Erlotinib Prolongs Survival in Never Smokers, Subgroup Analysis Shows

NEW ORLEANS--Subgroupanalysis of data from the TRIBUTEtrial indicates that erlotinib (Tarceva),when given in combination withcarboplatin (Paraplatin) and paclitaxel, provides a survival benefit tonever-smoking patients with previouslyuntreated advanced non-smallcelllung cancer (NSCLC). Vincent A.Miller, MD, of Memorial Sloan-Kettering Cancer Center, presentedthe results at the 40th Annual Meetingof the American Society of ClinicalOncology (abstract 7061).Erlotinib is a selective inhibitor ofthe tyrosine kinase (TK) domain ofthe epidermal growth factor receptor(EGFR), currently being investigatedin a number of cancers and approvedin the second-line treatment ofNSCLC; Data from the BR21 trialshowed a significant survival benefitof erlotinib monotherapy in advancedrefractory NSCLC (abstract 7022). Inthe phase III TRIBUTE study, patientswith previously untreated NSCLC receivedsix cycles of chemotherapy, togetherwith either oral erlotinib at 150mg/d or placebo. There was no selectionfor tumor expression of theEGFR; altogether 1,059 patients wereenrolled.In the trial as a whole, the additionof erlotinib resulted in no differencein overall survival, objective responserate, or time to disease progression.These data were subjected to furtheranalysis on the basis of prespecifiedsubgroups,including cancer stage(stage III or IV), tumor measurability,weight loss greater than 5% in theprevious 6 months, age, sex, race, tobaccohistory, baseline ECOG score,prior radiotherapy, prior cancer-relatedsurgery, histology, and presenceor absence of EGFR expression.10% Never SmokersIn all but one of these subgroups,the inclusion of erlotinib conferredno survival benefit; it should be noted,however, that many of these categorieswere too small to provide sufficientstatistical power to detect atreatment effect. The single exceptionwas the 10% of patients (64 in theerlotinib arm, and 41 in the placeboarm) who classified themselves in thebehavioral factors questionnaire asnever having smoked. When comparedwith former/current smokers,these never smokers tended to beyounger (age 58 vs 64), female (60%vs 37%), and to have adenocarcinoma(82% vs 58%).While median overall survival ofnever smokers on placebo was similarto that of current or former smokerson placebo (approximately 10months), never smokers on erlotinibhad a median survival of 22.5 months.Never smokers on erlotinib also hadimproved median time to disease progression-6 months vs 4.3 months fornever smokers on placebo.The degree to which these correlationswill ultimately assist in targetingtreatment remains to be determined.The correlation between never smoking and deriving survival benefitsfrom the EGFR inhibitors is likelyan obverse reflection of the variety ofmolecular insults that are deliveredby nicotine and other carcinogens intobacco smoke. Since a never-smokinghistory implies fewer possiblemechanisms of transformation to thecancerous phenotype, the probabilityis enhanced that one specific molecularpathway such as EGFR may beinvolved, and targeting it has a correspondinglygreater likelihood ofsuccess.In recent work (Proc Natl Acad Sci101:13306-13311, 2004), William Pao,MD, of Memorial Sloan-KetteringCancer Center, and his colleagues reportedthat EGFR gene mutations arecommon in lung cancers from neversmokers (fewer than 100 cigarettes intheir lifetime). The researchers lookedat tumors from 96 lung cancer patients,15 of whom were never smokers.About half of the never smokerswere found to have EGFR mutations,compared with only 5% of the currentor former smokers. The investigatorsalso showed that such mutationsare found in tumors responsiveto erlotinib. Others have previouslydetected such mutations in tumorssensitive to the EGFR inhibitorgefitinib (Iressa).Dr. Pao concluded that "adenocarcinomasfrom never smokers comprisea distinct subset of lung cancers,frequently containing mutations withinthe TK domain of EGFR that areassociated with gefitinib and erlotinibsensitivity."