Observational study investigating the relationship between tumour amphiregulin, epiregulin and epithelial growth factor receptor expression and response to anti-EGFR agents in advanced colorectal cancer.

Background:

The anti-EGFR agents, cetuximab and panitumumab are approved by NICE for the first-line treatment of patients with RAS wild-type (RAS-wt) advanced colorectal cancer (aCRC). However RAS-wt status is not sufficient to guarantee anti-EGFR benefit. Differential tumour expression of the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), as well as the EGFR receptor itself, are putative predictive biomarkers for response to anti-EGFR agents and may therefore help better identify patients who will benefit from treatment.

Objectives:

This study aims to assess the utility of tumour AREG, EREG and/or EGFR expression, alone or in combination, as predictive biomarkers for response to anti-EGFR agents in aCRC. The investigators will develop a scoring system and categorical cut off points to differentiate AREG/EREG/EGFR positive and negative cases and correlate these with response to therapy as assessed by:

Primary endpoint: Progression Free Survival (PFS) Secondary endpoints: Overall Survival (OS), Objective Response Rate (ORR), Disease Control Rate (DCR) Finally, the investigators will utilise digital pathology and artificial intelligence (AI) technologies to automate as far as possible the process of evaluating AREG/EREG/EGFR status.

During the study, the investigators will monitor the costs of implementing the test and time taken to derive test results in order to facilitate cost-effectiveness calculations and assess the feasibility of delivering the test in future routine clinical practice.

Study Design:

A multicentre UK observational cohort study (retrospective and prospectively recruited cohorts).

Study population:

Patients with RAS-wt aCRC who received or are receiving standard care palliative treatment with an anti-EGFR agent and chemotherapy of physician's choice. Within the retrospective cohort, patients who received single agent anti-EGFR therapy under previous Cancer Drugs Fund criteria will be accepted.

Key Inclusion Criteria:

• Biopsy proven advanced colorectal adenocarcinoma at time treatment commenced (either inoperable metastatic disease at diagnosis or inoperable recurrent disease)
• Aged 18 or over at time treatment commenced
• The patient has received or has consented to receive treatment with cetuximab or panitumumab

Key Exclusion Criteria:

• Stage I, II or III colorectal adenocarcinoma
• RAS mutant disease
• Eligible for potentially curative surgery (prospective cohort)
• Underwent cancer surgery subsequent to anti-EGFR therapy (retrospective cohort)
• Unable to provide informed consent (with the exception of patients in the retrospective cohort who have passed away)

Procedures:

The study is observational and does not involve participants undergoing any study-specific investigations or treatments. Results of routine investigations and outcomes from standard care with an anti-EGFR agent will be collected from medical notes and, for the prospective cohort, during routine clinic appointments. Date of death will also be recorded. Initial and follow-up radiological and clinical assessments will occur as per local standard practice. Previously obtained pathological specimens will be retrieved for immunohistochemical analysis of tumour AREG, EREG and EGFR expression.

Treatment During Study:

This study will observe outcomes from standard first line palliative treatment of RAS-wt aCRC. In line with current NICE guidelines, such treatment will involve physician's choice of panitumumab or cetuximab in combination with:

• 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) or
• 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) Where RAS mutation status is only available after commencement of treatment and the anti-EGFR agent is therefore commenced in cycle two, patients may still be recruited to the study.

It is anticipated that most patients in the retrospective cohort will have received current standard first line palliative treatment of RAS-wt aCRC as above. However, patients who were treated with single agent anti-EGFR therapy under previous Cancer Drugs Fund criteria may still be recruited.

Statistical Methods:

Sample size:

Data from 480 patients will be collected for the retrospective cohort and 480 patients will be recruited to the prospective cohort.

Primary endpoint analysis:

PFS will be calculated from date of commencing treatment to date of progression or death from any cause (whichever is sooner). Time of progression will be determined clinically or radiologically by the participant's treating oncologist. Where the anti-EGFR agent was commenced in cycle 2, the definition of the start of treatment will remain cycle 1 day 1 of palliative chemotherapy.

Key secondary endpoint analyses:

OS will be determined from date of commencing treatment to death. ORR is the proportion of patients with documented radiological complete or partial response on first follow-up imaging whereas DCR is the proportion of patients with either radiologically stable disease or a response. For the purpose of these analyses, those without follow-up imaging will be assumed to have progressed.

AREG/EREG/EGFR expression will be assessed as a continuous variable and using dichotomous classifiers ('high' and 'low') for each marker individually and in combination. Subgroup analyses will be performed for BRAF mutation positive tumours, primary tumour location (right versus left colon, and rectum) and previous surgery (primary excised versus in situ). Within the retrospective cohort, those who received single agent anti-EGFR therapy under previous Cancer Drugs Fund criteria will be analysed separately.

Inclusion Criteria:

• Biopsy proven advanced colorectal adenocarcinoma at time treatment commenced (either inoperable metastatic disease at diagnosis or inoperable recurrent disease)
• Aged 18 or over at time treatment commenced
• The patient has received or has consented to receive treatment with cetuximab or panitumumab

Exclusion Criteria:

• Stage I, II or III colorectal adenocarcinoma
• RAS mutant disease
• Eligible for potentially curative surgery (prospective cohort)
• Underwent cancer surgery subsequent to anti-EGFR therapy (retrospective cohort)
• Unable to provide informed consent (with the exception of patients in the retrospective cohort who have passed away)

Patients with RAS-wt aCRC who received or are receiving standard care palliative treatment with an anti-EGFR agent and chemotherapy of physician's choice. Within the retrospective cohort, patients who received single agent anti-EGFR therapy under previous Cancer Drugs Fund criteria will be accepted.