The recent advent of several new agents for the treatment of metastatic CRC has markedly enhanced the therapeutic armamentarium for this disease. Oxaliplatin in combination with infusional 5-FU in the FOLFOX-4 regimen has been shown to be effective in achieving an improved response and time to progression over LV5FU and IFL in the first-line setting (2
). The monoclonal antibodies cetuximab, targeting EGFR, and bevacizumab, targeting vascular endothelial growth factor, have also demonstrated therapeutic efficacy in CRC, and many studies to optimize their utilization in combination with chemotherapies are underway.
The high level of EGFR expression in CRC specimens has sparked great interest in using this target to develop more directed and specific therapies. To date, positive results with EGFR inhibition in CRC have only been reported for the monoclonal antibody cetuximab in combination with irinotecan-based regimens utilizing bolus 5-FU and FOLFIRI (18
). The combination of EGFR inhibition with FOLFOX-4 is currently being investigated in a randomized phase III trial of FOLFOX chemotherapy plus and minus cetuximab. However, while cetuximab and gefitinib target the same cellular pathway, there is very limited data on small molecule inhibitors of EGFR in combination with chemotherapy in CRC.
Despite preclinical evidence for chemosensitization, four major randomized trials have shown no benefit for the addition of gefitinib or erlotinib added to standard chemotherapy for non-small cell lung cancer (21
). Our data suggests that colorectal cancers differ substantially from non-small cell lung cancers in the ability of EGFR inhibitors to enhance the effects of chemotherapy. The response rate achieved in this study is higher than reported results with FOLFOX-4 alone in a similar setting. While acknowledging that a direct comparison of the two response rates is not possible, the high response rate seen with IFOX suggests that gefitinib exerts a chemosensitizing effect in CRC. This explanation is consistent with our prior IFOX experience with CRC patients who were receiving second-line therapy (30
), as well as the results from two phase III trials showing that cetuximab enhances the antitumor efficacy of irinotecan (18
Two previous studies have demonstrated inconsistent results when combining gefitinib at a dose of 250 mg/day with FOLFOX as first line therapy (31
). Zampino et al reported gefitinib combined with FOLFOX-6 showed response rates similar to that seen in our study (30
). However, this was not confirmed by Cascinu et al. using gefitinib combined with FOLFOX-4 (32
). Our study used a higher gefitinib dose of 500 mg/day, which may have added to the efficacy. The question of the efficacy of gefitinib or other oral EGFR inhibitors combined with chemotherapy in CRC will ultimately only be answered by randomized Phase III trials.
The median overall survival in this study was 20.5 months. When time to progression in our study population is calculated, regardless of any subsequent therapy they may have received after discontinuation from the study treatment, the result is 9.3 months.
As would be expected with combination therapy, certain toxicities were significantly increased over FOLFOX alone, as reported in multiple previous studies. Adverse events known to be increased by gefitinib from other phase I and II studies include diarrhea and skin changes (either acneiform rash or dry skin). For example, grade 3 diarrhea was experienced in 67% of patients receiving our study treatment compared with 12% reported previously, strongly suggesting an additive toxicity of gefitinib and 5-FU on the lower gastrointestinal tract (2
). Grade 3 or 4 neutropenia was also more prevalent compared to historical controls (60% for IFOX vs. 42% for FOLFOX alone).
This investigation showed no correlation between EGFR expression and response or survival. The limitations of sensitivity for detecting EGFR expression by the IHC assay may have obscured any effect of such expression on outcomes. The trend for increased survival in the EGFR negative patients in , although not statistically significant, is consistent with prior studies, which show an adverse prognosis for EGFR expression in CRC (7
). Previous studies have shown variation in EGFR detection depending on the type of fixative use as well as the duration of storage (33
In conclusion, this Phase II study demonstrated that EGFR tyrosine kinase inhibition with gefitinib may enhance the anti-tumor efficacy of FOLFOX-4 chemotherapy in patients with previously untreated metastatic CRC, but also increases toxicity. This study further adds to the growing body of evidence that targeting the EGFR pathway can sensitize some colorectal cancers to cytotoxic drugs.