Optimal integration of EGFR inhibitors in advanced colorectal cancer

In the second-line setting, the SPIRITT trial is a randomized phase II study being conducted in the United States. It will evaluate FOLFIRI with either panitumumab or bevacizumab after an oxaliplatin-bevacizumab–containing front-line regimen. SPIRITT will provide data not only comparing panitumumab and bevacizumab in the second line but also regarding the issue of “bevacizumab beyond disease progression.”

The phase III PICCOLO trial in the United Kingdom compares irinotecan, irinotecan-cyclosporine, and irinotecan-panitumumab in second-line treatment. ASPECCT is an international phase III trial evaluating panitumumab versus cetuximab as single agents in patients with metastatic colorectal cancer who failed to respond to a fluoropyrimidine, oxaliplatin, and irinotecan.

In the first-line setting, PEAK is an international randomized phase II study of a modified FOLFOX6 regimen with either panitumumab or bevacizumab. TAILOR, a phase III trial being conducted in China, is comparing FOLFOX4 with or without cetuxi¬mab in first-line disease. FIRE-3 is a German phase III investigation of FOLFIRI-cetuximab versus FOLFIRI-bevacizumab in first-line treatment of metastatic colorectal cancer.

CALGB (Cancer and Leukemia Group B) 80405 is a US trial to define the role of EGFR monoclonal antibodies in the front-line treatment of advanced colorectal cancer (Figure 1). This trial allows a chemotherapy backbone of either FOLFOX or FOLFIRI (investigator’s choice). It was originally designed as a three-arm trial, comparing chemotherapy with cetuximab, bevacizumab, or the combination. The trial has undergone two major amendments. The first was the requirement for tumors to be KRAS wild-type, and the second was elimination of the arm testing chemotherapy with the cetuximab-bevacizumab combination. As of March 2011, over 2,000 patients have been accrued, with an enrollment goal of 2,843 patients.³⁸

Given the popularity of bevacizumab-oxaliplatin–based first-line therapy, SWOG (Southwest Oncology Group) 0600 was designed to evaluate irinotecan-based treatment in the second line after previous FOLFOX-bevacizumab or CAPOX-bevacizumab. Its original design compared irinotecan-based chemotherapy with either cetuximab alone or with two different doses of bevacizumab. SWOG 0600 underwent amendments to exclude KRAS-mutant patients and to eliminate the combination of cetuximab and bevacizumab. It became a trial comparing the continuation of bevacizumab beyond disease progression into the second line versus switching to cetuximab. This trial recently closed due to poor accrual.

To use targeted therapy effectively, proper patient selection is critical. In 2009, ASCO recommended that KRAS testing be standard for patients who are candidates for EGFR antibody treatment and that patients with KRAS codon 12 or 13 mutations not receive anti-EGFR antibodies; however, a recent pooled dataset suggests that patients with a p.G13D codon 13 mutation may derive substantial benefit from cetuximab.^39,40 Additional retrospective data suggest that mutations in BRAF, a signaling protein downstream from KRAS in the EGFR pathway, may have a similar predictive role for lack of benefit from treatment with either cetuximab or panitumumab.^41,42 However, other data indicate that although BRAF mutations may be associated with a poor prognosis, some patients may still derive benefit from anti-EGFR antibody therapy.²³ As mutations in KRAS and BRAF are mutually exclusive, determination of BRAF mutation status should only be considered in patients who are KRAS wild-type. However, excluding patients with BRAF mutations from anti-EGFR antibody therapy is not standard at this time. Mutations in other effectors of EGFR signaling, such as PI3-kinase and NRAS, are also being evaluated as predictive factors, as are the roles of EGFR gene amplification and PTEN expression.^42,43

The body of clinical data evaluating anti-EGFR antibodies in the treatment of advanced colorectal cancer continues to increase rapidly. Over the past several years, the use of KRAS status to select patients has allowed more refined use of these drugs, and further evaluation of BRAF and other effectors of the EGFR signaling pathway promises to help restrict use of these agents to patients most likely to benefit, a key goal of “personalized medicine.” The data to support the use of cetuximab or panitumumab in the second- and third-line settings are strong, with trials consistently showing benefit in terms of response rate, PFS, and in some cases OS. This is especially true when analysis has been restricted to KRAS wild-type patients. Many patients and clinicians prefer to wait until later in the disease course to utilize these agents, given their comfort with first-line bevacizumab and the bothersome cutaneous toxicities associated with use of either cetuximab or panitumumab.