Encouraging Clinical Experience With Erlotinib in Lung Cancer

VANCOUVER, Canada-Onthe strength of the preclinical studiesthat established the dosing regimen,phase II clinical trials of the oral epidermalgrowth factor receptor (HER1/EGFR) tyrosine kinase inhibitor erlotinib(Tarceva) were begun and areyielding encouraging results, accordingto presentations at the 10th WorldConference on Lung Cancer.Roman Perez-Soler, MD, chairman,department of oncology, MontefioreMedical Center/Albert EinsteinCollege of Medicine, Bronx, New York,presented the final results from a phaseII trial of 57 patients with advanced,refractory NSCLC (stage IIIB/IV), givenerlotinib 150 mg/d (abstract P-611).There were 2 complete responses(4%), 5 partial responses (9%), and 22patients (39%) with stable disease. Themedian duration of response was 19.6weeks. The response durations were18 and 80 weeks, respectively, for the2 complete responders and 12 to 56weeks for those with a partial response.Median overall survival time was 8.4months, median progression-free survivaltime was 9 weeks, and median1-year survival time was 40%, Dr.Perez-Soler said.Baseline factors that predicted forresponse or overall survival includedtime since the initial diagnosis, timesince last chemotherapy, and ECOGperformance status. The extent of priorchemotherapy did not predict foreither outcome.Erlotinib treatment was associatedwith lung cancer symptom improvement.The incidence of fatigue, dyspnea,and cough decreased from 67%,61%, and 60%, respectively, at baselineto 49%, 37%, and 39% during thestudy.The most common drug-relatedadverse events were rash (67%), diarrhea(56%), dry skin (35%), pruritus(35%), fatigue (28%), and nausea(25%). Most events were mild to moderatein severity.Patients with grade 1 or grade 2-3rash survived significantly longer thanthose without rash, indicating that rashmay be a clinically important markerof HER1/EGFR kinase inhibition witherlotinib, Dr. Perez-Soler said.Erlotinib inBronchoalveolar CarcimemaIn lung cancer, the greatest responseto erlotinib may be in patients with thebronchoalveolar carcinoma (BAC)subtype, said Jyoti Patel, MD, ofMemorial Sloan-Kettering CancerCenter (abstract O-188). Dr. Patelpresented updated results of a phase IIstudy reported at ASCO 2003 (abstract2491).The study included 55 patients withBAC, including pure BAC, BAC withfocal invasion, or adenocarcinoma withBAC features. Most patients had notbeen previously treated (51 evaluablefor response). Patients received treatmentwith erlotinib 150 mg/d for atleast 1 month. In this BAC population,75% were former or current smokersand 76% had prior chemotherapy.Partial responses of more than 8weeks' duration were seen in 12 patients(24%). Nine responders are stillmaintaining a response, and three patientsprogressed at 3, 6, and 7 months,respectively. The median follow-up is7 months, and the median duration ofresponse has not been reached. Theprojected 1-year survival is 80%, Dr.Patel reported.Erlotinib was associated with a rapidimprovement in symptoms and adurable response, Dr. Patel said. She cited one symptomatic female patientwho had a "dramatic and swift" responseto erlotinib that has been durablesince July 2002.Several clinical characteristics appearedto affect response, most notablysmoking status. Responses wereseen in 50% of never-smokers comparedwith 15% of current/formersmokers (P = .02). "We believe thesedata are especially provocative in lightof other findings," Dr. Patel said.Women responded better thanmen, although this difference has notreached statistical significance. Responseswere similar for pure BAC vsBAC variants, and skin rash was notrelated to response in this study.There was significant drug-relatedtoxicity, including grade 3 rash (4 patients),grade 2 rash leading to treatmentinterruption or dose reductions(2), grade 3 arthralgia leading to treatmentdiscontinuation (1 patient), andgrade 3 diarrhea (1). Only 1 of 55 patients(2%) withdrew from the study,however, Dr. Patel added."To further understand erlotinib'simpressive activity in subsets of patients,"Dr. Patel explained, "we areprospectively constructing a tissue microarrayto discern differences in theEGFR and other signaling pathwaysbetween responding and nonrespondingpatients."Phase III TrialsMore will be determined about theefficacy of erlotinib when three ongoingphase III trials are completed. TheNational Cancer Institute of Canada'sBR.21 (n = 731) is the first randomized,double-blind, placebo-controlledphase III study of a HER1/EGFR-targetedagent in patients with advanced,refractory disease. The study, whichhas completed enrollment, compareserlotinib 150 mg/d with standard ofcare in patients with refractory stageIII/IV NSCLC.Two other randomized, doubleblind,placebo-controlled phase III trialshave examined erlotinib 150 mg/din combination with gemcitabine(Gemzar) and cisplatin (Platinol)(TALENT trial, outside of the US) orcarboplatin (Paraplatin) and paclitaxel(TRIBUTE trial, in the US), as firstlinetherapy in patients with stage IIIB/IV NSCLC and ECOG performancestatus 0-1. TRIBUTE and TALENTeach enrolled more than 1,000patients. Genentech, OSI Pharmaceuticals,and Roche recently announcedthat TRIBUTE and TALENT did notmeet their primary end points of improvingoverall survival."We are disappointed but not completelysurprised based on previouslyannounced failures of EGFR inhibitorsin this setting... ," said Susan D.Hellman, MD, MPH, Genentech's executivevice president, Developmentand Product Operations, and chiefmedical officer. "To optimize the therapeuticpotential of EGFR inhibitionin NSCLC, we will use clinical dataand conduct prespecified analyses oftumor biopsy material to identify potentialsubsets of patients who may bemore likely to benefit from treatmentwith Tarceva in combination with chemotherapy."