Randomized Phase II Trial of the Clinical and Biological Effects of Two Dose Levels of Gefitinib in Patients With Recurrent Colorectal Adenocarcinoma

Abstract

Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.

A phase II study to determine the ability of gefitinib to reverse fluoropyrimidine resistance in metastatic colorectal cancer (the INFORM study)

“…The lack of responses observed here is compatible with the previous phase II study reported by Rothenberg et al (2005), in which 115 patients with metastatic colorectal cancer received either 250 or 500 mg of daily gefitinib and only one partial response was observed, although a trend towards decreased posttreatment levels of activated Akt and Ki67 was observed in patients with a progression-free survival higher than the median. In a recent study combining gefitinib and irinotecan in patients with fluoropyrimidine-refractory, irinotecan-naive metastatic disease, there was no additional benefit from gefitinib (Chau et al, 2007).…”

“…A previous randomised phase II study has demonstrated that gefitinib has inhibitory effects on downstream regulators of cellular transformation in patients with previously treated colorectal cancer (Rothenberg et al, 2005). This, together with data showing that EGFR inhibition can reverse clinical resistance to chemotherapy (Cunningham et al, 2004), prompted the current study.…”

Epidermal growth factor receptor (EGFR) downstream signalling pathway in primary colorectal tumours and related metastatic sites: optimising EGFR-targeted treatment options

“…However, these latter assumptions should be considered purely speculative, as in our analysis we did not include information about other biological determinants, such as EGFR mutations or abnormal expression of other EGFR-driven downstream molecules, which may play a relevant role in EGFR-directed treatment selection. However, our observation seems to be similar to results reported by Rothenberg et al (2005), in which they were not able to confirm a correlation between the inhibition of Akt and MAPK and response to an EGFR TKI (gefitinib) in colorectal cancer, but suggested a definite trend for inhibition of the EGFR-driven activation of downstream regulators in patients achieving a longer progression-free survival. These results should be considered even more relevant if we consider that the timing adopted for tumour biopsies collection for biological studies could have been not optimal.…”

“…Recently in a series of 28 advanced colorectal patients treated with gefitinib monotherapy, biologic evaluation of total and activated EGR, activated Akt, MAPK and Ki 67 on paired preand 1-week post-treatment tumour samples could not confirm a gefitinib-induced decreased expression of these molecular markers (Rothenberg et al, 2005).…”

Cancer colorectaux métastatiques et thérapies ciblées anti-EGFR

“…Des essais sont également cours en situation adjuvante ou néoadjuvante [44]. Les petites molécules inhibitrices de type TKI (gefitinib, erlotinib) ciblant l'EGFR ont également été explorées dans les CCR avancés ou métastatiques [45][46][47][48][49][50][51][52]. Dans la plupart des études, l'expression d'EGFR n'était pas un pré-requis à l'inclusion.…”