Anti-EGFR Agents in Patients With Right-sided Advanced Colorectal Cancer With Wild-type RAS and AREG/EREG High Status

Inclusion Criteria for Registration:

* Age ≥18 years
* Biopsy-confirmed adenocarcinoma of the colon with a right primary tumour location
* aCRC defined as either M1 or locally inoperable disease
* Tumour RAS status either wild-type (by local testing) or unknown
* Fit for combination chemotherapy plus anti-EGFR agent
* Sufficient tumour material for EREG/AREG analysis
* Written informed consent for registration

Exclusion Criteria for Registration

* Tumour RAS-mutation present
* Prior chemotherapy for aCRC
* Prior anti-EGFR agent therapy

Inclusion Criteria for Randomisation:

* Registered in ARIEL-ENGIC
* Local testing confirms tumour RAS-wt status
* ARIEL-ENGIC central testing confirms tumour EREG/AREG high
* Tumour measurable by RECIST v1.1 criteria on CT scan
* Participants have had CT scan within the timeframes stipulated (If there is a contrast reaction, then non-contrast CT with MRI is acceptable, assuming at least one of these modalities shows measurable disease at baseline for ETS evaluation and both modalities are repeated at the trial timepoints at week 8 and 16 and every 8 weeks until disease progression.)
* Pre-randomisation laboratory tests :
* Neutrophils ≥1.5 x109/l and platelet count ≥100 x109/l
* Serum bilirubin ≤ 1.25 x upper limit of normal (ULN), alkaline phosphatase

  * 5x ULN, and serum transaminase (either AST or ALT) ≤ 2.5 x ULN
* Estimated creatinine clearance ≥50ml/min (creatinine clearance estimated as per local practice)
* WHO performance status (PS) 0, 1 or 2
* Fit for combination chemotherapy plus anti-EGFR agent
* Life expectancy of at least 12 weeks
* Women of childbearing potential must have a negative blood pregnancy test at the baseline visit.
* Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception
* Written informed consent for randomization.

Exclusion Criteria for Randomisation:

* Participant has received more than one cycle of chemotherapy since registration
* Participants with history of hypersensitivity to any component of their proposed trial treatment regimen or any of their excipients
* Participants in receipt of live vaccine within four weeks prior to randomisation
* Participants with a history interstitial pneumonitis/idiopathic lung disease (ILD) or pulmonary fibrosis
* Participants with a history of keratitis, ulcerative keratitis or severe dry eye
* Participants with a history of severe skin reaction which in the clinicians' opinion could be exacerbated by EGFR Mab (cf Steven's Johnson Syndrome)
* Complete dihydropyrimidine dehydrogenase (DPYD) deficiency
* Untreated brain metastases or spinal cord compression or primary brain tumours
* History or evidence upon physical examination of CNS disease unless adequately treated
* Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration
* Clinically significant (e.g. active) cardiovascular disease for example cerebrovascular accidents, myocardial infarction, 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 that are likely to have an impact upon survival or treatment delivery
* Known human immunodeficiency virus (HIV)
* Has documented presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to enrolment
* Has a positive hepatitis C virus (HCV) antibody test result at screening or within 3 months prior to enrolment. Note: Participants with a positive HCV antibody test result due to prior resolved disease can be randomised, only if a confirmatory HCV RNA test is obtained - Definite contraindications for the use of corticosteroids and antihistamines as premedication.
* Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies.
* Woman pregnant or lactating or expecting to conceive children within the projected duration of the study through 6 months after the last dose of bevacizumab and/or fluorouracil.