Rechallenge With Panitumumab Driven by RAS Dynamic of Resistance

Inclusion Criteria

1. Histologically confirmed diagnosis of metastatic colorectal cancer;
2. Age ≥ 18 years;
3. Written informed consent;
4. Documented WT RAS exons 2, 3 and 4 (KRas and NRas) and WT BRAF V600E for anti-EGFR treatment.
5. Complete or partial response to anti EGFR antibodies in any line either received as monotherapy or in combination with chemotherapy;
6. Imaging documented progression while on therapy with a therapeutic regimen including anti-EGFR mAb;
7. Imaging documented progression at the last treatment regimen that must be anti-EGFR free;
8. Patient must be RAS and EGFR ectodomain wild type in a liquid biopsy performed no longer that 4 weeks after progression to the last anti-EGFR free treatment
9. FFPE sample used for eligibility to anti-EGFR prescription (see criteria 4) must be available for custom gene panel profiling (as described in appendix B). Otherwise if sample is not available, center must have already perfomed a genotyping on this tissue sample according to appendix B.
10. ECOG performance status ≤ 2;
11. At least one measurable tumor lesion as per RECIST v1.1. Lesions in previously irradiated areas or those that have received other loco-regional therapies (i.e. percutaneous ablation) should not be considered measurable unless there is clear documented evidence of progression of the lesion since therapy. Imaging must be performed maximum within 28 days prior to registration;
12. Normal organ functions;
13. Negative serum pregnancy test within 1 week prior to the first study dose in all women of childbearing potential;
14. Subjects and their partners must be willing to avoid pregnancy during the trial. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception;
15. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.

Exclusion Criteria

1. History of severe infusion reactions to monoclonal antibodies cetuximab or panitumumab;
2. Symptomatic or untreated leptomeningeal disease and symptomatic brain metastasis;
3. Clinically significant cardiac disease including:

   1. congestive heart failure requiring treatment (NYHA grade ≥ 2), Left ventricular ejection fraction (LVEF) \< 45% as determined by Multigated acquisition (MUGA) scan or echocardiogram;
   2. history or presence of clinically significant ventricular arrhythmias or atrial fibrillation;
   3. clinically significant resting bradycardia;
   4. unstable angina pectoris ≤ 3 months prior to starting study drug;
   5. acute myocardial infarction ≤ 3 months prior to starting study drug;
   6. QTcF \> 480 msec;
4. History of thromboembolic or cerebrovascular events within the last 6 months, including transient ischemic attack, cerebrovascular accident, deep vein thrombosis, or pulmonary embolism;
5. Patients with interstitial pneumonitis or pulmonary fibrosis;
6. Abnormal organ or bone marrow functions defined as:

   1. Absolute neutrophil count \< 1.5 x 10/L;
   2. hemoglobin \< 9 g/dL;
   3. alkaline phosphatase \> 2.5 x upper normal limit (ULN), if liver metastases \> 5 x ULN;
   4. aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) \> 2.5 x ULN, if liver metastases \> 5 x ULN;
   5. bilirubin \> 1.5 x ULN, if liver metastases \> 2 x ULN;
   6. serum creatinine \> 1.5 x ULN and/or creatinine clearance ≤ 50 mL/min calculated according to Cockroft-Gault;
   7. Patients with platelet count \<100 x 10\^9/L
7. Previous or concurrent second malignancy. Exceptions: adequately treated basal cell or squamous cell skin cancer; in situ carcinoma of the cervix, treated curatively and without evidence of recurrence for at least 3 years prior to study entry; or other solid tumor treated curatively and without evidence of recurrence for at least 3 years prior to study entry.
8. Patients with positive serology for HIV, HBV, HCV.
9. Patients with a history of severe or life threatening hypersensitivity to the active substance or to any of the excipients.