NEW ORLEANS-The addition of the biological agent erlotinib (Tarceva) to first-line therapy with either cisplatin(Drug information on cisplatin)/gemcitabine (Gemzar) or carboplatin(Drug information on carboplatin) (Paraplatin)/ paclitaxel(Drug information on paclitaxel) produced no significant benefit in previously untreated patients with advanced non-small-cell lung cancer (NSCLC), two prospective multicenter, randomized, controlled phase III studies have found. Results of the trials, known outside the United States as TALENT and in the US known as TRIBUTE, were reported at the 40th annual meeting of the American Society of Clinical Oncology, respectively, by Ulrich Gatzemeier, MD, of the Center for Pneumonology and Thoracic Surgery, Grosshansdorf Hospital, Hamburg, Germany (abstract 7010), and by Roy S. Herbst, MD, PhD, chief, section of thoracic oncology at The University of Texas M. D. Anderson Cancer Center, Houston (abstract 7011). In both studies, the primary endpoint was overall survival. Secondary endpoints included time to progression, objective response, duration of response, and time to symptomatic progression. The investigators also assessed the expression of epithelial growth factor receptor (EGFR) and of HER2/neu. Most Had Stage IV Disease Both trials enrolled patients with stage III/IV NSCLC; in the TALENT trial, Dr. Gatzemeier said, two-thirds of patients had stage IV disease, and in the TRIBUTE trial, Dr. Herbst reported, 84% had stage IV NSCLC. The TRIBUTE trial included 1,059 patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 who were randomized to receive either erlotinib at 150 mg/d (n = 526) or placebo (n = 533) with six cycles of carboplatin/ paclitaxel, followed by maintenance monotherapy (abstract 7011). Randomization was stratified by stage, > 5% weight loss in the prior 6 months, measurable disease, and study site. The study was powered to detect a 25% or better increase in overall survival time, Dr. Herbst reported. For the TALENT study, 1,172 chemonaive patients from 164 sites worldwide were randomized to receive erlotinib at a dose of 150 mg/d or placebo with a maximum of six cycles of cisplatin/gemcitabine followed by monotherapy until disease progression. Patients were 18 years of age or older, with unresectable stage III or IV NSCLC and an ECOG PS of 0 or 1. Similar Findings Both the TRIBUTE and TALENT trials reported similar findings, with no significant differences seen in terms of 1-year survival, median survival, and median time to progression. In the TALENT trial, Dr. Gatzemeier reported, the response rate was about 30% in both arms. In the TRIBUTE trial, the objective response rate was about 20% in both arms. There was a suggestion of improved survival after 6 months, but further clinical studies will be needed to validate this finding, Dr. Herbst said. Overall survival time in the TALENT trial was 301 days in patients who received erlotinib with chemotherapy vs 309 days in patients in the control group. Time to progression was 167 vs 179 days, respectively. In the TRIBUTE trial, overall survival was 10.8 months for patients receiving erlotinib with their chemotherapy vs 10.6 months for those who received chemotherapy plus placebo. The objective responses of 21.5% and 19.3% seen with erlotinib vs placebo, respectively, were 5.5 months and 5.0 months in duration, respectively. Time to progression was approximately 5 months in both groups. No correlation was seen in either trial between EGFR or HER2/neu status and survival or response. Pharmacokinetic analyses in both trials showed no interference between erlotinib and the chemotherapy regimen. Addition of erlotinib to chemotherapy was not associated with a sigificant increase in serious adverse events in either trial, with the exception of diarrhea and skin rash, as has been reported in previous studies. (In the TRIBUTE trial, Dr. Herbst, noting that erlotinib appears to be a very safe drug, reported that while there were more fatal serious adverse events on the erlotinib arm [53 vs 47], only five of the fatalities were partially related to the study drug, with causality also attributed to concurrent therapy or to the underlying lung cancer.) TRIBUTE Subgroup Analysis Finds Benefit in Never Smokers At ASCO, an interesting observation from a TRIBUTE subgroup analysis was reported by Vincent A. Miller, MD, assistant attending physician in the Thoracic Oncology Service at Memorial Sloan-Kettering Cancer Center (abstract 7061): median survival time was significantly longer for the 64 never smokers-those reporting fewer than 100 cigarettes smoked during their lifetime on a behavioral factors questionnaire-who were treated with erlotinib/carboplatin/paclitaxel than for the 41 never smokers treated with placebo/carboplatin/paclitaxel (22.5 months vs 10.1 months, P = .01). (See also page 13.) (Median overall survival in this latter group of 41 patients on placebo plus chemotherapy was similar to that of former or current smokers in the same treatment arm.) Time to progression was also improved, at 6.0 months in the 64 never smokers receiving erlotinib vs 4.3 months in the 41 never smokers who received placebo. Compared with former/current smokers, the never smokers tended to be younger (58 vs 64 years old) and female (60% vs 37%), and more had adenocarcinoma (82% vs 58%).. The subgroup of patients who were never smokers was well balanced between the two arms in terms of known prognostic features. In univariate analyses of 17 prespecified factors recorded at study entry (eg, tumor stage [III or IV], weight loss, measurable disease, age, gender, race, smoking history, performance status, EGFR status, and histology), only smoking emerged as a predictive factor for overall survival. Noting that "recent studies indicate that better survival in never smokers may be influenced by the relatively higher incidence of EGFR mutations in the tyrosine kinase domain of the EGFR gene," the investigators stated that this finding "is consistent with results of prior studies of EGFR-tyrosine kinase inhibitors and warrants confirmation in a randomized trial." May Be Delayed Benefit In a discussion of the results, Dr. Herbst commented that "the lesson here may be the same as the one we had to learn with tamoxifen(Drug information on tamoxifen)." He explained that it took investigators some time to determine the appropriate stage at which to administer tamoxifen to realize its best potential effect in patients, and the use of erlotinib may present future investigators with the same type of challenge.