Title: ARIEL: A biomarker enrichment trial of anti-EGFR agents in patients with advanced colorectal cancer with wild-type RAS and right primary tumour location
Funder: Medical Research Council

Abstract: Not all bowel (colon)cancers are the same. It is known that tumours which start in the right side of the bowel (right-sided), behave differently than those on the left side. Patients with advanced cancer (cancer that has spread to other areas) whose tumours are right-sided do not tend to live as long as those with left-sided. Right-sided tumours may not respond as well to drugs used to treat cancer. It is therefore important for researchers to find ways to improve the treatments and cancer outcomes for patients with right-sided tumours._x000D_ _x000D_ Anti-EGFR agents (cetuximab and panitumumab) are drugs that switch off the growth signals from the Epidermal Growth Factor Receptor(EGFR), which is a protein on the cancer cell which makes cancer grow and spread. We know that if a protein (RAS) is altered and becomes abnormal on the tumour then a patient will not respond to treatment with anti-EGFR drugs. Doctors now test the tumours of all patients and only treat those patients without these abnormal RAS proteins (RAS-wt) with anti-EGFR drugs. _x000D_ _x000D_ These drugs are available to patients in the UK with RAS-wt advanced bowel cancer alongside chemotherapy. However in some patients with RAS-wt cancers the drugs do not work, despite the proteins being normal. This means that patients experience unpleasant side effects without any benefits. Cancer researchers have tried to understand why some patients benefit from anti-EGFR drugs, and some do not. _x000D_ _x000D_ Research has shown that some patients with tumours that start in the right-side of the bowel do not respond to this treatment and in many countries anti-EGFR drugs are not recommended for patients with a right-sided tumour. UK data shows that some patients with right-sided bowel cancers respond well to anti-EGFR drugs, but some patients do worse and their cancer grows more quickly and the side effects are more severe, than when treated with chemotherapy alone. This creates a problem for oncologists and patients. An extra test to help identify patients with right-sided bowel cancer that are most likely to benefit from anti-EGFR drugs would help resolve this._x000D_ _x000D_ Further research has found different tumour proteins (EREG and AREG) that identify those patients most likely to respond to anti-EGFR drugs, including patients with right-sided bowel cancers. Further research on the importance of this protein is needed before it can be used in clinics._x000D_ _x000D_ This trial will form a part of this research. We will test whether EREG and AREG levels in the tumour can help doctors identify the patients with advanced right-sided bowel cancer for whom treatment with anti-EGFR drugs will be helpful. The patient’s tumour sample can be tested for both RAS and EREG/AREG, meaning that there will be no need for an extra hospital visit. Only patients with high EREG/AREG levels measured in their tumour can enter the trial. Half the patients will be randomly selected by a computer to have chemotherapy, and half will be selected to have chemotherapy plus an anti-EGFR drug. At the end of treatment we will be able to tell whether testing for a tumour’s EREG/AREG level was able to predict which patients had a good response to using the anti-EGFR drug. _x000D_ _x000D_ Results from this trial may lead to a new test to help oncologists and patients make better decisions about their treatment. Further research on tumour samples may help us find new ways to treat patients with right-sided bowel cancers.

Lay abstract: Research question: To assess whether in RAS-wt advanced colorectal cancer (aCRC) patients (pts) with right primary tumour location (rPTL), stratification by EREG/AREG identifies pts who benefit from adding anti-EGFR agent to chemotherapy (chemo), and test feasibility of delivering EREG/AREG for routine practice. _x000D_ _x000D_ Background: For fit RAS-wt aCRC pts, standard treatment is chemo plus an anti-EGFR agent (cetuximab or panitumumab). However, meta-analysis shows that rPTL confers a worse prognosis than left-PTL and that anti-EGFR agents are ineffective in rPTL RAS-wt pts. USA national guidance now stipulates that rPTL pts should not receive anti-EGFR agents upfront. NICE continues to allow treatment of rPTL pts with anti-EGFR agents with no alternative biological agent available. A survey of UK oncologists has demonstrated heterogeneity of practice in this clinical situation._x000D_ _x000D_ Better pt selection for anti-EGFR agents by predictive biomarkers is possible; the most consistent data is for the EGFR ligands EREG and AREG. High expression conferring sensitivity; low expression resistance (validated in PICCOLO and COIN trials). _x000D_ _x000D_ In PICCOLO a combined EREG/AREG and PTL analysis revealed that in rPTL pts, high EREG/AREG was associated with marked panitumumab benefit; in rPTL pts with low expression, chemo plus panitumumab was significantly inferior to chemo alone. _x000D_ _x000D_ Pt interests may be better served by integrating EREG/AREG into routine care. However, more data is needed to change practice: EREG/AREG have to date been measured retrospectively; feasibility for delivery of results to sites must be demonstrated, and prospective confirmation is needed to confirm the benefit of EGFR therapy in pts with EREG/AREG-high, right-PTL cancer. _x000D_ _x000D_ Primary objective:To assess the efficacy of adding anti-EGFR therapy to chemo in pts with rPTL aCRC with high EREG/AREG, using early tumour shrinkage at 8 weeks._x000D_ _x000D_ Secondary Objectives:_x000D_ • Depth of response at 16 weeks_x000D_ • Overall survival _x000D_ • Overall Treatment Utility _x000D_ • Cost-effectiveness_x000D_ • Quality of life_x000D_ • Exploration of other candidate biomarkers _x000D_ _x000D_ Methods: A multi-centre, open label, randomised controlled trial in untreated pts with RAS-wt aCRC with rPTL. Stratification by EREG/AREG (high vs low at the 40th centile of expression); only EREG/AREG high pts randomised. _x000D_ _x000D_ RAS-wt or unknown RAS-status pts can be registered (central testing offered). In RAS-wt pts, EREG/AREG is measured by reverse transcriptase polymerase chain reaction. _x000D_ _x000D_ EREG/AREG high pts will receive chemo alone or chemo plus anti-EGFR agent. Randomisation (1:1) will be by minimisation with a random element, incorporating stratification for BRAF status, performance status and peritoneal metastases. _x000D_ 440 pts will be registered to randomise 162 EREG/AREG high pts. Recruitment period of 3 years from 40 centres. Minimum 1 year follow up for longer-term outcomes. An internal pilot will test the feasibility of biomarker delivery and recruitment, with predefined criteria for progression to the full trial. _x000D_ _x000D_ Timelines for delivery: Set-up from October 2020; first pt recruited October 2021; 3 years recruitment; 1 year follow-up; primary analysis 6 months after end of recruitment._x000D_ _x000D_ Impact and dissemination: Treatment decisions are being made based on PTL. Prospective validation of high EREG/AREG to identify sensitive rPTL pts will impact national and international practice to include EREG/AREG as routine testing, to improve pt outcomes.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS