Nikesh Jasani, MD

The epidermal growth factor receptor (EGFR) is a transmembrane protein with an extracellular ligand-binding domain and an intracellular ATP-dependent tyrosine kinase domain. Binding of ligand leads to autophosphorylation and activation of the signaling pathway, which regulates cell differentiation, proliferation, migration, protection from apoptosis, and angiogenesis.^1,2 EGFR is either overexpressed or upregulated in a majority of colorectal cancers, and higher degrees of EGFR staining have been correlated with inferior survival in a variety of tumor types.^3–6 Preclinical studies demonstrated the ability of monoclonal antibodies directed against EGFR to inhibit malignant cell proliferation and to act synergistically with chemotherapeutic agents in suppressing tumor cell lines.^7,8 Although early clinical development of anti-EGFR antibody therapy focused on cetuximab (Erbitux), more recent data have also demonstrated similar benefit with panitumumab (Vectibix), and the spectrum of benefit seen in clinical trials has been found in both advanced and refractory patients as well as in previously untreated patients with metastatic disease.

In selecting therapy for a patient with advanced colorectal cancer, clinicians must now choose among several chemotherapeutic agents (fluoropyrimidines, oxaliplatin, and irinotecan) and decide how to integrate targeted agents with chemotherapy. Bevacizumab (Avastin)–containing regimens are well established, with phase III data demonstrating a survival benefit in the first-line setting with irinotecan-based therapy and in the second-line setting with oxaliplatin-based treatment.^9,10 Choosing which EGFR-directed drug to use, which chemotherapy regimen to use as a backbone, and when in the sequence of treatment options to consider EGFR-directed therapy has become more complicated recently based on emerging data.

Cetuximab
Cetuximab is a chimeric IgG1 (immunoglobulin G1) monoclonal antibody that binds to EGFR with high specificity and affinity.⁷ It was initially approved by the US Food and Drug Administration (FDA) in February 2004 based on response rate data in combination with irinotecan for irinotecan-refractory patients. Although originally used only in patients with EGFR-expressing tumors, a number of studies have since suggested that response is independent of EGFR staining, and this is no longer used as a selection criterion for EGFR-directed therapy.^11–13 Rather than EGFR expression, it is KRAS mutation status that has emerged as the most important predictor for lack of benefit from anti-EGFR therapy. Multiple trials demonstrate either no benefit or inferior outcomes with the addition of EGFR-directed therapy in the approximately 40% of advanced colorectal cancer patients with activating KRAS mutations.

In an early phase II trial, cetuximab, given as a single agent to irinotecan-refractory patients, produced a partial response rate of 9%.¹⁴ The pivotal BOND-1 trial randomized 329 patients whose disease had progressed after an irinotecan-based regimen to receive both cetuximab and irinotecan or cetuximab as monotherapy (Table 1).¹⁵ The response rate in the combination-therapy group was significantly higher (22.9% vs 10.8%; P = 0.007), and the median time to disease progression (TTP) was significantly greater in the combination-therapy group (4.1 months vs 1.5 months; P < 0.001). There was no difference in median survival (8.6 months vs 6.9 months; P = 0.48), although crossover from monotherapy to combination therapy was permitted. The ability of cetuximab to restore sensitivity to treatment with irinotecan was seen regardless of whether patients had been pretreated with oxaliplatin or not.

The CO.17 trial randomized 572 patients with metastatic disease previously treated with a fluoropyrimidine, irinotecan, and oxaliplatin to receive treatment with single-agent cetuximab versus best supportive care (Table 1).¹⁶ It was completed prior to knowledge regarding the predictive effects of KRAS status, and the primary endpoint was overall survival (OS). Treatment with cetuximab was associated with improvement in response rate, progression-free survival (PFS), and OS (from 4.6 months to 6.1 months; hazard ratio [HR] for death 0.77; P = 0.005). In a retrospective analysis, cetuximab therapy in KRAS wild-type tumors doubled PFS from 1.9 months to 3.7 months (HR = 0.40; P < 0.0001), whereas there was no effect of cetuximab in the KRAS-mutant group (Table 1).¹⁷

Given the popularity of using oxaliplatin in front-line therapy for metastatic colorectal cancer, there was interest in demonstrating a role for cetuximab with irinotecan in second-line treatment, after failure of oxaliplatin. The EPIC trial randomized patients in this setting to receive irinotecan with or without cetuximab, with OS as the primary endpoint (Table 1).¹⁸ Although there was a trend favoring the addition of cetuximab, OS was not improved (median survival, 10.7 months with cetuximab-irinotecan vs 10.0 months with irinotecan; HR = 0.975), perhaps confounded by the fact that almost half of the irinotecan-alone patients continued on to receive cetuximab later. Combination therapy did increase the response rate from 4% to 16% (P < 0.0001) and increased PFS from 2.6 months to 4.0 months (HR = 0.692; P < 0.0001).

After demonstration of activity later in the disease course, investigators evaluated cetuximab in front-line treatment of advanced colorectal cancer and in combination with oxaliplatin. Unlike the consistently positive data in the salvage setting, the data in front-line therapy have been mixed. Tabernero et al conducted a phase II trial of FOLFOX4 (folinic acid, 5-fluorouracil [5-FU], oxaliplatin) with cetuximab as initial therapy in 43 patients, which yielded a confirmed response rate of 72%, a PFS of 12.3 months, and an OS of 30.0 months.¹⁹ Ten patients (23%) whose metastases were initially assessed as inoperable were rendered resectable by treatment.

In the OPUS randomized phase II study, FOLFOX4 versus FOLFOX4 plus cetuximab was tested in first-line therapy (Table 2).²⁰ The primary endpoint was confirmed response rate, which was unchanged in the overall population. However, KRAS status was assessed retrospectively in 233 patients, and the response rate increased from 37% to 61% (P = 0.011) with the addition of cetuximab in KRAS wild-type patients; PFS increased from 7.2 months to 7.7 months (HR = 0.57; P = 0.016) in this group. In the KRAS-mutant group, the addition of cetuximab appeared to have a detrimental effect, with a decrease in PFS from 8.6 months to 5.5 months (HR = 1.83; P = 0.019).

The CRYSTAL trial evaluated the addition of cetuximab to FOLFIRI (folinic acid, 5-FU, irinotecan) in a large phase III trial in first-line treatment of metastatic disease (Table 2).²¹ The primary endpoint was PFS, which was prolonged in the primary analysis population from 8.0 months to 8.9 months (P = 0.048). At the 2010 meeting of the American Society of Clinical Oncology (ASCO), an updated analysis was presented according to KRAS status.²² KRAS status was determined retrospectively in 1,063 of 1,198 patients, and 37% had KRAS mutations. In the KRAS wild-type population, the response rate increased from 39.7% with FOLFIRI to 57.3% with FOLFIRI-cetuximab, PFS increased from 8.4 months to 9.9 months (HR = 0.70; P = 0.001), and OS increased from 20.0 months to 23.5 months (HR = 0.796; P = 0.009). A pooled analysis of CRYSTAL and OPUS patients was also presented at the 2010 ASCO meeting.23 In the KRAS wild-type population, the addition of cetuximab to front-line chemotherapy increased the response rate from 38% to 57% (P < 0.0001), the median PFS from 7.6 months to 9.6 months (HR = 0.66; P < 0.0001), and the median OS from 19.5 months to 23.5 months (HR = 0.81; P = 0.006).

In contrast to these positive findings, several recent trials incorporating cetuximab into initial therapy have failed to show a benefit, even in KRAS wild-type patients. The COIN trial studied 1,630 patients in first-line treatment, testing the benefit of adding cetuximab to oxaliplatin with either infusional 5-FU or capecita¬bine (Xeloda), at the treating physician’s discretion (Table 2).²⁴ The trial was initiated prior to the emergence of data regarding the predictive value of KRAS mutation status, and patients were not selected for inclusion on this basis. After the trial completed accrual but prior to any data analysis, the primary endpoint was changed to examine OS only in patients without a KRAS mutation (43% of patients had KRAS mutations).

