features on the efficacy of programmed cell death-1 (PD-1) and ligand (PD-L1) inhibitors in patients with previously treated non–small-cell lung cancer (NSCLC).

Pembrolizumab for Previously Treated,PD-L1–expressing Advanced NSCLC: Real-world Time on Treatment and Overall Survival

BackgroundImmune checkpoint inhibitors have been rapidly adopted for therapy of advanced non–small-cell lung cancer (aNSCLC) based on clinical trial findings. Our aim was to examine outcomes in United States oncology practice settings for patients prescribed pembrolizumab monotherapy for previously treated, programmed death ligand-1 (PD-L1)–expressing aNSCLC, thus clinically similar to patients in the KEYNOTE-010 trial.Patients and MethodsThis retrospective observational study used a nationally representative database to identify adult patients with histologically confirmed aNSCLC and PD-L1 tumor proportion score (TPS) ≥ 1% previously treated with platinum-containing chemotherapy (and appropriate tyrosine kinase inhibitor if nonsquamous aNSCLC with EGFR/ALK genomic tumor aberration). Eligible patients initiated pembrolizumab monotherapy from January 1, 2016, to November 29, 2018; data cutoff was May 31, 2019. The Kaplan-Meier method was used to estimate real-world time on treatment (rwToT) and overall survival (OS).ResultsThe 349 eligible patients included 199 (57%) men; the median age was 68 years (range, 37-84 years); 70 (25%) of 278 patients with known performance status had Eastern Cooperative Oncology Group score ≥ 2. The median patient follow-up was 8.1 months (range, 1 day to 39.2 months). The median rwToT was 4.9 months (95% confidence interval [CI], 3.7-5.8 months) overall and 5.8 months (95% CI, 4.2-6.6 months) for the TPS ≥ 50% cohort (n = 218). The median OS was 13.8 months (95% CI, 11.0-16.5 months) and 16.5 months (95% CI, 13.7-22.0 months) overall and for TPS ≥ 50%, respectively; 12-month survival rates were 54% and 60%, respectively.ConclusionPatients treated at oncology practices with pembrolizumab monotherapy for previously treated PD-L1–expressing aNSCLC experienced rwToT and OS similar to treatment duration and OS in phase III clinical trial settings.     

Quantifying the Overall Survival Benefit With Early Radical Cystectomy for Patients With Histologically Confirmed T1 Non–muscle-invasive Bladder Cancer

IntroductionThe objective of this study was to examine the overall survival (OS) in patients diagnosed with high-grade T1 non–muscle-invasive bladder cancer treated with early radical cystectomy versus local treatment of the primary tumor, defined as endoscopic management with or without intravesical chemotherapy or immunotherapy.Patients and MethodsWe identified 4900 patients with histologically confirmed, clinically non-metastatic high-grade T1 bladder cancer undergoing surgical intervention using the National Cancer Database for the period 2010 to 2015. Multivariable logistic regression was used to examine predictors for the receipt of early radical cystectomy (defined as radical cystectomy within 90 days of diagnosis). We then employed multivariable Cox proportional hazards regression models and Kaplan-Meier curves to evaluate the OS according to surgical treatment (early radical cystectomy vs. local treatment).ResultsA minority (23.7%) of patients underwent early radical cystectomy. Independent predictors of undergoing early radical cystectomy included lower age, White race, and lower comorbidity status. The median OS was 74.0 months for patients diagnosed with high-grade T1 bladder cancer. The 1- and 5-year survival rates of patients undergoing early radical cystectomy were 94.8% and 71.0%, whereas they were 85.2% and 52.4%, for patients undergoing initial local treatment, respectively (P < .001). Compared with patients undergoing local treatment, patients undergoing early radical cystectomy had a lower risk of all-cause mortality (hazard ratio, 0.78; 95% confidence interval, 0.67-0.91; P = .002).ConclusionIn this cohort of patients presenting with high-grade T1 non–muscle-invasive bladder cancer, we found that early radical cystectomy was associated with an OS benefit compared with initial local treatment.     

Safety and Efficacy of PD-1 Inhibitors Among HIV-Positive Patients With Non–Small Cell Lung Cancer

Introduction

Despite widespread administration of programmed death receptor 1 (PD-1) pathway inhibitors among individuals with NSCLC, little is known about the safety and activity of these agents among human immunodeficiency virus (HIV) – infected patients since this population has largely been excluded from immunotherapy clinical trials.

