Randomized, Placebo-Controlled Phase III Study of Docetaxel Plus Carboplatin With Celecoxib and Cyclooxygenase-2 Expression As a Biomarker for Patients With Advanced Non-Small-Cell Lung Cancer: The NVALT-4 Study

Purpose Cyclooxygenase-2 (COX-2) protein expression in patients with non-small-cell lung cancer (NSCLC) may be not only a prognostic marker but also predictive for COX-2 inhibition. We hypothesized that COX-2 expression is associated with shorter survival and that celecoxib, being a potent COX-2 inhibitor, increases tumor response and survival. Patients and Methods A phase III study was performed in patients with stage IIIb/IV NSCLC who had pathologic confirmation, no prior chemotherapy, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function. Treatment consisted of docetaxel and carboplatin every 3 weeks for five cycles. Patients were randomly assigned to receive celecoxib 400 mg or placebo twice daily. COX-2 expression on tumor cells was detected by immunohistochemistry. Primary end point was overall survival (OS). Results From July 2003 to December 2007, 561 patients were randomly assigned. Toxicity was mild, and no increase in cardiovascular events was observed. Tumor response was 38% in the celecoxib arm and 30% in the placebo arm (P = .08). Median progression-free survival was 4.5 months (95% CI, 4.0 to 4.8) for the celecoxib arm and 4.0 months (95% CI, 3.6 to 4.9) for the placebo arm (hazard ratio [HR], 0.8; 95% CI, 0.6 to 1.1; P = .25). Median OS was 8.2 months (95% CI, 7.5 to 8.8) for both treatment arms (HR, 0.9; 95% CI, 0.6 to 1.2; P = .32). COX-2 expression did not independently predict survival. Benefit from celecoxib, restricted to patients with low COX-2 expression, was not significant when adjusted for prognostic factors. Conclusion In advanced NSCLC, celecoxib does not improve survival. In this study, COX-2 expression was not a prognostic biomarker and had no predictive value when celecoxib was added to chemotherapy. J Clin Oncol 29: 4320-4326. (C) 2011 by American Society of Clinical Oncolog

Comparison of clinical outcome after first-line platinum-based chemotherapy in different types of KRAS mutated advanced non-small-cell lung cancer

Objectives: As suggested by in-vitro data, we hypothesize that subtypes of ICRAS mutated non-small cell lung cancer (NSCLC) respond differently to chemotherapy regimens. Methods: Patients with advanced NSCLC and known KRAS mutation, treated with first-line platinumbased chemotherapy, were retrieved from hospital databases. Primary objective: to investigate overall response rate (ORR), progression free survival (PFS) and overall survival (OS) between different types of platinum-based chemotherapy per type of KRAS mutation. Results: 464 patients from 17 hospitals, treated between 2000 and 2013, were included. The majority of patients had stage IV disease (93%), had a history of smoking (98%) and known with an adenocarcinoma (91%). Most common types of ICRAS mutation were G12C (46%), G12V (20%) and G1 2D (10%). Platinum was combined with pemetrexed (n =334), taxanes (n = 68) or gemcitabine (n = 62). Patients treated with taxanes had a significant improved ORR (50%) compared to pemetrexed (21%) or gemcitabine (25%; p <0.01). Patients treated with bevacizumab in addition to taxanes (n =38) had the highest ORR (62%). The PFS was significantly improved in patients treated with taxanes compared to pemetrexed (HR = 0.72, p = 0.02), but not OS (HR= 0.87, p = 0.41). In patients with G12V, significantly improved ORR (p <0.01) was observed for taxanes, but not PFS or OS. Patients with G1 2C or G12D mutation had comparable ORR, PFS and OS in all treatment groups. Conclusion: KRAS mutated NSCLC patients treated with taxane-based chemotherapy had best ORR Response to chemotherapy regimens was different in types of ICRAS mutation. Especially patients with G12V had better response to taxane treatment. (C) 2015 Elsevier Ireland Ltd. All rights reserved