The response rate was increased modestly in the KRAS wild-type group by the addition of cetuximab, from 57% to 64% (P = 0.05). However, this did not translate into an improvement in survival, with a median survival of 17.9 months without cetuximab and 17.0 months with cetuximab (HR = 1.04; P = 0.68). There was also no prolongation of PFS in the KRAS wild-type patients, with PFS of 8.6 months in both arms (HR = 0.96; P = 0.60). The reason for the discrepant results of this study compared with other studies demonstrating a strong survival benefit for KRAS wild-type patients with cetuximab is unclear. Retrospective subgroup analysis suggested that perhaps benefit was seen with cetuximab when added to infusional 5-FU (FOLFOX) but not when added to capecitabine-based treatment (CAPOX).

A second negative trial recently reported at the 2010 ESMO (European Society for Medical Oncology) meeting was the Nordic VII trial, in which 571 patients were randomized to one of three bolus 5-FU–based arms: FLOX, FLOX with cetuximab until disease progression, or FLOX with cetuximab for 16 weeks and then maintenance cetuximab alone with reintroduction of FLOX at disease progression (Table 2).²⁵ The FLOX regimen consisted of a 5-FU IV bolus (500 mg/m2) plus folinic acid (60 mg/m2) on days 1–2 every 2 weeks and oxaliplatin (85 mg/m2) on day 1. Cetuximab was given at the standard dosage of 400 mg/m2 initially and then 250 mg/m2 weekly.

The primary endpoint was PFS, which was not significantly different among the three arms: 7.9 months versus 8.3 months versus 7.3 months with FLOX, FLOX-cetuximab, and “stop/go” FLOX-cetuximab, respectively. Overall response rates were also not significantly different between the three arms (41% vs 49% vs 47%), and OS was similarly unchanged in the three groups (20.4 months vs 19.7 months vs 20.3 months). In the 60% of patients without KRAS mutations, there was still no significant benefit seen for the addition of cetuximab: in comparing arm A (FLOX alone) versus arm B (FLOX + cetuximab), the response rate was 47% versus 46%, PFS was 8.7 versus 7.9 months (P = 0.66), and OS was 22.0 months versus 20.1 months (P = 0.66). Given that this trial used an unconventional chemotherapy regimen, the reason for the failure of the study to produce positive results is unclear.

Panitumumab
Panitumumab is a fully human IgG2 EGFR monoclonal antibody. Like cetuximab, it targets the extracellular domain of the EGFR and blocks downstream signaling, leading to antitumor effects.²⁶ Because it is fully humanized, panitumumab does not have the same risk of hypersensitivity reactions seen with the chimeric antibody cetuximab. This may be especially important in some areas of the southeastern United States, where reactions to cetuximab occur at a higher frequency than has been reported in clinical trials.²⁷ Panitumumab was approved for monotherapy of relapsed/refractory metastatic colorectal cancer by the FDA in September 2006. As with cetuximab, its use is now specified to tumors harboring wild-type KRAS.

Initial phase I data in patients with metastatic colorectal cancer treated with panitumumab showed a 13% response rate.²⁸ In phase II studies in relapsed and refractory metastatic disease, panitumumab (6 mg/kg every 2 weeks or 2.5 mg/kg every week) showed activity, with objective responses in 3%–13% and stable disease in 21%–33% of patients with EGFR immunostaining. ^12,29,30

A large randomized phase III study was conducted in 463 patients whose disease had progressed after prior therapies including 5-FU, irinotecan, and oxaliplatin (Table 1).³¹ Patients were randomized to receive either panitumumab (6 mg/kg every 2 weeks) and best supportive care (BSC) or BSC alone, and crossover was allowed from the control arm to panitumumab upon disease progression. The primary endpoint was PFS, which was 8 weeks for the panitumumab-treated patients versus 7.3 weeks in the BSC-alone group (HR = 0.54; P < 0.001). Similar to the phase II data, partial responses were seen in 10% of patients receiving panitumumab (versus none in the control group), and stable disease was seen in an additional 27% of panitumumab-treated patients. No significant improvement was seen in OS, which may have been due to the fact that 76% of patients in the BSC group crossed over to receive panitumumab at the time of disease progression.

KRAS testing was performed retrospectively. In KRAS wild-type patients, the median PFS was 12.3 weeks with panitumumab versus 7.3 weeks for BSC (HR = 0.45; P < 0.0001; Table 1), whereas in KRAS-mutant patients, the median PFS was 7.4 weeks with panitumumab and 7.3 weeks with BSC (HR = 0.99).³² The partial response rate with panitumumab was 17% in KRAS wild-type patients and 0% in KRAS-mutant patients.

Panitumumab has now been tested in phase III trials in both first-line and second-line settings. Peeters et al randomized 1,186 patients with metastatic disease to receive second-line therapy with FOLFIRI with or without panitumumab (Table 1).³³ As part of their first-line regimen, 19% of patients had received bevacizumab, and 67% had received oxaliplatin. After enrollment but prior to data analysis, the PFS and OS endpoints were changed to incorporate stratification for KRAS status. In the KRAS wild-type population, PFS was 5.9 months with the addition of panitumumab and 3.9 months for FOLFIRI alone (HR = 0.73; P = 0.004), and there was a trend toward improvement in OS (14.5 months vs 12.5 months; HR = 0.85; P = 0.12). No benefit was seen in KRAS-mutant patients treated with panitumumab.

In the first-line setting, the PRIME study randomized 1,183 previously untreated patients to receive first-line FOLFOX4 with or without panitumumab (Table 2).³⁴ As in the second-line trial, PFS and OS endpoints of the trial were changed prior to any efficacy analysis to specify KRAS wild-type patients. In this group, the median PFS was improved with panitumumab (9.6 months vs 8.0 months; HR = 0.80; P = 0.02). OS favored the panitumumab group (23.9 months vs 19.7 months), but this was not statistically significant (HR = 0.83; P = 0.07). In the KRAS-mutant patients, the addition of panitumumab was harmful, with de¬creases in PFS and OS compared with FOLFOX4 alone.

With two classes of approved targeted agents in colorectal cancer, there was natural interest in combining these agents. Initial promising data came from the BOND-2 randomized phase II trial, in which 83 patients refractory to irinotecan but naïve to EGFR- and VEGF (vascular endothelial growth factor)–targeted agents were randomized to receive cetuximab-bevacizumab with (CBI) or without (CB) the addition of irinotecan.³⁵ Irinotecan was given at the same dose and schedule at which the patient’s disease had previously progressed. The median TTP in the CBI arm was 7.3 months, whereas it was 4.9 months in the CB arm. The response rates were 37% and 20%, respectively. With a median follow-up of 28 months, the OS for the CBI arm was 14.5 months versus 11.4 months without irinotecan. As with BOND-1, this trial suggested that targeted therapy could restore sensitivity to irinotecan, and the encouraging response rates and survival data prompted phase III study.

In the PACCE trial, the addition of panitumumab to bevacizumab-chemotherapy was studied in 1,053 patients previously untreated for metastatic disease.³⁶ They received either oxaliplatin- or irinotecan-based chemotherapy (investigator choice) and then were randomized to receive additional panitumumab or no additional treatment. Almost 70% of patients received oxaliplatin-based chemotherapy. Despite the promise of BOND-2, the trial was halted early, after an interim analysis revealed increased toxicity and inferior PFS in the panitumumab cohorts. The PFS was 10.5 months in the bevacizumab-oxaliplatin–containing arm and 8.8 months with the further addition of panitumumab (HR = 1.44; P = 0.004). In the irinotecan-based cohorts, a similar decrement was seen with the addition of panitumumab (PFS, 11.9 vs 10.1 months; HR = 1.57). Even when the results were retrospectively analyzed by KRAS status, there was no improvement in outcomes seen in the KRAS wild-type population.

