Adding Erlotinib to Gemcitabine Increases Survival in Advanced Pancreatic Cancer

TORONTO, Canada-In aphase III international study of patientswith advanced pancreatic cancer,addition of erlotinib (Tarceva) togemcitabine (Gemzar) increased 1-year survival by 40%, marking the trialas "the first to show a survival benefitfor a targeted therapy in advanced pancreaticcancer", reported lead investigatorMalcolm Moore, MD, directorof the New Drug Development Programat Princess Margaret Hospital inToronto (abstract 1).Study ProtocolThe double-blind placebo-controlledphase III study was conductedby the National Cancer Institute ofCanada Clinical Trials Group atQueens University, with investigatorsfrom OSI Pharmaceuticals. A total of569 patients with locally advanced ormetastatic pancreatic cancer were enrolled.Treatment groups were wellbalanced in terms of performance status,locally advanced vs metastatic dis-ease, and presence of pain. Most of thepatients had measurable disease.Patients were randomized to receivegemcitabine at 1,000 mg/m² IVweekly for 7 of 8 weeks and then 3 of 4weeks plus daily oral placebo (n =284) or erlotinib (n = 285). Erlotinibwas given at a dose of 100 mg duringmost of the trial, however an additional,smaller cohort of patients receiving150 mg was later added to thestudy. The analyses reported are basedon the entire study group, Dr. Mooresaid.Survival ImprovementThe study met its primary endpointof overall survival. "The hazardratio of survival is 0.81, which translatesinto a 24% improvement in survivalfrom the use of erlotinib withgemcitabine," Dr. Moore said. Mediansurvival time for patients in theerlotinib arm was 6.4 months, vs 5.9months in the placebo arm. "The 1-year survival was improved from 17%to 24%, which is an approximate improvementof 40%," he told ONI.Median progression-free survivaltime for patients treated with erlotinibwas 3.75 months, vs 3.55 monthsfor patients randomized to placebo.Tumor response occurred in 57.5% ofpatients receiving erlotinib, vs 49.2%of patients receiving placebo.Rash Linked to BetterResponseIn all patient subsets, Dr. Mooresaid, the hazard ratio was always lessthan 1, indicating a positive effect infavor of erlotinib. This effect of erlotinibappeared to be pronounced insome patient subsets, he added, particularlypatients at performance status2 and those who had metastaticdisease. Nevertheless, he emphasized,because these are subset analyses, "theyare really just hypotheses-generating."Expected adverse events-rash, diarrhea,infection, and stomatitis-were generally tolerable and manageable,he reported. Similar to otherstudies with erlotinib, patients whodeveloped a rash responded better totreatment. Grade 3 and 4 toxicities"were relatively low in both arms," Dr.Moore said, and there were "no differencesin hematologic, in renal, or inhepatic toxicities between the arms."Quality-of-life assessments, he added,showed "no detrimental effects onquality of life from the addition oferlotinib to gemcitabine."Consider Therapeutic Index"The small improvement in survivalafforded to erlotinib-treated patientswas accompanied by increasedtoxicity, challenging us to think caretinibfully about the therapeutic index, whenan unselected population of patientswith pancreatic cancer is exposed tothe combination of gemcitabine anderlotinib," commented discussantJames L. Abbruzzese, MD, of TheUniversity of Texas M.D. AndersonCancer Center, Houston. An improvedunderstanding of the relationship betweenthe skin rash induced by erlo-tiniband improved patient outcome,he said, "will be a critical first step" inidentifying which patients will be likelyto benefit from EGFR antagonists.He also advocated "a detailed pharmacoeconomicanalysis to include thecosts of drug treatment as well as thecosts of managing incremental toxicityencountered with this combination."Refine Treatment Population"Based on these considerations, atthis time, I do not feel that the resultsclearly alter the standard of care forpatients treated with advanced pancreaticcancer, and continued refinementof the patient population mostlikely to benefit from this combinationwill be needed rather than to generallyadopt this regimen for all patients,"Dr. Abbruzzese said."In the end," he added, "I think thistrial's greatest contribution may be tofocus us, the oncology community, onincreasing our efforts to therapeuticallyexploit the molecular biology ofcomplex malignancies like pancreaticcancer, to look for opportunities tointervene earlier in the process of pancreaticcarcinogenesis, and finally tocontinue the hard work of identifyingwhich patients are likely to benefitfrom targeted therapy."