The present hypothesis is that anti-EGFR agents are active in tumors with low-level RAS mutation when the majority of tumor cells is still sensitive. While response rate may be high and may reflect sensitivity to anti-EGFR agents, PFS is anticipated to be shorter than in RAS wild-type patients due to the faster development of resistance when sensitive cells are eradicated and when the RAS-mutant anti-EGFR resistant clones become predominant.
The characteristics of low-level RAS mutant tumors would be:
* Objective response rate (ORR) high (reflecting the sensitive clone) * Progression-free survival (PFS) short (reflecting the more rapid outgrowth of RAS mutant clones)
Histologically confirmed, UICC stage IV metastatic adenocarcinoma of the colon or rectum
Primarily non-resectable metastases or surgical resection refused by the patient
RAS mutation determined by the local pathology
Age ≥18
Previous chemotherapy for metastatic disease with the exception of one cycle of FOLFIRI (e.g. while waiting for the result of RAS mutation frequency).
Patients planned to be treated with FOLFOX or another oxaliplatin-based regimen as first-line treatment
Primarily resectable metastases and the patient agrees to resection
Grade III or IV heart failure (NYHA classification)
Parallel
Panitumumab
DrugPanitumumab 6 mg/kg BW as 60-min i.v. infusion\* D1 \*If the 1st infusion is well tolerated, all subsequent infusions can be applied over 30-60 minutes.
Irinotecan
DrugIrinotecan 180 mg/m² BSA i.v., 30 - 90 min D1
Folinic acid
DrugFolinic acid (racemic) 400 mg/m²BSA i.v., 120 min D1
5-FU
Drug5-FU 400 mg/m² BSA, bolus, D1 5-FU 2400 mg/m² BSA i.v. infusion over a period of 46 h D1-2
Overall Response Rate
As primary endpoint ORR according to RECIST 1.1 will be evaluated separately for each arm of patients with defined low-frequency RAS mutation
Progression free survival (PFS)
PFS, separately for each arm of patients with defined low-frequency RAS mutation
Overall Survival (OS)
OS, separately for each arm of patients with defined low-frequency RAS mutation
Investigation of Early Tumor shrinkage (ETS) as an alternative early-on-treatment predictor of treatment efficacy
ETS, separately for each group of patients with defined low-frequency RAS mutation
Investigation of Depth of Response (DpR) to define the nadir of tumour response
DpR, separately for each arm of patients with defined low-frequency RAS Mutation.
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