Phase I study of gefitinib plus FOLFIRI in previously untreated patients with metastatic colorectal cancer

Background: In this study, the maximum tolerated dose and toxicity profile of FOLFIRI (infusional fluorouracil [5-FU]/leucovorin/irinotecan) plus gefitinib (an oral inhibitor of the epidermal growth factor receptor) were evaluated as first-line therapy in patients with metastatic colorectal cancer. Patients and Methods: Sixteen patients participated in this study. Oral gefitinib was administered at 250 mg or 500 mg daily in 2 dose-escalation cohorts. FOLFIRI was administered without dose escalation on a 14-day cycle with treatment on day 1 with irinotecan 180 mg/m(2), leucovorin 200 mg/m(2), and 5-FU 400 mg/m(2) bolus, followed by 5-FU 2400 mg/m(2) continuous infusion over 46 hours. Results: The maximum tolerated dose of gefitinib was 250 mg, with diarrhea and neutropenia noted as the principal dose-limiting toxicities. Dose reductions in 5-FU and irinotecan were required in 4 patients because of diarrhea and 1 patient because of neutropenia. A partial response was observed in 25% of patients, and 56% had stable disease for > 12 weeks, corresponding to a disease control rate of 81%. Conclusion: These findings suggest that gefitinib can be safely combined with FOLFIRI as first-line treatment of metastatic CRC and support the safety of further investigations of EGFR tyrosine kinase inhibitors with multiagent chemotherapy in this patient population.