Erlotinib Produces Responses in Patients With Bronchoalveolar Cell Carcinoma, Ongoing Phase II Trial Suggests

Oncology NEWS International Vol 12 No 9, Volume 12, Issue 9

This special supplement toOncology News International presents11 reports on novel agents targetingHER1/EGFR, VEGF, and HER2/neu receptorsin the treatment of non–small-cell lung cancer,colorectal cancer, mesothelioma, andglioblastoma. The reports summarizeselected presentations from theAmerican Society of Clinical Oncology (ASCO)39th Annual Meeting and a satellitesymposium held in conjunction with ASCO.

NEW YORK-Bronchoalveolarcell carcinoma (BAC) appears responsiveto erlotinib (OSI-774, Tarceva)in an ongoing phase II trial. Interimfindings also suggest that BAC mightbe more common than previously believedand perhaps behaves differentlyin smokers than in nonsmokers.Vincent Miller, MD, of MemorialSloan-Kettering Cancer Center in NewYork City reported a 26% responserate using erlotinib to treat BAC in 50evaluable patients and a trend towardhigher response in nonsmokers (ASCOabstract 2491). While 46% of patientswho never smoked responded to erlotinib,only 19% of former or currentsmokers did so."Erlotinib is an active drug in thisdisease. We believe the duration ofresponse is encouraging, and the treatmentis certainly well tolerated," Dr.Miller said in reporting interim resultsfrom the ongoing study. Speaking forco-investigators at his center andVanderbilt-Ingram Cancer Center inNashville, he said a phase III trial comparingerotinib to platinum-based chemotherapywas warranted.BAC Component in NSCLC
As defined by World Health Organizationcriteria, BAC accounts for only3% of cases of non-small-cell lungcancer (NSCLC). Dr. Miller suggest-ed, however, that as many as 20% ofNSCLC cases might have a BAC component."Our previous work suggeststhat pure BAC, BAC with focal invasion,and adenocarcinoma with BACfeatures have a similar clinical course,"he said. Screening and monitoring ofpatients for the current trial supportedthat observation, he added.From July 2002 to April 2003, areviewer at Memorial Sloan-Ketteringscreened 98 patients whose prior pathologyand/or clinical presentationsuggested the possibility of a BAC diagnosis.Dr. Miller said surgical pathologymaterial was reviewed for twothirdsof the patients and cytologicmaterial for the rest.The review ruled out BAC in 27patients. Among the remainder ofscreened patients, 52 had adenocarcinomawith BAC features, 2 had BACwith focal invasion, and 17 had pureBAC. Only one patient previously diagnosedwith BAC was ruled out. Conversely,the review found BAC featuresin 45 patients whose samples hadpreviously been classified as adenocarcinomaor NSCLC."This is not a rare bird to find whenyou start to look at your patients," Dr.Miller advised. "So one of the messagesis, one can't accept a pathologyreport that just says NSCLC. The physicianneeds to ask his or her pathologistfor more information particularlywhether or not a BAC componentmight be present."Three-Quarters Were Smokers
Of 71 patients potentially eligiblefor the trial, 55 consented for treatmentand 50 were evaluable for response.Their median age was 66 witha range of 33 to 85 years. Two-thirds ofthe patients were women, and threequarterswere former or current smokers.The majority, 38 patients, hadnever received chemotherapy, while12 patients had undergone one priorregimen.The patients received 150 mg oferlotinib daily. Erlotinib is a smallmolecule inhibitor of the HER1/epidermalgrowth factor receptor (HER1/EGFR) tyrosine kinase. Little is knownabout EGFR expression in BAC, Dr.Miller said. Anecdotally, however, hereported that BAC patients appearedto have some of the most dramaticresponses to erlotinib and gefitinib(ZD1839, Iressa), another EGFR inhibitor,in phase I trials with advancedNSCLC patients.Responses and Progression
Investigators noted partial responsesin 13 patients enrolled in the phaseII study and all but one has been confirmed.One patient who respondedprogressed after 3 months and anotherpatient after 7 months, but 11 responsesare ongoing. "The responsecan be quite dramatic and long lasting,"he said.At 3 months, 48 of 55 patients originallyenrolled in the trial were stillalive, according to Dr. Miller. Themedian duration of follow-up is 6months, he said, and the median durationof response had not yet beenreached.While four deaths occurred onstudy, Dr. Miller said two were due todisease progression in the first month,and a patient who died suddenly 9days after starting treatment had appearedbetter symptomatically. Noautopsy was performed.Rash and diarrhea were dose limitingin phase I. Only one respondingpatient did not have a rash in phase II.Four patients had grade 3 rash, andtwo patients reported grade 2 rashesto be intolerable, but none discontinuedbecause of rash, according to Dr.Miller.Predicting Response
In searching for clinical characteristicsthat might identify the subset ofpatients who were most likely to respondto erlotinib, the investigatorsfound that females were only slightlymore likely to respond. The responserate was also slightly higher in invasivevariants of BAC than in pure BAC, butDr. Miller said that both groups respondedsimilarly.Although the data did not reachstatistical significance, a history of neversmoking appeared to correlate withbeing more sensitive to erlotinib. Dr.Miller called the data provocative andspeculated that "lung cancer may havea different biology in never smokers."He said the investigators plan toconstruct a tissue microarray comparingerlotinib-sensitive and erlotinib-resistant patients and to examinethe frequency of tobacco-relatedmutations in both groups.