AREG, EREG and EGFR: Response to Anti-EGFR Agents in Colorectal Cancer

Association Between Tumour Amphiregulin, Epiregulin and Epidermal Growth Factor Receptor (EGFR) Expression and Response to Anti-EGFR Agents in Colorectal Cancer

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Colorectal Cancer Stage IV
• Intervention / Treatment: Diagnostic test: Immunohistochemistry

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 486

Contacts and Locations

Study Locations

• United Kingdom
  • Leeds, United Kingdom, LS9 7TF
    • St James's University Hospital
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust
  • Newcastle Upon Tyne, United Kingdom, NE7 7DN
    • The Newcastle upon Tyne Hospitals NHS Foundation Trust
  • Nottingham, United Kingdom, NG7 2UH
    • Nottingham University Hospitals Nhs Trust
  • Sheffield, United Kingdom, S5 7AU
    • Sheffield Teaching Hospitals NHS Foundation Trust
  • Wirral, United Kingdom, CH63 4JY
    • The Clatterbridge Cancer Centre
  • West Yorkshire
    • Huddersfield, West Yorkshire, United Kingdom
      • Calderdale and Huddersfield NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

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.

Description

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)

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Retrospective cohort; Patients with advanced colorectal cancer previously treated with an anti-EGFR agent (panitumumab or cetuximab).	Diagnostic test: Immunohistochemistry; Assessment of tumour amphiregulin, epiregulin and EGFR expression by immunohistochemistry.
Prospective cohort; Patients with advanced colorectal cancer newly starting treatment with an anti-EGFR agent (panitumumab or cetuximab).	Diagnostic test: Immunohistochemistry; Assessment of tumour amphiregulin, epiregulin and EGFR expression by immunohistochemistry.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival	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.	March 2023

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	OS will be determined from date of commencing treatment to death.	March 2023
Objective response rate	ORR is the proportion of patients with documented radiological complete or partial response on first follow-up imaging.	8-12 weeks post commencement of treatment
Disease control rate	DCR is the proportion of patients with either radiologically stable disease or a response on first follow-up imaging	8-12 weeks post commencement of treatment

Collaborators and Investigators

• Sponsor: University of Leeds
• Collaborators: University of Nottingham; University of Sheffield; Newcastle University; University of Liverpool; University of Manchester
• Investigators: Principal Investigator: Philip Quirke, PhD FRCPath, University of Leeds - Institute of Medical Research at St James's

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 23, 2019
• Primary Completion (ACTUAL): February 22, 2022
• Study Completion (ANTICIPATED): May 31, 2022

Study Registration Dates

• First Submitted: June 13, 2019
• First Submitted That Met QC Criteria: June 13, 2019
• First Posted (ACTUAL): June 14, 2019

Study Record Updates

• Last Update Posted (ACTUAL): February 23, 2022
• Last Update Submitted That Met QC Criteria: February 22, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: colorectal cancer; EGFR; cetuximab; panitumumab; anti-EGFR agents; amphiregulin; epiregulin
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms
• Other Study ID Numbers: N6AREG/EREG

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No