TALENT/TRIBUTE Studies Evaluate Erlotinib With Chemotherapy as First-Line Tx for Advanced NSCLC

January 1, 2005

This supplement to Oncology News International includes 17 reportson clinical trials of targeted therapies used alone, in combination with chemotherapy,or in combination with each other in the treatment of non–small-cell lung cancer (NSCLC),bronchoalveolar carcinoma, glioblastoma multiforme, and renal cell carcinoma.Included is a report on a novel targeted agent recently approved for treatment of NSCLC.

NEW ORLEANS-Theaddition of the biological agent erlotinib(Tarceva) to first-line therapywith either cisplatin/gemcitabine(Gemzar) or carboplatin (Paraplatin)/paclitaxel produced no significantbenefit in previously untreated patientswith advanced non-small-celllung cancer (NSCLC), two prospectivemulticenter, randomized, controlledphase III studies have found.Results of the trials, known outsidethe United States as TALENT and inthe US known as TRIBUTE, were reportedat the 40th annual meetingof the American Society of ClinicalOncology, respectively, by UlrichGatzemeier, MD, of the Center forPneumonology and Thoracic Surgery,Grosshansdorf Hospital, Hamburg,Germany (abstract 7010), and by RoyS. Herbst, MD, PhD, chief, section ofthoracic oncology at The Universityof Texas M. D. Anderson Cancer Center,Houston (abstract 7011).In both studies, the primary endpointwas overall survival. Secondaryendpoints included time to progression,objective response, duration ofresponse, and time to symptomaticprogression. The investigators also assessedthe expression of epithelialgrowth factor receptor (EGFR) and ofHER2/neu.Most Had Stage IV DiseaseBoth trials enrolled patients withstage III/IV NSCLC; in the TALENTtrial, Dr. Gatzemeier said, two-thirdsof patients had stage IV disease, andin the TRIBUTE trial, Dr. Herbst reported,84% had stage IV NSCLC.The TRIBUTE trial included 1,059patients with Eastern CooperativeOncology Group (ECOG) performancestatus (PS) of 0 or 1 who wererandomized to receive either erlotinibat 150 mg/d (n = 526) or placebo (n =533) with six cycles of carboplatin/paclitaxel, followed by maintenancemonotherapy (abstract 7011). Randomizationwas stratified by stage, >5% weight loss in the prior 6 months,measurable disease, and study site. Thestudy was powered to detect a 25% orbetter increase in overall survival time,Dr. Herbst reported.For the TALENT study, 1,172chemonaive patients from 164 sitesworldwide were randomized to receiveerlotinib at a dose of 150 mg/d orplacebo with a maximum of six cyclesof cisplatin/gemcitabine followed bymonotherapy until disease progression.Patients were 18 years of age orolder, with unresectable stage III or IVNSCLC and an ECOG PS of 0 or 1.Similar FindingsBoth the TRIBUTE and TALENTtrials reported similar findings, withno significant differences seen in termsof 1-year survival, median survival,and median time to progression. Inthe TALENT trial, Dr. Gatzemeier reported,the response rate was about30% in both arms.In the TRIBUTE trial, the objectiveresponse rate was about 20% in botharms. There was a suggestion of improvedsurvival after 6 months, butfurther clinical studies will be neededto validate this finding, Dr. Herbst said.Overall survival time in the TALENTtrial was 301 days in patients whoreceived erlotinib with chemotherapyvs 309 days in patients in the controlgroup. Time to progression was 167 vs179 days, respectively.In the TRIBUTE trial, overall survivalwas 10.8 months for patients receivingerlotinib with their chemotherapyvs 10.6 months for those whoreceived chemotherapy plus placebo.The objective responses of 21.5% and19.3% seen with erlotinib vs placebo,respectively, were 5.5 months and 5.0months in duration, respectively. Timeto progression was approximately 5months in both groups.No correlation was seen in eithertrial between EGFR or HER2/neu statusand survival or response. Pharmacokineticanalyses in both trials showedno interference between erlotinib andthe chemotherapy regimen.Addition of erlotinib to chemotherapywas not associated with a sigificantincrease in serious adverse events ineither trial, with the exception of diarrheaand skin rash, as has been reportedin previous studies. (In the TRIBUTEtrial, Dr. Herbst, noting thaterlotinib appears to be a very safe drug,reported that while there were morefatal serious adverse events on the erlotinibarm [53 vs 47], only five of thefatalities were partially related to thestudy drug, with causality also attributedto concurrent therapy or to theunderlying lung cancer.)TRIBUTE SubgroupAnalysis Finds Benefitin Never SmokersAt ASCO, an interesting observationfrom a TRIBUTE subgroupanalysis was reported by Vincent A.Miller, MD, assistant attending physicianin the Thoracic Oncology Serviceat Memorial Sloan-Kettering CancerCenter (abstract 7061): median survivaltime was significantly longer forthe 64 never smokers-those reportingfewer than 100 cigarettes smokedduring their lifetime on a behavioralfactors questionnaire-who were treatedwith erlotinib/carboplatin/paclitaxelthan for the 41 never smokers treatedwith placebo/carboplatin/paclitaxel(22.5 months vs 10.1 months, P = .01).(See also page 13.) (Median overallsurvival in this latter group of 41 patientson placebo plus chemotherapywas similar to that of former or currentsmokers in the same treatmentarm.)Time to progression was also improved,at 6.0 months in the 64 neversmokers receiving erlotinib vs 4.3months in the 41 never smokers whoreceived placebo.Compared with former/currentsmokers, the never smokers tended tobe younger (58 vs 64 years old) andfemale (60% vs 37%), and more hadadenocarcinoma (82% vs 58%)..The subgroup of patients whowere never smokers was well balancedbetween the two arms in terms ofknown prognostic features. In univariateanalyses of 17 prespecified factorsrecorded at study entry (eg, tumorstage [III or IV], weight loss, measurabledisease, age, gender, race, smokinghistory, performance status, EGFRstatus, and histology), only smokingemerged as a predictive factor foroverall survival.Noting that "recent studies indicatethat better survival in never smokersmay be influenced by the relativelyhigher incidence of EGFR mutationsin the tyrosine kinase domain of theEGFR gene," the investigators statedthat this finding "is consistent withresults of prior studies of EGFR-tyrosinekinase inhibitors and warrantsconfirmation in a randomized trial."May Be Delayed BenefitIn a discussion of the results, Dr.Herbst commented that "the lessonhere may be the same as the one wehad to learn with tamoxifen." He explainedthat it took investigators sometime to determine the appropriatestage at which to administer tamoxifento realize its best potential effectin patients, and the use of erlotinibmay present future investigators withthe same type of challenge.