Promising Response to TK Inhibitor Erlotinib in Second-Line Metastatic Colorectal Cancer

BOSTON-The oral tyrosinekinase (TK) inhibitor erlotinib (Tarceva)is active in combination withcapecitabine (Xeloda)/oxaliplatin(Eloxatin) in previously treated colorectalcancer, according to early resultsfrom a phase II study (abstract3580). Erlotinib plus capecitabine/oxaliplatinyielded a confirmed partialresponse rate of 24%, reported oncologistJeffrey A. Meyerhardt, MD, aninstructor in medicine at HarvardMedical School, Boston, Massachusetts.Dr. Meyerhardt and colleaguescalled that result "encouraging" comparedwith FOLFOX-4 (fluorouracil/leucovorin, oxaliplatin) and capecitabine/oxaliplatin alone in this setting,for which response rates of 9%and 15%, respectively, have beenreported.Higher Response Rate
"What we have so far is that [theregimen] has a higher response rate, amodestly increased time to progres-sion by about a month, and generally,people are tolerating these doses prettywell," Dr. Meyerhardt said. "It'sdefinitely worth pursuing further."The investigation is one of severalrecent studies suggesting a role for TKinhibitors (TKIs) in metastatic colorectalcancer. "There seems to besome interaction with the TK inhibitorsin combinations, and they'reworth pursuing," Dr. Meyerhardt toldOncology News International. "SingleagentTKIs seem not to be veryactive...but in combination, they seemto be a little more promising."In a separate ASCO presentation,European investigators described aphase I investigation of erlotinib pluscapecitabine/oxaliplatin, including 23patients treated at two different doselevels. Five patients had a partial response,14 had stable disease, and only4 had progressive disease, including 3in the lower-dose cohort (abstract3585).In addition, earlier in the year atthe ASCO 2004 Gastrointestinal CancersSymposium, Fisher et al reported"fairly good activity" for gefitinib (Iressa),which also inhibits TK activity,plus FOLFOX, Dr. Meyerhardt said(abstract 187).In part because capecitabine/oxaliplatinis "becoming an increasinglyattractive option" for metastatic colorectalcancer, Dr. Meyerhardt saidhe and colleagues sought to record theobjective response rate for erlotinibplus this combination in 27 previouslytreated patients, about three-quartersof whom had received prior irinotecan.Treatment consisted of 21-daycycles of oxaliplatin (130 mg/m² onday 1), capecitabine (1,000 mg/m²twice daily on days 1-14) and erlotinib(150 mg daily). The capecitabine dosewas reduced to 750 mg/m² twice dailyafter 13 patients had been enrolled.Of 25 evaluable patients, confirmedpartial responses were seen in 6 (24%);with a median follow-up period of 7.2months, duration of responses rangedfrom 10+ to 26+ weeks. Another 10patients (40%) had stable disease forat least 12 weeks. Median time to progressionwas 5.3 months, and overallsurvival time had not been reached asof this analysis, which Dr. Meyerhardtemphasized is incomplete and not matureyet.The proportion of patients experiencingany grade 3/4 toxicity was 92%before the capecitabine dose reduction,and 64% afterward. At the lowerdose level, toxicities are "manageable,"investigators said; the main grade 3/4toxicity was diarrhea, occurring inabout 50% of patients at either doselevel.The search for an improved second-line therapy continues: Dr. Meyerhardtsaid his group is consideringinvestigation of a chemotherapy combinationplus bevacizumab (Avastin),an inhibitor of the epidermal growthfactor receptor.