The inferior outcome with the combination of EGFR- and VEGF-directed therapy was confirmed in the phase III CAIRO-2 trial, in which 755 previously untreated patients were randomized to receive capecitabine-oxaliplatin-bevacizumab with or without the addition of cetuximab.³⁷ As with the PACCE study, PFS was the primary endpoint here, and initial results were later retrospectively analyzed according to KRAS status.

In the full study population, the addition of cetuximab was associated with a decrease in PFS from 10.7 to 9.4 months (HR = 1.22; P = 0.01). In the KRAS wild-type population, PFS was almost identical (10.6 months vs 10.5 months), and there was no difference in OS (22.4 months vs 21.8 months; P = 0.64). This result suggested that the lack of benefit for combining targeted agents seen in the PACCE study is not restricted to panitumumab but rather applies to the combination of bevacizumab and EGFR-directed monoclonal antibodies as a class.

The use of EGFR-targeted therapy in the neoadjuvant treatment of advanced colorectal cancer may have the potential to increase the resectability rate in patients with isolated liver metastases. This remains an active area of investigation, but several reports have already been published. In the CRYSTAL trial, first-line addition of cetuximab to FOLFIRI increased the response rate in KRAS wild-type patients (39.7% vs 57.3%), and there was a statistically significant increase in the rate of R0 resection with curative intent (1.7 vs 4.8%; P = 0.002).21

The CELIM trial was a randomized phase II study evaluating FOLFOX6-cetuximab versus FOLFIRI-cetuxi¬mab specifically in a population of patients with unresectable liver-only colorectal metastases.¹³ The primary endpoint was response rate, which was quite good in both groups (68% with FOLFOX6-cetuximab, 57% with FOLFIRI-cetuximab). KRAS status was evaluated retrospectively, and in the wild-type population, the combined response rate was 70% versus only 41% in KRAS-mutant patients, a difference that was highly statistically significant (P = 0.008). In this study of patients deemed initially unresectable, R0 resections were subsequently performed in 34% of patients. The use of EGFR antibodies in the neoadjuvant setting is especially appealing, given the consistently high response rates seen and the fact that the largest phase III trial evaluating bevacizumab with chemotherapy in the front-line setting demonstrated no improvement in response rate.¹⁰

There are a number of ongoing clinical trials that will provide important data to help clinicians choose the optimal targeted regimens for their patients. KRAS wild-type status is now a standard inclusion criterion for ongoing trials.

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.

The CRYSTAL trial provided strong support for the front-line use of cetuximab with FOLFIRI, although recent disappointing results in the COIN and Nordic VII trials have suggested that perhaps there is greater benefit in combining EGFR antibodies with irinotecan than with oxaliplatin. The combination of cetuximab with oxaliplatin-based therapy remains an area of uncertainty, with negative results in the phase III COIN and Nordic VII trials contrasting with very high response rates seen with FOLFOX-cetuximab in the phase II OPUS and CELIM trials.

With the increasing data showing benefit for panitumumab in phase III trials (both in first- and second-line treatment settings), selection of either agent is reasonable. In certain areas where there is a high rate of hypersensitivity reactions to cetuximab, panitumumab may be a preferred agent. There remains no evidence to support the use of panitumumab after cetuximab failure or vice versa.

The CAIRO-2 and PACCE ¬trials failed to validate the hope that a combination of targeted therapies would be additive or synergistic, and this overly toxic strategy has been eliminated from ongoing trials. The use of cetuximab in the neoadjuvant setting continues to be an active area of investigation, given the high response rates that have been reported in KRAS wild-type patients. Finally, a direct comparison of cetuximab versus bevacizumab with chemotherapy in the first-line setting remains a critical question to be addressed by ongoing studies, including CALGB 80405.

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33. Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 2010;28:4706–4713.

34. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010;28:4697–4705.

35. Saltz LB, Lenz HJ, Kindler HL, et al. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol 2007;25:4557–4561.

36. Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 2009;27:672–680.

37. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009;360:563–572.

38. Cancer Trials Support Unit. www.ctsu.org. Accessed April 20, 2011.

39. Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 2009;27:2091–2096.

40. De Roock W, Jonker DJ, Di Nicolantonio F, et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 2010;304:1812–1820.

41. Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008;26:5705–5712.

42. De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 2010;11:753–762.

43. Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol 2009;27:5924–5930.

Affiliations: Drs. Nelson and Jasani are Assistant Professors, Department of General Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Conflicts of interest: The authors have nothing to disclose.

The epidermal growth factor receptor (EGFR) is a transmembrane protein with an extracellular ligand-binding domain and an intracellular ATP-dependent tyrosine kinase domain. Binding of ligand leads to autophosphorylation and activation of the signaling pathway, which regulates cell differentiation, proliferation, migration, protection from apoptosis, and angiogenesis.^1,2 EGFR is either overexpressed or upregulated in a majority of colorectal cancers, and higher degrees of EGFR staining have been correlated with inferior survival in a variety of tumor types.^3–6 Preclinical studies demonstrated the ability of monoclonal antibodies directed against EGFR to inhibit malignant cell proliferation and to act synergistically with chemotherapeutic agents in suppressing tumor cell lines.^7,8 Although early clinical development of anti-EGFR antibody therapy focused on cetuximab (Erbitux), more recent data have also demonstrated similar benefit with panitumumab (Vectibix), and the spectrum of benefit seen in clinical trials has been found in both advanced and refractory patients as well as in previously untreated patients with metastatic disease.

In selecting therapy for a patient with advanced colorectal cancer, clinicians must now choose among several chemotherapeutic agents (fluoropyrimidines, oxaliplatin, and irinotecan) and decide how to integrate targeted agents with chemotherapy. Bevacizumab (Avastin)–containing regimens are well established, with phase III data demonstrating a survival benefit in the first-line setting with irinotecan-based therapy and in the second-line setting with oxaliplatin-based treatment.^9,10 Choosing which EGFR-directed drug to use, which chemotherapy regimen to use as a backbone, and when in the sequence of treatment options to consider EGFR-directed therapy has become more complicated recently based on emerging data.

Cetuximab
Cetuximab is a chimeric IgG1 (immunoglobulin G1) monoclonal antibody that binds to EGFR with high specificity and affinity.⁷ It was initially approved by the US Food and Drug Administration (FDA) in February 2004 based on response rate data in combination with irinotecan for irinotecan-refractory patients. Although originally used only in patients with EGFR-expressing tumors, a number of studies have since suggested that response is independent of EGFR staining, and this is no longer used as a selection criterion for EGFR-directed therapy.^11–13 Rather than EGFR expression, it is KRAS mutation status that has emerged as the most important predictor for lack of benefit from anti-EGFR therapy. Multiple trials demonstrate either no benefit or inferior outcomes with the addition of EGFR-directed therapy in the approximately 40% of advanced colorectal cancer patients with activating KRAS mutations.

In an early phase II trial, cetuximab, given as a single agent to irinotecan-refractory patients, produced a partial response rate of 9%.¹⁴ The pivotal BOND-1 trial randomized 329 patients whose disease had progressed after an irinotecan-based regimen to receive both cetuximab and irinotecan or cetuximab as monotherapy (Table 1).¹⁵ The response rate in the combination-therapy group was significantly higher (22.9% vs 10.8%; P = 0.007), and the median time to disease progression (TTP) was significantly greater in the combination-therapy group (4.1 months vs 1.5 months; P < 0.001). There was no difference in median survival (8.6 months vs 6.9 months; P = 0.48), although crossover from monotherapy to combination therapy was permitted. The ability of cetuximab to restore sensitivity to treatment with irinotecan was seen regardless of whether patients had been pretreated with oxaliplatin or not.

