ARIEL: A biomarker enrichment trial of anti-EGFR agents in patients with advanced colorectal cancer with wild-type RAS and right primary tumour location
A simple genetic test could determine which patients with right-sided bowel cancer will benefit from a targeted therapy, sparing others from ineffective treatment with harmful side effects. For patients with advanced colorectal cancer that has not spread to the right side of the colon, standard treatment includes chemotherapy plus an anti-EGFR drug. But a large analysis showed these drugs do not work for right-sided tumours, and US guidelines now recommend against using them. UK practice varies, with no alternative biological therapy available. The problem is that some right-sided patients may still benefit, but doctors cannot identify them. This trial will test whether measuring levels of two molecules—EREG and AREG—in tumour tissue can pick out those patients. Of 440 registered patients, only those with high EREG/AREG expression will be randomly assigned to receive chemotherapy alone or with an anti-EGFR drug. If the approach works, it could change national and international guidelines to include EREG/AREG testing as routine practice, improving outcomes for a subset of patients while avoiding unnecessary toxicity for others.
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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. 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. 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). 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. 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. 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. Secondary Objectives: • Depth of response at 16 weeks • Overall survival • Overall Treatment Utility • Cost-effectiveness • Quality of life • Exploration of other candidate biomarkers 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. 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. 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. 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. 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. 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.
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