Factors Associated With Survival in Complete Pathologic Response Non–Small Cell Lung Cancer

ObjectivesThere is a strong association with improved survival for patients with non–small cell lung cancer (NSCLC) who have developed a pathological complete response (pCR) after neoadjuvant therapy. A national database was used to investigate factors associated with long-term survival in this cohort of patients.PatientsRetrospective review was completed of the National Cancer Database of patients who obtained pCR and had neoadjuvant therapy for stage I to stage III NSCLC between 2004 and 2014. All patients had neoadjuvant chemotherapy with or without radiation therapy.MethodsUnivariate and multivariable analysis was performed on factors associated with overall survival (OS), including gender, clinical stage, and nodal count. Patients were divided into 2 groups based on the Commission on Cancer–recommended median number of lymph nodes (LNs) examined: 0 to 9 LNs and ≥10 LNs. Chi-square and Wilcoxon rank-sum tests were used to compare patient, hospital, and clinical variables between groups.ResultsIncreased age (hazard ratio [HR] 1.02, 95% confidence interval [CI], 1.00-1.03), neoadjuvant radiation therapy (HR 1.48, 95% CI, 1.10-2.00), and pneumonectomy (HR 1.64, 95% CI, 1.22-2.22) were associated with worse survival in the 759-patient cohort. Multivariable regression demonstrated having ≥10 nodes harvested (HR 0.71, 95% CI, 0.56-0.89) was associated with improved survival as was every increase in LN harvest up to 17 LNs. No significant differences in 5-year OS were found between clinical stage I, II, and III, respectively (66.1% vs. 60.9% vs. 58.6%, P = .288).ConclusionThis study shows that younger age, increasing LN harvest, female sex, the absence of neoadjuvant radiation therapy and non-pneumonectomy resections are all associated with improved OS in patients with NSCLC who have developed pCR.     

Advanced Non–Small-Cell Lung Cancer in the Elderly

Systemic chemotherapy provides improvement in both survival and quality of life for patients with advanced non–small-cell lung cancer (NSCLC). Elderly patients have more comorbidities and tend to tolerate more poorly aggressive chemotherapy and radiation therapy than younger individuals. Our purpose in this article is to summarize recent studies of single-agent chemotherapy and combination regimens with cytotoxic or targeted therapies in the management of elderly patients with advanced NSCLC. We have reviewed the available evidence in the literature to gauge the results of therapy for elderly patients with lung cancer. We found that single-agent chemotherapy remains the standard of care for nonselected elderly patients. Retrospective analyses suggest that the efficacy of platinum-based combination chemotherapy is similar in fit older and younger patients, with increased but acceptable toxicity for elderly patients. Therefore, the outcomes in the fit elderly mirror results observed in younger patients, although toxicity is generally greater.     

Pulsatile Erlotinib in EGFR-Positive Non–Small-Cell Lung Cancer Patients With Leptomeningeal and Brain Metastases: Review of the Literature

Patients with epidermal growth factor receptor (EGFR)-positive (EGFR⁺) non–small-cell lung cancer (NSCLC) show improved response rates when treated with tyrosine kinase inhibitors (TKIs) such as erlotinib. However, standard daily dosing of erlotinib often does not reach therapeutic concentrations within the cerebrospinal fluid (CSF), resulting in progression of central nervous system (CNS) disease. Intermittent, high-dose administration of erlotinib reaches therapeutic concentrations within the CSF and is well tolerated in patients. Experience with “pulsatile” dosing, however, is limited. We review the literature on the pharmacology and clinical outcomes of pulsatile erlotinib in the treatment of EGFR⁺ NSCLC with brain and leptomeningeal metastases, and include available data on the use of next-generation TKIs in CNS progression. We also provide our institution's experience with patients treated with pulsatile erlotinib for CNS metastasis, and propose clinical criteria for its use. Pulsatile erlotinib is a reasonable alternative in EGFR⁺ patients with new or worsening CNS disease, without evidence of systemic progression, and without confirmed T790M resistance mutations within the CNS.     