The CO.17 trial randomized 572 patients with metastatic disease previously treated with a fluoropyrimidine, irinotecan, and oxaliplatin to receive treatment with single-agent cetuximab versus best supportive care (Table 1).¹⁶ It was completed prior to knowledge regarding the predictive effects of KRAS status, and the primary endpoint was overall survival (OS). Treatment with cetuximab was associated with improvement in response rate, progression-free survival (PFS), and OS (from 4.6 months to 6.1 months; hazard ratio [HR] for death 0.77; P = 0.005). In a retrospective analysis, cetuximab therapy in KRAS wild-type tumors doubled PFS from 1.9 months to 3.7 months (HR = 0.40; P < 0.0001), whereas there was no effect of cetuximab in the KRAS-mutant group (Table 1).¹⁷

Given the popularity of using oxaliplatin in front-line therapy for metastatic colorectal cancer, there was interest in demonstrating a role for cetuximab with irinotecan in second-line treatment, after failure of oxaliplatin. The EPIC trial randomized patients in this setting to receive irinotecan with or without cetuximab, with OS as the primary endpoint (Table 1).¹⁸ Although there was a trend favoring the addition of cetuximab, OS was not improved (median survival, 10.7 months with cetuximab-irinotecan vs 10.0 months with irinotecan; HR = 0.975), perhaps confounded by the fact that almost half of the irinotecan-alone patients continued on to receive cetuximab later. Combination therapy did increase the response rate from 4% to 16% (P < 0.0001) and increased PFS from 2.6 months to 4.0 months (HR = 0.692; P < 0.0001).

After demonstration of activity later in the disease course, investigators evaluated cetuximab in front-line treatment of advanced colorectal cancer and in combination with oxaliplatin. Unlike the consistently positive data in the salvage setting, the data in front-line therapy have been mixed. Tabernero et al conducted a phase II trial of FOLFOX4 (folinic acid, 5-fluorouracil [5-FU], oxaliplatin) with cetuximab as initial therapy in 43 patients, which yielded a confirmed response rate of 72%, a PFS of 12.3 months, and an OS of 30.0 months.¹⁹ Ten patients (23%) whose metastases were initially assessed as inoperable were rendered resectable by treatment.

In the OPUS randomized phase II study, FOLFOX4 versus FOLFOX4 plus cetuximab was tested in first-line therapy (Table 2).²⁰ The primary endpoint was confirmed response rate, which was unchanged in the overall population. However, KRAS status was assessed retrospectively in 233 patients, and the response rate increased from 37% to 61% (P = 0.011) with the addition of cetuximab in KRAS wild-type patients; PFS increased from 7.2 months to 7.7 months (HR = 0.57; P = 0.016) in this group. In the KRAS-mutant group, the addition of cetuximab appeared to have a detrimental effect, with a decrease in PFS from 8.6 months to 5.5 months (HR = 1.83; P = 0.019).

The CRYSTAL trial evaluated the addition of cetuximab to FOLFIRI (folinic acid, 5-FU, irinotecan) in a large phase III trial in first-line treatment of metastatic disease (Table 2).²¹ The primary endpoint was PFS, which was prolonged in the primary analysis population from 8.0 months to 8.9 months (P = 0.048). At the 2010 meeting of the American Society of Clinical Oncology (ASCO), an updated analysis was presented according to KRAS status.²² KRAS status was determined retrospectively in 1,063 of 1,198 patients, and 37% had KRAS mutations. In the KRAS wild-type population, the response rate increased from 39.7% with FOLFIRI to 57.3% with FOLFIRI-cetuximab, PFS increased from 8.4 months to 9.9 months (HR = 0.70; P = 0.001), and OS increased from 20.0 months to 23.5 months (HR = 0.796; P = 0.009). A pooled analysis of CRYSTAL and OPUS patients was also presented at the 2010 ASCO meeting.23 In the KRAS wild-type population, the addition of cetuximab to front-line chemotherapy increased the response rate from 38% to 57% (P < 0.0001), the median PFS from 7.6 months to 9.6 months (HR = 0.66; P < 0.0001), and the median OS from 19.5 months to 23.5 months (HR = 0.81; P = 0.006).

In contrast to these positive findings, several recent trials incorporating cetuximab into initial therapy have failed to show a benefit, even in KRAS wild-type patients. The COIN trial studied 1,630 patients in first-line treatment, testing the benefit of adding cetuximab to oxaliplatin with either infusional 5-FU or capecita¬bine (Xeloda), at the treating physician’s discretion (Table 2).²⁴ The trial was initiated prior to the emergence of data regarding the predictive value of KRAS mutation status, and patients were not selected for inclusion on this basis. After the trial completed accrual but prior to any data analysis, the primary endpoint was changed to examine OS only in patients without a KRAS mutation (43% of patients had KRAS mutations).

The response rate was increased modestly in the KRAS wild-type group by the addition of cetuximab, from 57% to 64% (P = 0.05). However, this did not translate into an improvement in survival, with a median survival of 17.9 months without cetuximab and 17.0 months with cetuximab (HR = 1.04; P = 0.68). There was also no prolongation of PFS in the KRAS wild-type patients, with PFS of 8.6 months in both arms (HR = 0.96; P = 0.60). The reason for the discrepant results of this study compared with other studies demonstrating a strong survival benefit for KRAS wild-type patients with cetuximab is unclear. Retrospective subgroup analysis suggested that perhaps benefit was seen with cetuximab when added to infusional 5-FU (FOLFOX) but not when added to capecitabine-based treatment (CAPOX).

A second negative trial recently reported at the 2010 ESMO (European Society for Medical Oncology) meeting was the Nordic VII trial, in which 571 patients were randomized to one of three bolus 5-FU–based arms: FLOX, FLOX with cetuximab until disease progression, or FLOX with cetuximab for 16 weeks and then maintenance cetuximab alone with reintroduction of FLOX at disease progression (Table 2).²⁵ The FLOX regimen consisted of a 5-FU IV bolus (500 mg/m2) plus folinic acid (60 mg/m2) on days 1–2 every 2 weeks and oxaliplatin (85 mg/m2) on day 1. Cetuximab was given at the standard dosage of 400 mg/m2 initially and then 250 mg/m2 weekly.

The primary endpoint was PFS, which was not significantly different among the three arms: 7.9 months versus 8.3 months versus 7.3 months with FLOX, FLOX-cetuximab, and “stop/go” FLOX-cetuximab, respectively. Overall response rates were also not significantly different between the three arms (41% vs 49% vs 47%), and OS was similarly unchanged in the three groups (20.4 months vs 19.7 months vs 20.3 months). In the 60% of patients without KRAS mutations, there was still no significant benefit seen for the addition of cetuximab: in comparing arm A (FLOX alone) versus arm B (FLOX + cetuximab), the response rate was 47% versus 46%, PFS was 8.7 versus 7.9 months (P = 0.66), and OS was 22.0 months versus 20.1 months (P = 0.66). Given that this trial used an unconventional chemotherapy regimen, the reason for the failure of the study to produce positive results is unclear.

Panitumumab
Panitumumab is a fully human IgG2 EGFR monoclonal antibody. Like cetuximab, it targets the extracellular domain of the EGFR and blocks downstream signaling, leading to antitumor effects.²⁶ Because it is fully humanized, panitumumab does not have the same risk of hypersensitivity reactions seen with the chimeric antibody cetuximab. This may be especially important in some areas of the southeastern United States, where reactions to cetuximab occur at a higher frequency than has been reported in clinical trials.²⁷ Panitumumab was approved for monotherapy of relapsed/refractory metastatic colorectal cancer by the FDA in September 2006. As with cetuximab, its use is now specified to tumors harboring wild-type KRAS.

