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

Abstract

There are data suggesting that inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase signalling may reverse resistance to fluoropyrimidine treatment. To investigate this further, the INFORM study was an open-label, non-comparative phase II study of gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE, USA) 250 mg daily in combination with 5-fluorouracil (5-FU administered as an intravenous 400 mg m À2 bolus injection followed by 2800 mg m À2 infusion over 46 h and folinic acid administered as a 350 mg infusion over 2 h) every 2 weeks for up to 12 cycles in 24 patients with metastatic colorectal cancer refractory to previous fluoropyrimidine treatment. There were no objective responses. The stable disease rate was 37.5% (95% CI: 18.80, 59.41), median progression-free survival measured 116 days and overall survival was 226 days. Quality of life was unchanged compared to baseline values, and the commonest toxicities were diarrhoea, rash and fatigue with 7 out of 24 (29%) patients having a grade 3 or 4 toxicity. Gefitinib does not sensitise patients with fluoropyrimidine refractory metastatic colorectal cancer to 5-FU chemotherapy.

Phosphorylated Insulin-Like Growth Factor 1 Receptor is Implicated in Resistance to the Cytostatic Effect of Gefitinib in Colorectal Cancer Cells

“…10 However, phase I/II clinical trials have produced the disappointing results that gefitinib has negligible activity in advanced CRC patients as a monotherapeutic agent, 11,12 and more recent studies showed that gefitinib did not appear to add substantial efficacy to irinotecan or capecitabine 13,14 or sensitize patients with fluoropyrimidine refractory CRC to 5-Fu chemotherapy. 15 These data support the notion of existing intrinsic or de novo resistance to gefitinib treatment in CRC, and the resistance mechanism of this inhibitor has yet to be determined.…”

Investigation of the Genome-Wide Genetic and Epigenetic Networks for Drug Discovery Based on Systems Biology Approaches in Colorectal Cancer

“…Moreover, estradiol has been found that it reduced proliferation and apoptosis in CRC (Sasso et al, 2019). For gefitinib, there are a number of phase I and II studies investigating the effects caused by the combination with standard 5-fluorouracil (5-FU)-based regimes with response rates ranging from 25 to 59%, although these trials did not include chemotherapy-resistant individuals (Kuo et al, 2005;Cho et al, 2006;Hofheinz et al, 2006;Wolpin et al, 2006;Stebbing et al, 2008). Moreover, ClnicalTrials.gov identifier NCT00025350, has completed phase II trial for using gefitinib in patients with recurrent metastatic CRC.…”

Growth Factors and the Redox State as New Therapeutic Targets for Colorectal Cancer

“…These data suggest that inhibition of the EGFR signaling pathway could revert resistance to treatment with the fluoropyrimidines and irinotecan. On the basis of this hypothesis, some authors have carried out assays using tyrosine kinase inhibitors of EGFR, such as gefitinib (Stebbing et al, 2008), as well as inhibitors of the Src tyrosine kinase (Ischenko et al, 2008).…”