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

Sponsor

University of Leeds (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03986541

Collaborator

University of Liverpool (Other), University of Manchester (Other), Newcastle University (Other), University of Nottingham (Other), University of Sheffield (Other)

486

Enrollment

Locations

32.2

Anticipated Duration (Months)

69.4

Patients Per Site

2.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer Stage IV	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 Design

Study Type:

Observational

Actual Enrollment :

486 participants

Observational Model:

Cohort

Time Perspective:

Other

Official Title:

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

Actual Study Start Date :

Sep 23, 2019

Actual Primary Completion Date :

Feb 22, 2022

Anticipated Study Completion Date :

May 31, 2022

Arms and Interventions

Arm	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.

Arm

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.

Outcome Measures

Primary Outcome Measures

Progression free survival [March 2023]
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.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Calderdale and Huddersfield NHS Foundation Trust	Huddersfield	West Yorkshire	United Kingdom
2	St James's University Hospital	Leeds		United Kingdom	LS9 7TF
3	The Christie NHS Foundation Trust	Manchester		United Kingdom	M20 4BX
4	The Newcastle upon Tyne Hospitals NHS Foundation Trust	Newcastle Upon Tyne		United Kingdom	NE7 7DN
5	Nottingham University Hospitals NHS Trust	Nottingham		United Kingdom	NG7 2UH
6	Sheffield Teaching Hospitals NHS Foundation Trust	Sheffield		United Kingdom	S5 7AU
7	The Clatterbridge Cancer Centre	Wirral		United Kingdom	CH63 4JY