Initial phase I data in patients with metastatic colorectal cancer treated with panitumumab showed a 13% response rate.²⁸ In phase II studies in relapsed and refractory metastatic disease, panitumumab (6 mg/kg every 2 weeks or 2.5 mg/kg every week) showed activity, with objective responses in 3%–13% and stable disease in 21%–33% of patients with EGFR immunostaining. ^12,29,30

A large randomized phase III study was conducted in 463 patients whose disease had progressed after prior therapies including 5-FU, irinotecan, and oxaliplatin (Table 1).³¹ Patients were randomized to receive either panitumumab (6 mg/kg every 2 weeks) and best supportive care (BSC) or BSC alone, and crossover was allowed from the control arm to panitumumab upon disease progression. The primary endpoint was PFS, which was 8 weeks for the panitumumab-treated patients versus 7.3 weeks in the BSC-alone group (HR = 0.54; P < 0.001). Similar to the phase II data, partial responses were seen in 10% of patients receiving panitumumab (versus none in the control group), and stable disease was seen in an additional 27% of panitumumab-treated patients. No significant improvement was seen in OS, which may have been due to the fact that 76% of patients in the BSC group crossed over to receive panitumumab at the time of disease progression.

KRAS testing was performed retrospectively. In KRAS wild-type patients, the median PFS was 12.3 weeks with panitumumab versus 7.3 weeks for BSC (HR = 0.45; P < 0.0001; Table 1), whereas in KRAS-mutant patients, the median PFS was 7.4 weeks with panitumumab and 7.3 weeks with BSC (HR = 0.99).³² The partial response rate with panitumumab was 17% in KRAS wild-type patients and 0% in KRAS-mutant patients.

Panitumumab has now been tested in phase III trials in both first-line and second-line settings. Peeters et al randomized 1,186 patients with metastatic disease to receive second-line therapy with FOLFIRI with or without panitumumab (Table 1).³³ As part of their first-line regimen, 19% of patients had received bevacizumab, and 67% had received oxaliplatin. After enrollment but prior to data analysis, the PFS and OS endpoints were changed to incorporate stratification for KRAS status. In the KRAS wild-type population, PFS was 5.9 months with the addition of panitumumab and 3.9 months for FOLFIRI alone (HR = 0.73; P = 0.004), and there was a trend toward improvement in OS (14.5 months vs 12.5 months; HR = 0.85; P = 0.12). No benefit was seen in KRAS-mutant patients treated with panitumumab.

In the first-line setting, the PRIME study randomized 1,183 previously untreated patients to receive first-line FOLFOX4 with or without panitumumab (Table 2).³⁴ As in the second-line trial, PFS and OS endpoints of the trial were changed prior to any efficacy analysis to specify KRAS wild-type patients. In this group, the median PFS was improved with panitumumab (9.6 months vs 8.0 months; HR = 0.80; P = 0.02). OS favored the panitumumab group (23.9 months vs 19.7 months), but this was not statistically significant (HR = 0.83; P = 0.07). In the KRAS-mutant patients, the addition of panitumumab was harmful, with de¬creases in PFS and OS compared with FOLFOX4 alone.

With two classes of approved targeted agents in colorectal cancer, there was natural interest in combining these agents. Initial promising data came from the BOND-2 randomized phase II trial, in which 83 patients refractory to irinotecan but naïve to EGFR- and VEGF (vascular endothelial growth factor)–targeted agents were randomized to receive cetuximab-bevacizumab with (CBI) or without (CB) the addition of irinotecan.³⁵ Irinotecan was given at the same dose and schedule at which the patient’s disease had previously progressed. The median TTP in the CBI arm was 7.3 months, whereas it was 4.9 months in the CB arm. The response rates were 37% and 20%, respectively. With a median follow-up of 28 months, the OS for the CBI arm was 14.5 months versus 11.4 months without irinotecan. As with BOND-1, this trial suggested that targeted therapy could restore sensitivity to irinotecan, and the encouraging response rates and survival data prompted phase III study.

In the PACCE trial, the addition of panitumumab to bevacizumab-chemotherapy was studied in 1,053 patients previously untreated for metastatic disease.³⁶ They received either oxaliplatin- or irinotecan-based chemotherapy (investigator choice) and then were randomized to receive additional panitumumab or no additional treatment. Almost 70% of patients received oxaliplatin-based chemotherapy. Despite the promise of BOND-2, the trial was halted early, after an interim analysis revealed increased toxicity and inferior PFS in the panitumumab cohorts. The PFS was 10.5 months in the bevacizumab-oxaliplatin–containing arm and 8.8 months with the further addition of panitumumab (HR = 1.44; P = 0.004). In the irinotecan-based cohorts, a similar decrement was seen with the addition of panitumumab (PFS, 11.9 vs 10.1 months; HR = 1.57). Even when the results were retrospectively analyzed by KRAS status, there was no improvement in outcomes seen in the KRAS wild-type population.

The inferior outcome with the combination of EGFR- and VEGF-directed therapy was confirmed in the phase III CAIRO-2 trial, in which 755 previously untreated patients were randomized to receive capecitabine-oxaliplatin-bevacizumab with or without the addition of cetuximab.³⁷ As with the PACCE study, PFS was the primary endpoint here, and initial results were later retrospectively analyzed according to KRAS status.

In the full study population, the addition of cetuximab was associated with a decrease in PFS from 10.7 to 9.4 months (HR = 1.22; P = 0.01). In the KRAS wild-type population, PFS was almost identical (10.6 months vs 10.5 months), and there was no difference in OS (22.4 months vs 21.8 months; P = 0.64). This result suggested that the lack of benefit for combining targeted agents seen in the PACCE study is not restricted to panitumumab but rather applies to the combination of bevacizumab and EGFR-directed monoclonal antibodies as a class.

The use of EGFR-targeted therapy in the neoadjuvant treatment of advanced colorectal cancer may have the potential to increase the resectability rate in patients with isolated liver metastases. This remains an active area of investigation, but several reports have already been published. In the CRYSTAL trial, first-line addition of cetuximab to FOLFIRI increased the response rate in KRAS wild-type patients (39.7% vs 57.3%), and there was a statistically significant increase in the rate of R0 resection with curative intent (1.7 vs 4.8%; P = 0.002).21

The CELIM trial was a randomized phase II study evaluating FOLFOX6-cetuximab versus FOLFIRI-cetuxi¬mab specifically in a population of patients with unresectable liver-only colorectal metastases.¹³ The primary endpoint was response rate, which was quite good in both groups (68% with FOLFOX6-cetuximab, 57% with FOLFIRI-cetuximab). KRAS status was evaluated retrospectively, and in the wild-type population, the combined response rate was 70% versus only 41% in KRAS-mutant patients, a difference that was highly statistically significant (P = 0.008). In this study of patients deemed initially unresectable, R0 resections were subsequently performed in 34% of patients. The use of EGFR antibodies in the neoadjuvant setting is especially appealing, given the consistently high response rates seen and the fact that the largest phase III trial evaluating bevacizumab with chemotherapy in the front-line setting demonstrated no improvement in response rate.¹⁰

There are a number of ongoing clinical trials that will provide important data to help clinicians choose the optimal targeted regimens for their patients. KRAS wild-type status is now a standard inclusion criterion for ongoing trials.

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.

The CRYSTAL trial provided strong support for the front-line use of cetuximab with FOLFIRI, although recent disappointing results in the COIN and Nordic VII trials have suggested that perhaps there is greater benefit in combining EGFR antibodies with irinotecan than with oxaliplatin. The combination of cetuximab with oxaliplatin-based therapy remains an area of uncertainty, with negative results in the phase III COIN and Nordic VII trials contrasting with very high response rates seen with FOLFOX-cetuximab in the phase II OPUS and CELIM trials.