Tumor Burden is Predictive of Survival in Patients With Non–Small-Cell Lung Cancer and With Activating Epidermal Growth Factor Receptor Mutations Who Receive Gefitinib

BackgroundAlthough activating epidermal growth factor receptor (EGFR) mutations are excellent predictors of gefitinib outcome in non–small-cell lung cancer (NSCLC), most patients become resistant to gefitinib. Despite our knowledge of the molecular basis of acquired resistance, clinical predictors have not been well elucidated. This study was undertaken to evaluate predictors of clinical outcome in patients with NSCLC and with EGFR mutations treated with gefitinib.Patients and MethodsA total of 170 patients with NSCLC and with EGFR mutations received gefitinib as a first-line (n = 50) and a second-line or more (n = 120) treatment at Seoul National University Hospital. Treatment outcomes were compared between groups based on clinicopathologic factors, such as treatment line, metastatic site, and mutation subtype.ResultsSurvival outcomes were similar between first-line and second-line or greater gefitinib treatment (overall response rate, 2P = .832; progression-free survival [PFS], 2P = .373; and overall survival [OS], 2P = .290). When the number of metastatic sites was at least 3, significantly reduced survival was observed (median PFS 8.5 vs. 14.0 months, 2P < .001; median OS 21.4 vs. 25.6 months, 2P = .002). In addition, the presence of at least 3 organs with metastases was an independent predictor of PFS (hazard ratio [HR] 1.97 [95% CI, 1.37-2.85]; 2P < .001) and OS (HR 2.00 [95% CI, 1.18-3.39]; 2P = .010). Patients who failed to respond to gefitinib within 6 months of treatment had more lymph node metastases and more sites of metastasis than those who responded later.ConclusionsTumor burden, expressed as the number of metastatic sites, is predictive of inferior survival in patients with NSCLC and with activating EGFR mutations who are treated with gefitinib.     

dNLR-Based Score Predicting Overall Survival Benefit for The Addition of Platinum-Based Chemotherapy to Pembrolizumab in Advanced NSCLC With PD-L1 Tumor Proportion Score ≥50%

Introduction: Both pembrolizumab (P) as a monotherapy or in combination with platinum-based chemotherapy (PCT) represent standard first-line treatment options for advanced non-small cell lung cancer (aNSCLC) with PD-L1 tumor proportion score (TPS)≥50%. No predictive biomarkers exist to guide treatment decisions.Methods: 423 consecutive patients with EGFR/ALK/ROS1-wild-type PD-L1 TPS≥50% aNSCLC receiving P (n = 302) or PCT (n = 121) as a first-line treatment were identified in the electronic databases of 5 Israeli cancer centers. Overall survival (OS, months [mo]) was assessed in correlation with blood biomarkers (BB: NLR, dNLR, PLR, SII, LIPI, ALI); a predictive score was developed.Results: In the propensity score matching analysis (n = 236; 118 patients in each group matched for age, sex and ECOG PS), mOS was 17.2mo (95% CI, 13.2-36.5) and 21.3mo (95% CI, 14.8-NR) in groups P and PCT, respectively (P = .44). In group P, NLR, dNLR, PLR, LIPI, and ALI significantly correlated with OS in uni- and multivariate COX regression analyses (P < .05), whereas in group PCT, none of the BB demonstrated a significant correlation. A predictive score was developed (each parameter receiving one point): age≥65, female sex, never-smoking status, adenocarcinoma histology, dNLR≥3. In patients with predictive score 3-5, OS was significantly longer with PCT as compared to P: mOS NR (95% CI, 15.3-NR) and 8.7mo (95% CI, 5.8-13.7) (P = .0005), while OS didn't differ significantly in patients with predictive score 0-2 (P = .61).Conclusion: With the limitations of the retrospective analysis, the proposed dNLR-based score appears to predict OS with P and PCT.     

Correlation of Neutrophil to Lymphocyte Ratio and Absolute Neutrophil Count With Outcomes With PD-1 Axis Inhibitors in Patients With Advanced Non–Small-Cell Lung Cancer

Introduction

Programmed death-1 (PD-1) axis inhibitors have become standard therapy in advanced non–small-cell lung cancer (NSCLC). Response might be delayed and pseudo-progression occasionally occurs in patients who eventually benefit from treatment. Additional markers beyond programmed death ligand 1 (PD-L1) expression are needed to assist in patient selection, response evaluation, and treatment decisions.

