Anti-EGFR mAbs: clinical perspective


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The choice of first-line treatment for patients with mCRC is based on tumor- and patient-related factors and molecular information to determine the individual treatment aim and intensity. Recent advances (ie, extended RAS testing) enable tailored patient assignment to the most beneficial treatment approach.

Unresectable metastatic disease

Upfront therapy

Several clinical trials have shown the efficacy of anti-EGFR mAbs in combination with chemotherapy in treating mCRC, irrespective of the age of patients included (Table 1).

(To view a larger version of Table 1, click here.)

Cetuximab

In the CRYSTAL trial, 1,198 untreated patients with mCRC were randomized to FOLFIRI alone or in combination with cetuximab.5,113 In the intent-to-treat (ITT) population, PFS (the primary end point) significantly improved in the cetuximab arm (8.9 versus 8.0 months, hazard ratio [HR 0.85];P=0.048), but not OS. However, for patients who exhibited wt KRAS, a greater and statistically significant benefit was observed for both PFS (9.9 versus 8.7 months, HR 0.68) and OS (23.5 versus 20.0 months, HR 0.796; P=0.0093). Cetuximab has also been evaluated in combination with FOLFOX in the randomized Phase II OPUS trial.114,115 In patients with wt KRAS, the combination significantly improved PFS (8.3 versus 7.2 months, HR 0.567; P=0.0064), without benefit to OS (22.8 versus 18.5 months, HR 0.855; P=0.39). If cetuximab is combined with an oxaliplatin-based chemotherapy backbone, infusional 5-fluorouracil (5-FU) is preferable to an oral (XELOX) or bolus (FLOX) fluoropyrimidine-containing regimen. In fact, in the COIN trial,69 although the RR was superior in the experimental arm (64% versus 57%, P=0.049), neither OS (primary end point; 17.0 versus 17.9 months, HR 1.04; P=0.67) nor PFS (8.6 months in both arms, HR 0.96; P=0.60) improved by adding cetuximab to oxaliplatin-based chemotherapy. Similarly, in the NORDIC VII trial,116 patients with wt KRAS derived no benefit from cetuximab plus FLOX in terms of PFS (primary end point; 8.7 versus 7.9 months, HR 1.07; P=0.66) or OS (22.0 versus 20.1 months, HR 1.14; P=0.48). In comparison with the OPUS trial, in which infusional 5-FU was administered in combination with oxaliplatin, the different fluoropyrimidine (capecitabine or bolus 5-FU) schedules used in these two trials in combination with oxaliplatin might explain the negative outcomes.

Panitumumab

In first-line treatment, panitumumab has been evaluated in a randomized trial in combination with FOLFOX. Retrospective analyses of the PRIME study clearly demonstrated the negative predictive value of KRAS mutation in exons 3 and 4 and NRAS mutations in exons 2, 3, and 4 in patients treated with panitumumab and FOLFOX.95 In patients with any RAS mutation, the addition of panitumumab to FOLFOX had a detrimental effect on PFS (7.3 versus 8.7 months, HR 1.31; P=0.008) and OS (15.5 versus 18.7, HR 1.21; P=0.040). In contrast, in 512 patients with tumors characterized by all wt RAS genes, both PFS (primary end point; 10.1 versus 7.9 months, HR 0.72; P=0.004) and OS (26.0 versus 20.2 months, HR 0.78; P=0.04) were significantly in favor of the combination.

Head to head with bevacizumab

In the randomized Phase III AIO KRK-0306 (FIRE-3) study,117 FOLFIRI was evaluated either with cetuximab or bevacizumab in 592 wt KRAS patients. In the ITT population, no difference in RR (primary end point; 62% versus 58%, odds ratio 1.249; P=0.183) was observed between the study arms. In contrast, a significant advantage in favor of the cetuximab-containing arm was reported (72% versus 63%, P=0.017). While PFS were superimposable (10 versus 10.3 months, HR 1.06;P=0.547), OS was significantly better in the cetuximab arm (28.7 versus 25 months, HR 0.77;P=0.017). Recent analyses demonstrated a more pronounced OS benefit in wt RAS patients (33.1 versus 25.6 months, HR 0.70; P=0.011) favoring the cetuximab arm.118 In this trial, the authors retrospectively evaluated the outcome of second-line therapies. The study recommended FOLFOX plus bevacizumab or irinotecan plus cetuximab according to the randomization arm, but clinicians could choose any second-line regimen. First-line PFS according to second-line antibody use was 9.2 months for anti-vascular endothelial growth factor (VEGF), 9.7 months for anti-EGFR mAbs, and 11.3 months for no mAbs, respectively (P=0.001). Correspondingly, OS was 25.2 months for anti-VEGF, 23.7 months for anti-EGFR, and 30.8 months for no mAbs (P=0.02). OS according to oxaliplatin use was 27.1 months for oxaliplatin versus 29.1 months for no oxaliplatin (P=0.10). In the recently published randomized Phase II PEAK study,119 FOLFOX was evaluated either in combination with panitumumab or bevacizumab in 285 previously untreated wt KRAS patients. In the ITT group, PFS (primary end point; 10.9 versus 10.1 months, HR 0.87; P=0.353) was similar between the study arms, whereas OS was superior in the panitumumab arm (34.2 versus 24.3 months, HR 0.62; P=0.009). In the subgroup with all wt RAS genes, the panitumumab arm was superior in terms of PFS (13.0 versus 9.5 months, HR 0.65; P=0.029) and OS (41.3 versus 28.9 months, HR 0.63; P=0.058). Therefore, the similar results in both the FIRE-3 and PEAK trials suggest the beneficial impact of anti-EGFR mAbs plus chemotherapy in patients with all-wt RAS genes.

However, conflicting results arose from the large CALGB/SWOG 80405 trial.120 Previously untreated patients with wt KRAS mCRC were randomized to receive either bevacizumab or cetuximab in combination with chemotherapy (FOLFOX or FOLFIRI, by investigator choice). Surprisingly, no differences in either OS (primary end point; 29 versus 29.9 months, HR 0.92; P=0.34) or PFS (10.8 versus 10.4 months, HR 1.04; P=0.55) were observed between the treatment arms. Nonetheless, it is expected that expanded RAS testing may identify subsets of patients who derive benefit from specific regimens. In anticipation of this possibility, the current evidence enhances the positioning of anti-EGFR mAbs in the first-line treatment of mCRC.