Messersmith WA et al. (2004) Phase I trial of irinotecan, infusional 5-fluorouracil, and leucovorin (FOLFIRI) with erlotinib (OSI-774): early termination due to increased toxicities. Clin Cancer Res 10: 6522–6527

Combinations of EGFR-targeting agents and conventional chemotherapy have shown promise in the treatment of colorectal cancer, and their safety profile has been satisfactory. A recent trial has revealed excessive toxicity, however, in patients receiving a combination of erlotinib (an oral EGFR tyrosine kinase inhibitor) and the standard FOLFIRI chemotherapy regimen.

This phase I study was designed to assess escalating doses of the combination in individual cohorts of six patients with advanced colorectal cancer. The trial was terminated after the first cohort developed severe toxicities at the lowest dose level (100 mg/day erlotinib continuously and FOLFIRI at ∼80% of the standard doses). Toxicities included grade 3 vomiting (one patient) grade 3 diarrhea (four patients), grade 3 or 4 neutropenia (three patients) and grade 4 pulmonary embolism (one patient). Four subjects also developed a disfiguring, acneiform rash on the face and upper chest or back. It was necessary to discontinue, interrupt or reduce the dose of erlotinib and/or FOLFIRI in all six patients, and no patient received more than two 6-week cycles of therapy. After one cycle, five patients had stable disease and one patient had a partial response.

Concluding that the combination of erlotinib with FOLFIRI caused severe toxicity in this study, authors Messersmith et al. stress that the safety of any such combinations should be tested.