Molecular analysis of non-small cell lung cancer identifies subsets with different sensitivity to insulin-like growth factor I receptor inhibition.

PURPOSE: This study aimed to identify molecular determinants of sensitivity of non-small cell lung cancer (NSCLC) to anti-insulin-like growth factor receptor (IGF-IR) therapy. EXPERIMENTAL DESIGN: A total of 216 tumor samples were investigated, of which 165 consisted of retrospective analyses of banked tissue and an additional 51 were from patients enrolled in a phase II study of figitumumab, a monoclonal antibody against IGF-IR, in stage IIIb/IV NSCLC. Biomarkers assessed included IGF-IR, epidermal growth factor receptor, IGF-II, IGF-IIR, insulin receptor substrate 1 (IRS-1), IRS-2, vimentin, and E-cadherin. Subcellular localization of IRS-1 and phosphorylation levels of mitogen-activated protein kinase and Akt1 were also analyzed. RESULTS: IGF-IR was differentially expressed across histologic subtypes (P = 0.04), with highest levels observed in squamous cell tumors. Elevated IGF-IR expression was also observed in a small number of squamous cell tumors responding to chemotherapy combined with figitumumab (P = 0.008). Because no other biomarker/response interaction was observed using classical histologic subtyping, a molecular approach was undertaken to segment NSCLC into mechanism-based subpopulations. Principal component analysis and unsupervised Bayesian clustering identified three NSCLC subsets that resembled the steps of the epithelial to mesenchymal transition: E-cadherin high/IRS-1 low (epithelial-like), E-cadherin intermediate/IRS-1 high (transitional), and E-cadherin low/IRS-1 low (mesenchymal-like). Several markers of the IGF-IR pathway were overexpressed in the transitional subset. Furthermore, a higher response rate to the combination of chemotherapy and figitumumab was observed in transitional tumors (71%) compared with those in the mesenchymal-like subset (32%; P = 0.03). Only one epithelial-like tumor was identified in the phase II study, suggesting that advanced NSCLC has undergone significant dedifferentiation at diagnosis. CONCLUSION: NSCLC comprises molecular subsets with differential sensitivity to IGF-IR inhibition.

Second- and third-line treatment of patients with non-small-cell lung cancer with erlotinib in the community setting: retrospective study of patient healthcare utilization and symptom burden.

INTRODUCTION: The purpose of this study was to describe treatment use patterns and outcomes with single-agent erlotinib among patients with advanced non-small-cell lung cancer (NSCLC) in the community oncology setting. PATIENTS AND METHODS: Retrospective chart review identified patients treated with single-agent erlotinib as either second- or third-line therapy from 4 community oncology clinics. Medical records were extracted for medical outcomes and resource utilization. Patients reported outcome measures of symptom burden and functioning. RESULTS: A total of 45 patients with stage IIIB/IV disease in second- (n = 27) or third-line (n = 18) therapy were 44% female and 84% white (16% black), with mean age of 66.7 years (SD, 9.2). Over 93% of the patients had previous platinum-based chemotherapy. Patients were treated with erlotinib for an average of 24 weeks. Dose reductions (24%) and treatment delays (29%) were due to skin reactions, diarrhea, and fatigue. The most common reasons for stopping erlotinib therapy were disease progression (53%), death (22%), and toxicities (11%). Patients' physical functioning improved during the first 3 months of erlotinib therapy. Hospitalizations (22%) were not due to erlotinib complications, and unplanned medical visits to the clinics were rare. CONCLUSION: Data from this community sample were generally in agreement with the major clinical trial of erlotinib. Erlotinib is well tolerated by second- and third-line patients with advanced NSCLC in the community setting.

Phase III study of pemetrexed plus carboplatin compared with etoposide plus carboplatin in chemotherapy-naive patients with extensive-stage small-cell lung cancer.

PURPOSE: Following a phase II trial in which pemetrexed-platinum demonstrated similar activity to that of historical etoposide-platinum controls, a phase III study was conducted to compare pemetrexed-carboplatin with etoposide-carboplatin for the treatment of extensive-stage small-cell lung cancer (ES-SCLC). PATIENTS AND METHODS: Chemotherapy-naive patients with ES-SCLC and an Eastern Cooperative Oncology Group performance status of zero to 2 were randomly assigned to receive pemetrexed-carboplatin (pemetrexed 500 mg/m(2) on day 1; carboplatin at area under the serum concentration-time curve [AUC] 5 on day 1) or etoposide-carboplatin (etoposide 100 mg/m(2) on days 1 through 3; carboplatin AUC 5 on day 1) every 3 weeks for up to six cycles. The primary objective of the study was noninferiority of pemetrexed-carboplatin overall survival with a 15% margin. RESULTS: Accrual was terminated with 908 of 1,820 patients enrolled after results of a planned interim analysis. In the final analysis, pemetrexed-carboplatin was inferior to etoposide-carboplatin for overall survival (median, 8.1 v 10.6 months; hazard ratio [HR],1.56; 95% CI, 1.27 to 1.92; log-rank P < .01) and progression-free survival (median, 3.8 v 5.4 months; HR, 1.85; 95% CI, 1.58 to 2.17; log-rank P < .01). Objective response rates were also significantly lower for pemetrexed-carboplatin (31% v 52%; P < .001). Pemetrexed-carboplatin had lower grade 3 to 4 neutropenia, febrile neutropenia, and leukopenia than etoposide-carboplatin; grade 3 to 4 thrombocytopenia was comparable between arms and anemia was higher in the pemetrexed-carboplatin arm. CONCLUSION: Pemetrexed-carboplatin is inferior for the treatment of ES-SCLC. Planned translational research and pharmacogenomic analyses of tumor and blood samples may help explain the study results and provide insight into new treatment strategies.