nd safety of cetuximab have not been documented in patients with tumours where EGFR was not detected.
In metastatic colorectal cancer, the incidence of KRAS mutations is in the range of 30 - 50%. Study data demonstrate that patients with metastatic colorectal cancer and activating KRAS mutations are highly unlikely to benefit from treatment with cetuximab or a combination of cetuximab and chemotherapy and as add-on to FOLFOX4 a significant negative effect on progression-free survival time (PFS) was shown.
Cetuximab as a single agent or in combination with chemotherapy was investigated in 5 randomised controlled clinical studies and several supportive studies. The 5 randomised studies investigated a total of 3734 patients with metastatic colorectal cancer, in whom EGFR expression was detectable and who had an ECOG performance status of 2. The majority of patients included had an ECOG performance status of 1. In all studies, cetuximab was administered as described in section 4.2.
The KRAS status was recognised as predictive factor for the treatment with cetuximab in 4 of the randomised controlled studies (EMR 62 202-013, EMR 62 202-047, CA225006, and CA225025). KRAS mutational status was available for 2072 patients. Only in study EMR 62 202-007, an analysis was not possible.
In addition, cetuximab was investigated in combination with chemotherapy in an investigator-initiated randomised controlled phase-III study (COIN, COntinuous chemotherapy plus cetuximab or INtermittent chemotherapy). In this study EGFR expression was not an inclusion criterion. Tumour samples from approximately 81% of patients were analysed retrospectively for KRAS expression.
Cetuximab in combination with chemotherapy
• EMR 62 202-013: This randomised study in patients with metastatic colorectal cancer who had not received prior treatment for metastatic disease compared the combination of cetuximab and irinotecan plus infusional 5-fluorouracil/folinic acid (FOLFIRI) (599 patients) to the same chemotherapy alone (599 patients). The proportion of patients with KRAS wild-type tumours from the patient population eva luable for KRAS status comprised 63%.
The efficacy data generated in this study are summarised in the table below:
|
KRAS wild-type population
|
KRAS mutant population
|
|
Variable/ statistic
|
Cetuximab plus FOLFIRI
|
FOLFIRI
|
Cetuximab plus FOLFIRI
|
FOLFIRI
|
|
|
(N=316)
|
(N=350)
|
(N=214)
|
(N=183)
|
|
OS
|
|
|
|
months, median
|
23.5
|
20.0
|
16.2
|
16.7
|
|
(95% CI)
|
(21.2, 26.3)
|
(17.4, 21.7)
|
(14.9, 17.9)
|
(14.9, 19.4)
|
|
Hazard Ratio (95% CI)
|
0.796 (0.670, 0.946)
|
1.035 (0.834, 1.284)
|
|
p-value
|
0.0093
|
