First Line mFOLFOXIRI + PANITUMUMAB vs mFOLFOX + PANITUMUMAB IN RAS AND BRAF WT METASTATIC COLORECTAL CANCER PATIENTS

Inclusion Criteria:

* Written informed consent to study procedures and to molecular analyses.
* Histologically proven diagnosis of colorectal cancer.
* Initially unresectable metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease.
* At least one measurable lesion according to RECIST 1.1.
* Availability of a tumour tissue sample (primary tumour and/or metastatic sites).
* Male or female of 18-75 years of age
* ECOG PS ≤2 for patients aged ≤70 years; ECOG PS 0 for patients aged 71 to 75 years.
* Life expectancy of at least 12 weeks
* Previous adjuvant chemotherapy allowed only if with fluoropyrimidine monotherapy and more than 6 months elapsed between the end of adjuvant and first relapse.
* RAS (codons 12, 13, 59, 61, 117 and 146 of KRAS and NRAS genes) and BRAF (V600E mutation) wt status of primary colorectal cancer or related metastasis (local or central laboratory assessment).
* Neutrophils ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hgb ≥9 g/dl.
* Total bilirubin ≤ 1.5 fold the upper-normal limits (UNL), ASAT (SGOT) and/or ALAT (SGPT) ≤ 2.5 x UNL (or \<5 x UNL in the case of liver metastases), alkaline phosphatase ≤ 2.5 x UNL (or \<5 x UNL in case of liver metastases).
* Creatinine clearance ≥50 mL/min or serum creatinine ≤1.5 x UNL.
* Male subjects with female partners of childbearing potential must be willing to use adequate contraception - Contraception, starting with the first dose of study therapy through 180 days after the last dose of treatment.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

* Women of childbearing potential must have a negative blood pregnancy test at the baseline visit
* Female subjects of childbearing potential must be willing to use an adequate method of contraception - Contraception, for the course of the study starting with the first dose of study therapy through 180 days after the last dose of treatment.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

* Will and ability to comply with the protocol.

Exclusion Criteria:

* Previous treatment for metastatic disease.
* Radiotherapy to any site within 4 weeks before the study.
* Previous adjuvant oxaliplatin-containing chemotherapy.
* Previous treatment with EGFR inhibitors.
* Untreated brain metastases or spinal cord compression or primary brain tumours.
* History or evidence upon physical examination of CNS disease unless adequately treated.
* Symptomatic peripheral neuropathy \> 1 grade NCIC-CTG criteria.
* Creatinine clearance \< 50 mL/min or serum creatinine \>1.5 x UNL.
* Clinical signs of malnutrition.
* Neutrophils \<1.5 x 109/L, Platelets \<100 x 109/L, Hgb \<9 g/dl.
* Diagnosis of interstitial pneumonitis or pulmonary fibrosis.
* Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration.
* Clinically significant (e.g. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF), serious cardiac arrhythmia requiring medication.
* Treatment with any investigational drug within 30 days prior to enrolment or 2 investigational agent half-lives (whichever is longer)
* Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ.
* Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.
* Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness, or hepatitis B or C.
* Definite contraindications for the use of corticosteroids and antihistamines as premedication.
* History of severe allergic reactions or hypersensitivity to trial drugs or any of their excipients.
* Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies.
* Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study and until 180 days after the last trial treatment.