Dynamic Monitoring and Predictive Value of Circulating Tumor Cells in EGFR-Mutated Advanced Non–Small-Cell Lung Cancer Patients Treated With First-Line EGFR Tyrosine Kinase Inhibitors

BackgroundThere is an urgent need to develop a convenient and less invasive technique to monitor the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutated non–small-cell lung cancer (NSCLC). We proposed folate receptor–based assay to count circulating tumor cells (CTCs) to predict and dynamically monitor the therapeutic response to first-line EGFR-TKIs in patients with EGFR-mutated NSCLC.Patients and MethodsEligible patients were enrolled, and 3 mL of blood was obtained before initial treatment, 1 month after treatment, and every 2 months thereafter. CTCs were isolated on the basis of negative enrichment by immunomagnetic beads and detected by a ligand-targeted PCR method.ResultsA total of 232 patients with EGFR-mutated NSCLC and treated with first-line EGFR-TKIs were included. Patients with low baseline CTC count had a markedly longer progression-free survival (hazard ratio = 0.48; P < .001) and overall survival (hazard ratio = 0.52; P = .002) than those with high count. This difference remained significant in multivariate analysis. Dynamic change of CTC count was significantly associated with partial response (P = .042) and stable disease/progressive disease (P = .032). Notably, dynamic monitoring of CTC provided evidence of resistance to EGFR-TKIs before computed tomographic scanning with a median lead time of 113 days (range, 45-169 days).ConclusionThe current evidence suggests that folate receptor–positive CTC counts can be used for both the dynamic monitoring and prediction of outcome in EGFR-mutated NSCLC patients treated with EGFR-TKIs, which could serve as an alternative or supplement to computed tomographic scanning.     

A Phase II Study of Nivolumab in Patients With Advanced Non–small-cell Lung Cancer who Responded to Prior PD-1/L1 Inhibitors: West Japan Oncology Group 9616L (WJOG9616L)

Immune-checkpoint inhibitors (ICIs) play an important role in treatment for advanced non–small-cell lung cancer. Over one-half of patients, however, have relapse. Although rechallenge treatment of anti-cancer drugs that showed efficacy in prior lines of therapy has been broadly accepted in lung cancer, evidence of efficacy of rechallenge of ICIs has been limited to anecdotal case series. We therefore plan a phase II study. The primary endpoint is to assess the overall response rate of nivolumab in patients with advanced non–small-cell lung cancer who responded to prior ICIs. Secondary endpoints are disease control rate, progression-free survival, overall survival, and safety. Sixty patients will be enrolled in this trial. Programmed death-ligand 1 expression level in circulating tumor cells will be evaluated as a surrogate biomarker for the prediction of the efficacy.     

PD-L1 Expression in Circulating Tumor Cells as a Promising Prognostic Biomarker in Advanced Non–small-cell Lung Cancer Treated with Immune Checkpoint Inhibitors

BackgroundCirculating tumor cells (CTCs) are a promising source of biological information in cancer. Data correlating PD-L1 expression in CTCs with patients’ response to immune checkpoint inhibitors (ICIs) in non–small-cell lung cancer (NSCLC) are still lacking.MethodsThis is a prospective single-center cohort study enrolling patients with advanced NSCLC. CTCs were identified and counted with the CellSearch system. PD-L1 expression on CTCs was assessed with phycoerythrin-conjugated anti-human PD-L1 antibody, clone MIH3 (BioLegend, USA). Primary endpoint was the correlation between the CTCs PD-L1 expression and overall survival (OS). Among secondary objectives, we evaluated the correlation between PD-L1 expression on CTCs and matched tumor tissue and the correlation of CTC number and baseline tumor size (BTS).ResultsThirty-nine patients treated with anti-PD-1/PD-L1 agents as second- or third-line therapy were enrolled. Patients were divided into 3 groups: no CTC detectable (CTCnull, n = 15), PD-L1 positive CTC (CTCpos, n = 13), and PD-L1 negative CTC (CTCneg, n = 11). Median OS in patients with CTCneg was 2.2 months, 95% confidence interval (CI), 0.8-3.6 (reference) versus 3.7 months, 95% CI, 0.1-7.5 (hazard ratio [HR] 0.33; 95% CI, 0.13-0.83; P = .019) in patients with CTCpos versus 16.0 months, 95% CI, 2.2-29.8 (HR 0.17; 95% CI, 0.06-0.45; P< .001) in patients with CTCnull. No correlation was found between PD-L1 expression on CTCs and on tumor tissue. CTC number was correlated with BTS.ConclusionPD-L1 expression on CTCs is a promising biomarker in patients with NSCLC treated with ICIs. Further validation as predictive biomarker is needed.     

Clinical Features and Management of Acquired Resistance to PD-1 Axis Inhibitors in 26 Patients With Advanced Non–Small Cell Lung Cancer

Introduction

With expanding indications for programmed death 1 (PD-1) axis inhibitors in non–small cell lung cancer (NSCLC), acquired resistance (AR) to these therapies is increasingly being encountered. We sought to characterize clinical patterns of AR to PD-1 axis inhibitors in patients with advanced NSCLC, and evaluate subsequent outcome and management strategies for such patients.