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.