Real-World Effectiveness of Nivolumab Monotherapy After Prior Systemic Therapy in Advanced Non–Small-Cell Lung Cancer in the United States

BackgroundIn phase 3 clinical trials, nivolumab prolonged overall survival (OS) compared to chemotherapy in patients with previously treated advanced non–small-cell lung cancer (NSCLC). This retrospective real-world study evaluated OS in patients receiving nivolumab for previously treated advanced NSCLC primarily in US community hospitals.Patients and MethodsPatient data were taken from electronic health records in the Flatiron Health oncology database. OS was evaluated in patients receiving nivolumab monotherapy for nonsquamous or squamous advanced NSCLC after prior chemotherapy; subgroup analyses were performed by Eastern Cooperative Oncology Group performance status (ECOG PS), age, and other baseline characteristics. Cox analysis was used to determine OS predictors.ResultsOf 3019 included patients, 1968 (65%) had nonsquamous and 1051 (35%) had squamous histology. In both cohorts, approximately 20% of patients had a verified ECOG PS ≥ 2, and > 25% were aged ≥ 75 years. For all patients, median OS in the nonsquamous and squamous cohorts was 8.6 months (95% confidence interval [CI], 8.0-9.3) and 7.4 months (95% CI, 6.8-8.5), respectively; for those with ECOG PS 0-1, median OS was 10.8 months (95% CI, 9.8-11.8) and 8.7 months (95% CI, 7.6-9.7), respectively. In both cohorts, programmed death ligand 1 expression ≥ 1% and ECOG PS 0-1 were associated with longer OS (P < .05); the number of prior lines of therapy and age ≥ 75 years had no significant association with OS.ConclusionsThis study confirmed the effectiveness of nivolumab monotherapy for previously treated advanced NSCLC in real-world clinical practice. Poor ECOG PS, but not advanced age, was associated with shorter OS.     

Crizotinib in the Treatment of Non–Small-Cell Lung Cancer

An anaplastic lymphoma kinase (ALK) translocation giving rise to activated ALK tyrosine kinase is present in approximately 5% of non–small-cell lung cancers (NSCLCs). Crizotinib is an oral tyrosine kinase inhibitor targeting ALK, met proto-oncogene, and c-ros oncogene 1 (ROS1). It was recently approved in several countries for the treatment of patients with advanced, ALK-rearranged NSCLC. In 2012, results from the first phase III trial showing superiority of crizotinib compared with standard chemotherapy in second-line treatment of ALK-positive NSCLC were presented. Furthermore, crizotinib was recently shown to be active in ROS1-rearranged NSCLC. Here, we give an overview of the molecular pathogenesis of ALK-rearranged NSCLC, the pharmacokinetic and pharmacodynamic properties of crizotinib, and clinical trials of crizotinib for ALK-rearranged NSCLC.     

Sequential CT Findings in Patients With Non–small-cell Lung Cancer Receiving Nivolumab

Background

Nivolumab is a novel immunotherapy that was recently approved for treatment of advanced non–small-cell lung cancer (NSCLC). Patients treated with checkpoint inhibitors may show variable computed tomography (CT) features on follow-up imaging, and it is unclear how reliable conventional response criteria are to determine patient management and outcomes. We report the spectrum of sequential CT findings in patients with advanced stage lung cancer who received nivolumab in an effort to better inform appropriate imaging strategies.

Use of Cetuximab After Failure of Gefitinib in Patients With Advanced Non–Small-Cell Lung Cancer

BackgroundGefitinib and cetuximab are both epidermal growth factor receptor (EGFR) target therapies used to treat patients with non–small-cell lung cancer (NSCLC) with different mechanisms. To clarify the effectiveness of cetuximab after failure of gefitinib treatment, we investigated the clinical features of patients with NSCLC who received cetuximab-containing chemotherapy after failure of gefitinib.Patients and MethodsWe analyzed the clinical data and mutational studies of patients with NSCLC in the National Taiwan University Hospital who had received gefitinib and, after failure of gefitinib, cetuximab-containing chemotherapy.ResultsFifteen patients who received cetuximab-containing chemotherapy after failure of gefitinib were identified. Four were responders to gefitinib therapy, and 3 were responders to cetuximab-containing chemotherapy. Ten were sequenced for EGFR and KRAS mutations. Six of the 10 patients had EGFR mutations, and all 10 patients had wild-type (WT) KRAS. In the 4 patients who had the gefitinib-resistant EGFR T790M mutation, 2 were responders to cetuximab-containing chemotherapy. The other cetuximab responder had WT EGFR.ConclusionCetuximab might add benefit in treatment after failure of gefitinib, regardless of EGFR mutational status. Treatment with cetuximab should be further explored, even in patients who have previously received gefitinib treatment.     