With the increasing data showing benefit for panitumumab in phase III trials (both in first- and second-line treatment settings), selection of either agent is reasonable. In certain areas where there is a high rate of hypersensitivity reactions to cetuximab, panitumumab may be a preferred agent. There remains no evidence to support the use of panitumumab after cetuximab failure or vice versa.

The CAIRO-2 and PACCE ¬trials failed to validate the hope that a combination of targeted therapies would be additive or synergistic, and this overly toxic strategy has been eliminated from ongoing trials. The use of cetuximab in the neoadjuvant setting continues to be an active area of investigation, given the high response rates that have been reported in KRAS wild-type patients. Finally, a direct comparison of cetuximab versus bevacizumab with chemotherapy in the first-line setting remains a critical question to be addressed by ongoing studies, including CALGB 80405.

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22. Van Cutsem E, Lang I, Folprecht G, et al. Cetuximab plus FOLFIRI: final data from the CRYSTAL study on the association of KRAS and BRAF biomarker status with treatment outcome. J Clin Oncol 2010;28[15S]:3570.

23. Bokemeyer C, Kohne C, Rougier P, et al. Cetuximab with chemotherapy (CT) as first-line treatment for metastatic colorectal cancer (mCRC): analysis of the CRYSTAL and OPUS studies according to KRAS and BRAF mutation status. J Clin Oncol 2010;28[15S]:3506.

24. Maughan TS, Adams R, Smith CG, et al. Identification of potentially responsive subsets when cetuximab is added to oxaliplatin-fluoropyrimidine chemotherapy (CT) in first-line advanced colorectal cancer (aCRC): mature results of the MRC COIN trial. J Clin Oncol 2010;28[15S]:3502.

25. Tveit K, Guren T, Glimelius B, et al. Randomized phase III study of 5-fluorouracil/folinate/oxaliplatin given continuously or intermittently with or without cetuximab, as first-line treatment of metastatic colorectal cancer: the Nordic VII study (NCT00145314), by The Nordic Colorectal Cancer Biomodulation Group. Ann Oncol 2010;21(suppl 8):viii9. Abstract LBA20.

26. Yang XD, Jia XC, Corvalan JR, Wang P, Davis CG. Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hematol 2001;38:17–23.

27. O’Neil BH, Allen R, Spigel DR, et al. High incidence of cetuximab-related infusion reactions in Tennessee and North Carolina and the association with atopic history. J Clin Oncol 2007;25:3644–3648.

28. Weiner LM, Belldegrun AS, Crawford J, et al. Dose and schedule study of panitumumab monotherapy in patients with advanced solid malignancies. Clin Cancer Res 2008;14:502–508.

29. Hecht JR, Patnaik A, Berlin J, et al. Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer 2007;110:980–988.

30. Muro K, Yoshino T, Doi T, et al. A phase 2 clinical trial of panitumumab monotherapy in Japanese patients with metastatic colorectal cancer. Jpn J Clin Oncol 2009;39:321–326.

31. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007;25:1658–1664.

32. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:1626–1634.

33. Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 2010;28:4706–4713.

34. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010;28:4697–4705.

35. Saltz LB, Lenz HJ, Kindler HL, et al. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol 2007;25:4557–4561.

36. Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 2009;27:672–680.

37. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009;360:563–572.

38. Cancer Trials Support Unit. www.ctsu.org. Accessed April 20, 2011.

39. Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 2009;27:2091–2096.

40. De Roock W, Jonker DJ, Di Nicolantonio F, et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 2010;304:1812–1820.

41. Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008;26:5705–5712.

42. De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 2010;11:753–762.

43. Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol 2009;27:5924–5930.

Affiliations: Drs. Nelson and Jasani are Assistant Professors, Department of General Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Conflicts of interest: The authors have nothing to disclose.

The epidermal growth factor receptor (EGFR) is a transmembrane protein with an extracellular ligand-binding domain and an intracellular ATP-dependent tyrosine kinase domain. Binding of ligand leads to autophosphorylation and activation of the signaling pathway, which regulates cell differentiation, proliferation, migration, protection from apoptosis, and angiogenesis.^1,2 EGFR is either overexpressed or upregulated in a majority of colorectal cancers, and higher degrees of EGFR staining have been correlated with inferior survival in a variety of tumor types.^3–6 Preclinical studies demonstrated the ability of monoclonal antibodies directed against EGFR to inhibit malignant cell proliferation and to act synergistically with chemotherapeutic agents in suppressing tumor cell lines.^7,8 Although early clinical development of anti-EGFR antibody therapy focused on cetuximab (Erbitux), more recent data have also demonstrated similar benefit with panitumumab (Vectibix), and the spectrum of benefit seen in clinical trials has been found in both advanced and refractory patients as well as in previously untreated patients with metastatic disease.

In selecting therapy for a patient with advanced colorectal cancer, clinicians must now choose among several chemotherapeutic agents (fluoropyrimidines, oxaliplatin, and irinotecan) and decide how to integrate targeted agents with chemotherapy. Bevacizumab (Avastin)–containing regimens are well established, with phase III data demonstrating a survival benefit in the first-line setting with irinotecan-based therapy and in the second-line setting with oxaliplatin-based treatment.^9,10 Choosing which EGFR-directed drug to use, which chemotherapy regimen to use as a backbone, and when in the sequence of treatment options to consider EGFR-directed therapy has become more complicated recently based on emerging data.

Cetuximab
Cetuximab is a chimeric IgG1 (immunoglobulin G1) monoclonal antibody that binds to EGFR with high specificity and affinity.⁷ It was initially approved by the US Food and Drug Administration (FDA) in February 2004 based on response rate data in combination with irinotecan for irinotecan-refractory patients. Although originally used only in patients with EGFR-expressing tumors, a number of studies have since suggested that response is independent of EGFR staining, and this is no longer used as a selection criterion for EGFR-directed therapy.^11–13 Rather than EGFR expression, it is KRAS mutation status that has emerged as the most important predictor for lack of benefit from anti-EGFR therapy. Multiple trials demonstrate either no benefit or inferior outcomes with the addition of EGFR-directed therapy in the approximately 40% of advanced colorectal cancer patients with activating KRAS mutations.

In an early phase II trial, cetuximab, given as a single agent to irinotecan-refractory patients, produced a partial response rate of 9%.¹⁴ The pivotal BOND-1 trial randomized 329 patients whose disease had progressed after an irinotecan-based regimen to receive both cetuximab and irinotecan or cetuximab as monotherapy (Table 1).¹⁵ The response rate in the combination-therapy group was significantly higher (22.9% vs 10.8%; P = 0.007), and the median time to disease progression (TTP) was significantly greater in the combination-therapy group (4.1 months vs 1.5 months; P < 0.001). There was no difference in median survival (8.6 months vs 6.9 months; P = 0.48), although crossover from monotherapy to combination therapy was permitted. The ability of cetuximab to restore sensitivity to treatment with irinotecan was seen regardless of whether patients had been pretreated with oxaliplatin or not.

The CO.17 trial randomized 572 patients with metastatic disease previously treated with a fluoropyrimidine, irinotecan, and oxaliplatin to receive treatment with single-agent cetuximab versus best supportive care (Table 1).¹⁶ It was completed prior to knowledge regarding the predictive effects of KRAS status, and the primary endpoint was overall survival (OS). Treatment with cetuximab was associated with improvement in response rate, progression-free survival (PFS), and OS (from 4.6 months to 6.1 months; hazard ratio [HR] for death 0.77; P = 0.005). In a retrospective analysis, cetuximab therapy in KRAS wild-type tumors doubled PFS from 1.9 months to 3.7 months (HR = 0.40; P < 0.0001), whereas there was no effect of cetuximab in the KRAS-mutant group (Table 1).¹⁷

Given the popularity of using oxaliplatin in front-line therapy for metastatic colorectal cancer, there was interest in demonstrating a role for cetuximab with irinotecan in second-line treatment, after failure of oxaliplatin. The EPIC trial randomized patients in this setting to receive irinotecan with or without cetuximab, with OS as the primary endpoint (Table 1).¹⁸ Although there was a trend favoring the addition of cetuximab, OS was not improved (median survival, 10.7 months with cetuximab-irinotecan vs 10.0 months with irinotecan; HR = 0.975), perhaps confounded by the fact that almost half of the irinotecan-alone patients continued on to receive cetuximab later. Combination therapy did increase the response rate from 4% to 16% (P < 0.0001) and increased PFS from 2.6 months to 4.0 months (HR = 0.692; P < 0.0001).

