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

BOSTON-The oral tyrosine kinase (TK) inhibitor erlotinib (Tarceva) is active in combination with capecitabine(Drug information on capecitabine) (Xeloda)/oxaliplatin (Eloxatin) in previously treated colorectal cancer, according to early results from a phase II study (abstract 3580). Erlotinib plus capecitabine/oxaliplatin yielded a confirmed partial response rate of 24%, reported oncologist Jeffrey A. Meyerhardt, MD, an instructor in medicine at Harvard Medical School, Boston, Massachusetts. Dr. Meyerhardt and colleagues called that result "encouraging" compared with FOLFOX-4 (fluorouracil/ leucovorin, oxaliplatin(Drug information on oxaliplatin)) and capecitabine/ oxaliplatin alone in this setting, for which response rates of 9% and 15%, respectively, have been reported. Higher Response Rate
"What we have so far is that [the regimen] has a higher response rate, a modestly increased time to progres- sion by about a month, and generally, people are tolerating these doses pretty well," Dr. Meyerhardt said. "It's definitely worth pursuing further." The investigation is one of several recent studies suggesting a role for TK inhibitors (TKIs) in metastatic colorectal cancer. "There seems to be some interaction with the TK inhibitors in combinations, and they're worth pursuing," Dr. Meyerhardt told Oncology News International. "Singleagent TKIs seem not to be very active...but in combination, they seem to be a little more promising." In a separate ASCO presentation, European investigators described a phase I investigation of erlotinib plus capecitabine/oxaliplatin, including 23 patients treated at two different dose levels. Five patients had a partial response, 14 had stable disease, and only 4 had progressive disease, including 3 in the lower-dose cohort (abstract 3585). In addition, earlier in the year at the ASCO 2004 Gastrointestinal Cancers Symposium, Fisher et al reported "fairly good activity" for gefitinib(Drug information on gefitinib) (Iressa), which also inhibits TK activity, plus FOLFOX, Dr. Meyerhardt said (abstract 187). In part because capecitabine/oxaliplatin is "becoming an increasingly attractive option" for metastatic colorectal cancer, Dr. Meyerhardt said he and colleagues sought to record the objective response rate for erlotinib plus this combination in 27 previously treated patients, about three-quarters of whom had received prior irinotecan(Drug information on irinotecan). Treatment consisted of 21-day cycles of oxaliplatin (130 mg/m² on day 1), capecitabine (1,000 mg/m² twice daily on days 1-14) and erlotinib (150 mg daily). The capecitabine dose was reduced to 750 mg/m² twice daily after 13 patients had been enrolled. Of 25 evaluable patients, confirmed partial responses were seen in 6 (24%); with a median follow-up period of 7.2 months, duration of responses ranged from 10+ to 26+ weeks. Another 10 patients (40%) had stable disease for at least 12 weeks. Median time to progression was 5.3 months, and overall survival time had not been reached as of this analysis, which Dr. Meyerhardt emphasized is incomplete and not mature yet. The proportion of patients experiencing any grade 3/4 toxicity was 92% before the capecitabine dose reduction, and 64% afterward. At the lower dose level, toxicities are "manageable," investigators said; the main grade 3/4 toxicity was diarrhea, occurring in about 50% of patients at either dose level. The search for an improved second- line therapy continues: Dr. Meyerhardt said his group is considering investigation of a chemotherapy combination plus bevacizumab(Drug information on bevacizumab) (Avastin), an inhibitor of the epidermal growth factor receptor.