Blood Predictive Biomarkers for Patients With Non–small-cell Lung Cancer Associated With Clinical Response to Nivolumab

BackgroundImmunotherapy is a promising cancer treatment, but surrogate biomarkers of clinical efficacy have not been fully validated. The aim of this work was to evaluate several biomarkers as predictors of response to nivolumab monotherapy in patients with non–small-cell lung cancer.Patients and MethodsBlood samples was collected at baseline, at 2 months after treatment start, and at disease progression. Lactate dehydrogenase level (LDH), neutrophils, and leukocyte values were obtained from medical record. Interleukin (IL)-8, IL-11, and kynurenine/tryptophan levels were determined by enzyme-linked immunosorbent assay. Total protein was extracted from circulating CD8+ T cells, and BCL-2 interacting mediator of cell death (BIM) protein expression tested by western blotting.ResultsBaseline LDH levels were significantly higher in non-responder patients than in those who responded (P = .045). The increase in indoleamine 2,3 dioxygenase activity was related to progression of disease, mainly in patients who did not respond to nivolumab treatment (P = .001). Increased levels of circulating IL-8 were observed in initially responding patients at time of progression, and it was related to lower overall survival (hazard ratio, 7.49; P = .025). A highest expression of BIM in circulating CD8+ T cells could be related to clinical benefit. The Student t test and Mann-Whitney U test were used to compare groups for continuous variables. Time to events was estimated using the Kaplan-Meier method, and compared by the log-rank test.ConclusionsChanges in plasma LDH and IL-8, indoleamine 2,3 dioxygenase activity, and BIM expression in CD8+ T cells could be used to monitor and predict clinical benefit from nivolumab treatment in these patients.     

Vitamin D Receptor Genetic Variants are Associated With Chemotherapy Response and Prognosis in Patients With Advanced Non–Small-Cell Lung Cancer

BackgroundThe aim of this study was to explore the association between vitamin D receptor (VDR) genetic polymorphisms and platinum-based chemotherapy response as well as the prognosis of non–small-cell lung cancer (NSCLC) in a Chinese cohort.Patients and MethodsSeven hundred fifty-five patients with advanced NSCLC (stage III [A + B] or stage IV) were enrolled. Platinum-based chemotherapy was given to each patient with NSCLC, and the therapeutic effect was evaluated. The VDR polymorphisms were genotyped.ResultsThree hundred twenty-one (42.5%) patients responded to chemotherapy (complete response [CR] or partial response [PR]) and 434 (57.5%) patients were nonresponders (stable disease [SD] or progressive disease [PD]). The genotypic and allelic frequencies of FokI, BsmI, and TaqI were not significantly different between chemotherapy responders and nonresponders. However, the genotypic and allelic frequencies of ApaI thymine (T) > guanine (G) were significantly different between the responders and nonresponders. Multivariate logistic regression analysis showed that GG genotype carriers of ApaI T > G had a higher chance of being responders. The ApaI T > G polymorphisms affected mean overall survival (OS). The GG genotype carriers of ApaI polymorphisms had a longer mean OS compared with TT carriers. Multivariate Cox regression analyses showed that ApaI T > G was significantly associated with OS.ConclusionWe found that there was an effect of ApaI T > G polymorphisms of the VDR gene on the chemotherapy response in patients with NSCLC, as well as a prognostic role of the VDR gene polymorphisms in Chinese patients with advanced NSCLC.     

Plasma Nucleosome Levels Might Predict Response to Therapy in Patients With Advanced Non–Small-Cell Lung Cancer

BackgroundRecent progress in the field of anticancer drug discovery has created many options for improving the survival of patients with cancer. However, more effective diagnostic tools indicating early therapeutic efficacy or disease progression are still needed to improve the management of patients with inoperable cancer.Patients and MethodsPlasma nucleosome levels were quantified in 134 patients with advanced non–small-cell lung cancer before the first cycle of chemotherapy. It was also evaluated before the second and third cycles of chemotherapy in 42 patients receiving first-line chemotherapy. Nucleosomes were correlated with response to therapy as assessed by computed tomography after the third therapy cycle.ResultsPatients who went into remission had significantly lower nucleosome levels before therapy cycles 2 and 3 than patients with no change or progression. High levels and insufficient decreases in nucleosome levels during the course of chemotherapy indicated poor outcome. Nucleosome levels before the second cycle detected poor response to therapy with a sensitivity and specificity of 69.2% and 75%, respectively (area under the receiver operating characteristic [ROC] curve, 0.816). Early prediction of disease progression was achieved with a sensitivity and specificity of 85.7% and 92.9%, respectively, for nucleosome levels before cycle 2 (area under the ROC curve, 0.930).ConclusionThe monitoring of plasma nucleosome levels during the course of first-line chemotherapy could identify patients who are likely to have insufficient response to therapy and disease progression at an early stage. This might help in individualizing treatment and could lead to better management of advanced-stage lung cancer.