After demonstration of activity later in the disease course, investigators evaluated cetuximab in front-line treatment of advanced colorectal cancer and in combination with oxaliplatin. Unlike the consistently positive data in the salvage setting, the data in front-line therapy have been mixed. Tabernero et al conducted a phase II trial of FOLFOX4 (folinic acid, 5-fluorouracil [5-FU], oxaliplatin) with cetuximab as initial therapy in 43 patients, which yielded a confirmed response rate of 72%, a PFS of 12.3 months, and an OS of 30.0 months.¹⁹ Ten patients (23%) whose metastases were initially assessed as inoperable were rendered resectable by treatment.

In the OPUS randomized phase II study, FOLFOX4 versus FOLFOX4 plus cetuximab was tested in first-line therapy (Table 2).²⁰ The primary endpoint was confirmed response rate, which was unchanged in the overall population. However, KRAS status was assessed retrospectively in 233 patients, and the response rate increased from 37% to 61% (P = 0.011) with the addition of cetuximab in KRAS wild-type patients; PFS increased from 7.2 months to 7.7 months (HR = 0.57; P = 0.016) in this group. In the KRAS-mutant group, the addition of cetuximab appeared to have a detrimental effect, with a decrease in PFS from 8.6 months to 5.5 months (HR = 1.83; P = 0.019).

The CRYSTAL trial evaluated the addition of cetuximab to FOLFIRI (folinic acid, 5-FU, irinotecan) in a large phase III trial in first-line treatment of metastatic disease (Table 2).²¹ The primary endpoint was PFS, which was prolonged in the primary analysis population from 8.0 months to 8.9 months (P = 0.048). At the 2010 meeting of the American Society of Clinical Oncology (ASCO), an updated analysis was presented according to KRAS status.²² KRAS status was determined retrospectively in 1,063 of 1,198 patients, and 37% had KRAS mutations. In the KRAS wild-type population, the response rate increased from 39.7% with FOLFIRI to 57.3% with FOLFIRI-cetuximab, PFS increased from 8.4 months to 9.9 months (HR = 0.70; P = 0.001), and OS increased from 20.0 months to 23.5 months (HR = 0.796; P = 0.009). A pooled analysis of CRYSTAL and OPUS patients was also presented at the 2010 ASCO meeting.23 In the KRAS wild-type population, the addition of cetuximab to front-line chemotherapy increased the response rate from 38% to 57% (P < 0.0001), the median PFS from 7.6 months to 9.6 months (HR = 0.66; P < 0.0001), and the median OS from 19.5 months to 23.5 months (HR = 0.81; P = 0.006).

In contrast to these positive findings, several recent trials incorporating cetuximab into initial therapy have failed to show a benefit, even in KRAS wild-type patients. The COIN trial studied 1,630 patients in first-line treatment, testing the benefit of adding cetuximab to oxaliplatin with either infusional 5-FU or capecita¬bine (Xeloda), at the treating physician’s discretion (Table 2).²⁴ The trial was initiated prior to the emergence of data regarding the predictive value of KRAS mutation status, and patients were not selected for inclusion on this basis. After the trial completed accrual but prior to any data analysis, the primary endpoint was changed to examine OS only in patients without a KRAS mutation (43% of patients had KRAS mutations).

The response rate was increased modestly in the KRAS wild-type group by the addition of cetuximab, from 57% to 64% (P = 0.05). However, this did not translate into an improvement in survival, with a median survival of 17.9 months without cetuximab and 17.0 months with cetuximab (HR = 1.04; P = 0.68). There was also no prolongation of PFS in the KRAS wild-type patients, with PFS of 8.6 months in both arms (HR = 0.96; P = 0.60). The reason for the discrepant results of this study compared with other studies demonstrating a strong survival benefit for KRAS wild-type patients with cetuximab is unclear. Retrospective subgroup analysis suggested that perhaps benefit was seen with cetuximab when added to infusional 5-FU (FOLFOX) but not when added to capecitabine-based treatment (CAPOX).

A second negative trial recently reported at the 2010 ESMO (European Society for Medical Oncology) meeting was the Nordic VII trial, in which 571 patients were randomized to one of three bolus 5-FU–based arms: FLOX, FLOX with cetuximab until disease progression, or FLOX with cetuximab for 16 weeks and then maintenance cetuximab alone with reintroduction of FLOX at disease progression (Table 2).²⁵ The FLOX regimen consisted of a 5-FU IV bolus (500 mg/m2) plus folinic acid (60 mg/m2) on days 1–2 every 2 weeks and oxaliplatin (85 mg/m2) on day 1. Cetuximab was given at the standard dosage of 400 mg/m2 initially and then 250 mg/m2 weekly.

The primary endpoint was PFS, which was not significantly different among the three arms: 7.9 months versus 8.3 months versus 7.3 months with FLOX, FLOX-cetuximab, and “stop/go” FLOX-cetuximab, respectively. Overall response rates were also not significantly different between the three arms (41% vs 49% vs 47%), and OS was similarly unchanged in the three groups (20.4 months vs 19.7 months vs 20.3 months). In the 60% of patients without KRAS mutations, there was still no significant benefit seen for the addition of cetuximab: in comparing arm A (FLOX alone) versus arm B (FLOX + cetuximab), the response rate was 47% versus 46%, PFS was 8.7 versus 7.9 months (P = 0.66), and OS was 22.0 months versus 20.1 months (P = 0.66). Given that this trial used an unconventional chemotherapy regimen, the reason for the failure of the study to produce positive results is unclear.

Panitumumab
Panitumumab is a fully human IgG2 EGFR monoclonal antibody. Like cetuximab, it targets the extracellular domain of the EGFR and blocks downstream signaling, leading to antitumor effects.²⁶ Because it is fully humanized, panitumumab does not have the same risk of hypersensitivity reactions seen with the chimeric antibody cetuximab. This may be especially important in some areas of the southeastern United States, where reactions to cetuximab occur at a higher frequency than has been reported in clinical trials.²⁷ Panitumumab was approved for monotherapy of relapsed/refractory metastatic colorectal cancer by the FDA in September 2006. As with cetuximab, its use is now specified to tumors harboring wild-type KRAS.

Initial phase I data in patients with metastatic colorectal cancer treated with panitumumab showed a 13% response rate.²⁸ In phase II studies in relapsed and refractory metastatic disease, panitumumab (6 mg/kg every 2 weeks or 2.5 mg/kg every week) showed activity, with objective responses in 3%–13% and stable disease in 21%–33% of patients with EGFR immunostaining. ^12,29,30

A large randomized phase III study was conducted in 463 patients whose disease had progressed after prior therapies including 5-FU, irinotecan, and oxaliplatin (Table 1).³¹ Patients were randomized to receive either panitumumab (6 mg/kg every 2 weeks) and best supportive care (BSC) or BSC alone, and crossover was allowed from the control arm to panitumumab upon disease progression. The primary endpoint was PFS, which was 8 weeks for the panitumumab-treated patients versus 7.3 weeks in the BSC-alone group (HR = 0.54; P < 0.001). Similar to the phase II data, partial responses were seen in 10% of patients receiving panitumumab (versus none in the control group), and stable disease was seen in an additional 27% of panitumumab-treated patients. No significant improvement was seen in OS, which may have been due to the fact that 76% of patients in the BSC group crossed over to receive panitumumab at the time of disease progression.

