optimal anti-egfr treatment of mcrc patients with low-frequency ras mutation

Conditions: Treatment Related Cancer

Summary: 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)


Eligibility criteria:
inclusion criteria: * 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 * ecog performance status 0-2 * patients suitable for chemotherapy administration * patient's written declaration of consent obtained * estimated life expectancy \> 3 months * presence of at least one measurable reference lesion according to the recist 1.1 criteria * primary tumor tissue available and patient consents to storage and molecular and genetic profiling of tumor material. molecular profiling of blood samples is optionally performed. * adequate bone marrow function: * leukocytes ≥ 3.0 x 109/l with neutrophils ≥ 1.5 x 109/l * thrombocytes ≥ 100 x 109/l * haemoglobin ≥ 5.6 mmol/l (equivalent to 9 g/dl) * adequate hepatic function: * serum bilirubin ≤ 1.5 x upper limit of normal (uln) * alat and asat ≤ 2.5 x uln (in the presence of hepatic metastases, alat and asat ≤ 5 x uln) * adequate renal function: ▫ creatinine clearance (calculated according to cockcroft and gault) ≥ 50 ml/min * no previous chemotherapy for metastatic disease. patient with need of immediate treatment (high tumor load, symptoms) may have received one application of folfiri prior to study treatment. exclusion criteria: * 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) * medical or psychological impairments associated with restricted ability to give consent or not allowing conduct of the study * previous chemotherapy for the colorectal cancer with the exception of adjuvant treatment, completed at least 6 months before entering the study * participation in an investigational clinical study or experimental drug treatment within 30 days prior to study inclusion or within a period of 5 half-lives of the substances administered in the investigational clinical study or during an experimental drug treatment prior to inclusion in the study, depending on which period is longest * known hypersensitivity or allergic reaction to any of the following substances: 5-fluorouracil, folinic acid, panitumumab, irinotecan, and chemically related substances and/or hypersensitivity to any of the excipients of any of the aforementioned substances including known hypersensitivity reactions to monoclonal antibodies nci ctcae grade ≥ 3. * known hypersensitivity to chinese hamster ovary cell (cho) - cellular products or other recombinant human or humanised monoclonal antibodies * history of uncontrolled bronchial asthma * patients with interstitial pneumonitis or pulmonary fibrosis * patients with known brain metastasis * history of acute or subacute intestinal occlusion or chronic inflammatory bowel disease or chronic diarrhoea * symptomatic peritoneal carcinomatosis * severe, non-healing wounds, ulcers or bone fractures * patients with acute or chronic infection requiring systemic therapy * known history of positive testing for human immunodeficiency virus (hiv) or known acquired immunodeficiency syndrome (aids) * active or chronic hepatitis b virus (hbv) or hepatitis c virus (hcv) infection (positive hbv surface antigen or hcv rna if anti-hcv antibody screening test positive; serologic tests required in patients who receive study treatment). * known dpd deficiency (specific screening not required) * known glucuronidation deficiency (gilbert's syndrome);(specific screening not required * treatment with sorivudine or brivudine within 28 days before study enrollment or requirement for concomitant antiviral treatment with sorivudine or brivudine * history of a second primary malignancy during the past 5 years before inclusion in the study or during participation in the study, with the exception of a basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ, if these were treated curatively. * known previous or ongoing alcohol or drug abuse * pregnant or breast-feeding patients * any other severe concomitant disease or disorder which, in the investigator's opinion, could influence the patient's ability to participate in the study or influence his/her safety during the study or interfere with interpretation of study results * both, absent and restricted legal capacity

Keywords: colorectal cancer fire low-ras mcrc panitumumab