Oxaliplatin-Based 5FU Regimens
Initial Phase II results assessing first-line cetuximab administration with oxaliplatin-based regimens suggested that outcomes with this chemotherapy could be similar to that described in the CRYSTAL study with irinotecan-based chemotherapy. In the OPUS study randomizing patients to oxaliplatin, 5FU and folinic acid (FOLFOX) with or without cetuximab, a substantial improvement in the primary end point, RR, was observed in Ras wild-type compared with Ras-mutant patients when treated with cetuximab (57 vs 34%). There was also a clear suggestion that patients with Ras-mutant cancers had diminished chemotherapy/cetuximab responses relative to those patients with Ras-mutant cancers treated with FOLFOX alone (34 vs 53%). However, these results did not translate into huge gains or losses in PFS or OS with either treatment arm, suggesting, in line with previous observations, that RR has limited value as a surrogate marker when biological therapies are being assessed.
The Phase II CELIM study compared the addition of cetuximab to either FOLFIRI or FOLFOX (Table 1). Again, there was a suggestion in this study that Ras wild-type patients were more likely to respond to cetuximab treatment than patients with Ras-mutant disease (70 vs 41%). On the basis of PFS and OS outcomes, the investigators' overall conclusion was that first-line cetuximab use with either FOLFOX or FOLFIRI was a reasonable option. Undoubtedly, the survival outcomes in this trial were promising, but it was easy to speculate that this may not have been the case outside a Phase II setting in which patients tend to be heavily selected for fitness. Furthermore, with the benefit of hindsight, it was difficult to draw any firm conclusions from this study as it offered the least robust data of the trials described in Table 1: patient numbers were limited; treatment arms were nonblinded; and there was no standard chemotherapy arm assessed.
Two Phase III trials assessing first-line CRC cetuximab use have now been reported, both attempting to address the two key questions detailed in the introduction. Given the limitations described above in the OPUS and CELIM Phase II trials, these later phase trials seemed crucial to confirm that cetuximab use with oxaliplatin-based regimens could mirror the positive outcomes observed in the CRYSTAL study with irinotecan-based treatment. In short, neither the COIN or NORDIC VII study have been able to demonstrate this.
As the largest cetuximab Phase III study described in CRC, the COIN trial permitted investigators to choose between FOLFOX, or capecitabine and oxaliplatin (XELOX) regimens, then patients were randomized to receive additional cetuximab or chemotherapy alone (Table 1). The primary end point was OS in Ras wild-type patients, with no significant difference observed between cetuximab and chemotherapy alone arms (17.0 vs 17.9 months, respectively). PFS was 8.6 months in both arms, although, in line with the earlier Phase II studies, there was an increased RR observed in Ras wild-type patients. Overall, these results were consistent with the OPUS study and supported the hypothesis that RR is an unreliable surrogate marker for biological therapies, as cancers responding to such treatments may select for more aggressive resistant cancer cells when they relapse.
One limitation of the COIN study was a significant incidence of problematic diarrhea in the 64% of cetuximab patients who received XELOX as their chemotherapy regimen: it is possible that a consequent dose reduction of capecitabine in the cetuximab arm may have diminished the efficacy data and precluded a positive outcome. It was also suggested that there may be a potential interaction between capecitabine and cetuximab which would impair the efficacy of EGFR inhibition. At this point, the limitations of the COIN trial coupled with the perceived success of the CELIM and OPUS studies led to a general consensus that oxaliplatin-based regimens were still a reasonable option with first-line cetuximab use, although it was recommended that its specific combination with XELOX- and capecitabine-based regimens should be avoided.
Finally, the recently reported Phase III NORDIC VII trial assessed the bolus oxaliplatin–5FU regimen with or without cetuximab in the first-line setting (Table 1). Again this trial has been unable to generate positive answers to either of the key questions raised in our introduction. There were no significant differences in OS, PFS or RR. Consistent with the COIN study, there was a paradoxical trend towards poorer OS in patients receiving cetuximab, despite an initially encouraging trend towards improved RR and PFS in the overall population. It was also surprising to find a trend towards worsening PFS in the Ras wild-type patients treated with cetuximab, while patients with Ras-mutant cancers appeared to have improved PFS with the EGFR inhibitor. A criticism of the NORDIC VII study was that oxaliplatin–5FU may be a suboptimal regimen due to its use of bolus 5FU, although OS results were comparable, for instance, with the OPUS trial whose patients would likely have been heavily selected for Phase II eligibility.