KRAS testing was performed retrospectively. In KRAS wild-type patients, the median PFS was 12.3 weeks with panitumumab versus 7.3 weeks for BSC (HR = 0.45; P < 0.0001; Table 1), whereas in KRAS-mutant patients, the median PFS was 7.4 weeks with panitumumab and 7.3 weeks with BSC (HR = 0.99).³² The partial response rate with panitumumab was 17% in KRAS wild-type patients and 0% in KRAS-mutant patients.

Panitumumab has now been tested in phase III trials in both first-line and second-line settings. Peeters et al randomized 1,186 patients with metastatic disease to receive second-line therapy with FOLFIRI with or without panitumumab (Table 1).³³ As part of their first-line regimen, 19% of patients had received bevacizumab, and 67% had received oxaliplatin. After enrollment but prior to data analysis, the PFS and OS endpoints were changed to incorporate stratification for KRAS status. In the KRAS wild-type population, PFS was 5.9 months with the addition of panitumumab and 3.9 months for FOLFIRI alone (HR = 0.73; P = 0.004), and there was a trend toward improvement in OS (14.5 months vs 12.5 months; HR = 0.85; P = 0.12). No benefit was seen in KRAS-mutant patients treated with panitumumab.

In the first-line setting, the PRIME study randomized 1,183 previously untreated patients to receive first-line FOLFOX4 with or without panitumumab (Table 2).³⁴ As in the second-line trial, PFS and OS endpoints of the trial were changed prior to any efficacy analysis to specify KRAS wild-type patients. In this group, the median PFS was improved with panitumumab (9.6 months vs 8.0 months; HR = 0.80; P = 0.02). OS favored the panitumumab group (23.9 months vs 19.7 months), but this was not statistically significant (HR = 0.83; P = 0.07). In the KRAS-mutant patients, the addition of panitumumab was harmful, with de¬creases in PFS and OS compared with FOLFOX4 alone.

With two classes of approved targeted agents in colorectal cancer, there was natural interest in combining these agents. Initial promising data came from the BOND-2 randomized phase II trial, in which 83 patients refractory to irinotecan but naïve to EGFR- and VEGF (vascular endothelial growth factor)–targeted agents were randomized to receive cetuximab-bevacizumab with (CBI) or without (CB) the addition of irinotecan.³⁵ Irinotecan was given at the same dose and schedule at which the patient’s disease had previously progressed. The median TTP in the CBI arm was 7.3 months, whereas it was 4.9 months in the CB arm. The response rates were 37% and 20%, respectively. With a median follow-up of 28 months, the OS for the CBI arm was 14.5 months versus 11.4 months without irinotecan. As with BOND-1, this trial suggested that targeted therapy could restore sensitivity to irinotecan, and the encouraging response rates and survival data prompted phase III study.

In the PACCE trial, the addition of panitumumab to bevacizumab-chemotherapy was studied in 1,053 patients previously untreated for metastatic disease.³⁶ They received either oxaliplatin- or irinotecan-based chemotherapy (investigator choice) and then were randomized to receive additional panitumumab or no additional treatment. Almost 70% of patients received oxaliplatin-based chemotherapy. Despite the promise of BOND-2, the trial was halted early, after an interim analysis revealed increased toxicity and inferior PFS in the panitumumab cohorts. The PFS was 10.5 months in the bevacizumab-oxaliplatin–containing arm and 8.8 months with the further addition of panitumumab (HR = 1.44; P = 0.004). In the irinotecan-based cohorts, a similar decrement was seen with the addition of panitumumab (PFS, 11.9 vs 10.1 months; HR = 1.57). Even when the results were retrospectively analyzed by KRAS status, there was no improvement in outcomes seen in the KRAS wild-type population.

The inferior outcome with the combination of EGFR- and VEGF-directed therapy was confirmed in the phase III CAIRO-2 trial, in which 755 previously untreated patients were randomized to receive capecitabine-oxaliplatin-bevacizumab with or without the addition of cetuximab.³⁷ As with the PACCE study, PFS was the primary endpoint here, and initial results were later retrospectively analyzed according to KRAS status.

In the full study population, the addition of cetuximab was associated with a decrease in PFS from 10.7 to 9.4 months (HR = 1.22; P = 0.01). In the KRAS wild-type population, PFS was almost identical (10.6 months vs 10.5 months), and there was no difference in OS (22.4 months vs 21.8 months; P = 0.64). This result suggested that the lack of benefit for combining targeted agents seen in the PACCE study is not restricted to panitumumab but rather applies to the combination of bevacizumab and EGFR-directed monoclonal antibodies as a class.

The use of EGFR-targeted therapy in the neoadjuvant treatment of advanced colorectal cancer may have the potential to increase the resectability rate in patients with isolated liver metastases. This remains an active area of investigation, but several reports have already been published. In the CRYSTAL trial, first-line addition of cetuximab to FOLFIRI increased the response rate in KRAS wild-type patients (39.7% vs 57.3%), and there was a statistically significant increase in the rate of R0 resection with curative intent (1.7 vs 4.8%; P = 0.002).21

The CELIM trial was a randomized phase II study evaluating FOLFOX6-cetuximab versus FOLFIRI-cetuxi¬mab specifically in a population of patients with unresectable liver-only colorectal metastases.¹³ The primary endpoint was response rate, which was quite good in both groups (68% with FOLFOX6-cetuximab, 57% with FOLFIRI-cetuximab). KRAS status was evaluated retrospectively, and in the wild-type population, the combined response rate was 70% versus only 41% in KRAS-mutant patients, a difference that was highly statistically significant (P = 0.008). In this study of patients deemed initially unresectable, R0 resections were subsequently performed in 34% of patients. The use of EGFR antibodies in the neoadjuvant setting is especially appealing, given the consistently high response rates seen and the fact that the largest phase III trial evaluating bevacizumab with chemotherapy in the front-line setting demonstrated no improvement in response rate.¹⁰

There are a number of ongoing clinical trials that will provide important data to help clinicians choose the optimal targeted regimens for their patients. KRAS wild-type status is now a standard inclusion criterion for ongoing trials.

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.

The CRYSTAL trial provided strong support for the front-line use of cetuximab with FOLFIRI, although recent disappointing results in the COIN and Nordic VII trials have suggested that perhaps there is greater benefit in combining EGFR antibodies with irinotecan than with oxaliplatin. The combination of cetuximab with oxaliplatin-based therapy remains an area of uncertainty, with negative results in the phase III COIN and Nordic VII trials contrasting with very high response rates seen with FOLFOX-cetuximab in the phase II OPUS and CELIM trials.

With the increasing data showing benefit for panitumumab in phase III trials (both in first- and second-line treatment settings), selection of either agent is reasonable. In certain areas where there is a high rate of hypersensitivity reactions to cetuximab, panitumumab may be a preferred agent. There remains no evidence to support the use of panitumumab after cetuximab failure or vice versa.

The CAIRO-2 and PACCE ¬trials failed to validate the hope that a combination of targeted therapies would be additive or synergistic, and this overly toxic strategy has been eliminated from ongoing trials. The use of cetuximab in the neoadjuvant setting continues to be an active area of investigation, given the high response rates that have been reported in KRAS wild-type patients. Finally, a direct comparison of cetuximab versus bevacizumab with chemotherapy in the first-line setting remains a critical question to be addressed by ongoing studies, including CALGB 80405.

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Affiliations: Drs. Nelson and Jasani are Assistant Professors, Department of General Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Conflicts of interest: The authors have nothing to disclose.