Fluorescence In situ Hybridization Subgroup Analysis of TRIBUTE, a Phase III Trial of Erlotinib Plus Carboplatin and Paclitaxel in Non-Small Cell Lung Cancer

Purpose: TRIBUTE was a phase III trial evaluating the addition of erlotinib to carboplatin and paclitaxel as a first-line treatment for advanced non-small cell lung cancer that did not meet its primary end point of improving overall survival. Here, we assess the value of using epidermal growth factor receptor (EGFR) gene copy number in tumor biopsy samples, as determined by fluorescence in situ hybridization (FISH), as a predictor of treatment outcome. Methods: EGFR FISH analysis was done using LSI EGFR SpectrumOrange/CEP7 Spectrum-Green probe. Results: Of 275 samples, 245 (89.1%) were successfully analyzed by FISH, One hundred (40.8%) of patients were EGFR FISH(+). Median overall survival was not different between FISH (+) and FISH (-) patients in either the chemotherapy+erlotinib arm or the chemotherapy+placebo arm. In FISH (+) patients, median time to progression (TTP) was 6.3 months in the erlotinib arm versus 5.8 months in the placebo arm (hazard ratio, 0.59; 95% confidence interval, 0.350.99; P = 0.0430); in FISH(-) patients, median TTP was 4.6 months versus 6.0 months (hazard ratio, 1.42; 95% confidence interval, 0.95-2.14; P = 0.0895; treatment interaction test, P = 0.007). After 6 months of treatment, a notable separation of the TTP curves in favor of erlotinib emerged. Objective response rates were 11.6% versus 29.8% in FISH(+) patients (chemotherapy+erlotinib arm versus chemotherapy+placebo arm; P = 0.0495) and 21.8% versus 25.4%, respectively, for FISH(-) patients (P = 0.6954). Conclusions: EGFR gene copy number by FISH did not predict survival benefit. However, among EGFR FISH(+) patients,TTP was longer in patients who received erlotinib and continued to receive it after completing first-line therapy.