A search of the literature did not find strong evidence to support the use of cetuximab and irinotecan in the treatment of metastatic colorectal cancer. The expert reference panel supported publication of the protocol on the basis of the information summarised below.
Monoclonal antibodies (mABs) targeting the epidermal growth factor receptor (EGFR) prolong survival in patients with metastatic colorectal cancer (mCRC) harbouring KRAS exon 2 wild type tumours. Recent evidence suggest that other RAS mutations (exon 3 and 4 of KRAS and exons 2, 3, 4 of NRAS) may also be predictive of resistancer,r and many studies suggest that anti-EGFR mAB treatment may have a detrimental effect on PFS and OS in patients with NRAS mutations.r As such, cetuximab should not be used in patients with any RAS mutations.
The 2 weekly schedule of irinotecan used in this protocol is preferred to 3 weekly irinotecan as it is associated with less toxicity and is the schedule currently used in clinical trials.
The incremental benefit and additional toxicity attributable to combination treatment compared with best supportive care in individuals with RAS wild type tumours has not been determined in a head to head study. Conclusions regarding the benefit of combination treatment rely on a series of indirect comparisons and extrapolations, each of which raises uncertainty regarding benefit and risk.
The FOLFIRI regimen is preferred to single agent irinotecan as second-line therapy for mCRC as it is associated with less toxicity in particular grade3/4 diarrhoea and alopecia.r (link to FOLFIRI + Cetuximab ID 1212 protocol)
Source |
Study and year published |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase III trials |
EPIC 2008r |
Yes |
No |
Irinotecan 350 mg/m2 q21 days +
weekly cetux 250 mg/m2
No selection for KRAS; subset analysis not representative for overall efficacy results
No OS benefit possibly due to crossover
|
Phase II trials |
BOND 2004r |
Yes |
Yes |
Various schedules of irinotecan used (weekly, 2 weekly and 3 weekly)
No selection for KRAS
No OS benefit
|
|
MABEL 2008r |
Yes |
Yes |
Various schedules of irinotecan used (weekly, 2 weekly and 3 weekly) |
Observational studies |
- |
N/A |
- |
- |
Case series |
- |
N/A |
- |
- |
Guidelines |
Date published/revised |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
v.1 2014 |
Yes |
Yes |
|
BCCA |
Sept 2013 |
Yes |
No |
Irinotecan 180 mg/m2 + cetux 500 mg/m2
q14 days |
CCO |
March 2013 |
Yes |
Yes |
|
N/A = not available
Efficacy
The rate of response in the combination-therapy group was significantly higher than that in the monotherapy group (22.9% vs. 10.8%; p=0.007). The median time to progression was significantly greater in the combination-therapy group (4.1 vs 1.5 months; p<0.001). The median survival was 8.6 months in the combination-therapy group and 6.9 months in the monotherapy group (p=0.48).r
Kaplan-Meier curves for (A) time to disease progression and (B) overall survivalr
(A)
© New England Journal of Medicine 2004
(B)
© New England Journal of Medicine 2004
Toxicity
Grade 3 or 4
Adverse Eventsr |
Cetuximab + Irinotecan
(n=212) (%) |
Cetuximab
(n=115) (%) |
p-value |
Anaemia |
4.7 |
2.6 |
0.55 |
Neutropenia |
9.4 |
0 |
<0.001 |
Thrombocytopenia |
0.5 |
0.9 |
1.00 |
Diarrhoea |
21.2 |
1.7 |
<0.001 |
Asthenia |
13.7 |
10.4 |
0.49 |
Acne-like rash |
9.4 |
5.2 |
0.20 |
Nausea and vomiting |
7.1 |
4.3 |
0.47 |
Abdominal pain |
3.3 |
5.2 |
0.39 |
Stomatitis |
2.4 |
0.9 |
0.67 |
Dyspnoea |
1.4 |
13.0 |
<0.001 |
Fever |
2.4 |
0 |
0.17 |
Hypersensitivity reaction |
0 |
3.5 |
0.01 |
Death |
0 |
0 |
1.00 |
Note: 4 patients randomly assigned to combination group did not receive irinotecan and were evaluated for safety in the monotherapy group. 2 patients randomly assigned to combination group did not receive any study medication.