The study we presented at ASCO is the CHRONOS study which is a phase II study of anti-EGFR re-challenge with panitumumab in metastatic colorectal cancer driven by liquid biopsy assessing circulating tumour DNA. The rationale of the study is that we previously described that resistance under therapeutic EGFR blockade with monoclonal antibodies in metastatic colorectal cancer is driven by expansion of RAS and EGFR at the domain clones. The good thing is that you can monitor this in the blood through circulating tumour DNA by liquid biopsy. There is a decline in resistance-conferring alleles upon therapy withdrawal so this pulsatile behaviour provides the rationale for a re-challenge when you have the clearance of these tumour mutations that confer resistance in blood and thus the tumour regains sensitivity.
What was the methodology used in the study?
CHRONOS is a phase II study evaluating a patient with performance status 0 to 2 that should have responded to a previous line of anti-EGFR treatment. We monitored, we assessed in blood, circulating tumour DNA for mutation of EGFR at the domain RAS and BRAF by digital droplet PCR at the moment of re-challenge. Only if we found complete clearance of these mutated alleles the patient was allowed to enter the study and received panitumumab at standard dose until progression.
As for the statistics, the primary endpoint was objective response rate and six responses were required to declare the study positive.
What were the key findings?
First of all we found at the molecular screening that 30% of patients still presented with mutated RAS, BRAF or EGFR at the domain mutated alleles. These patients were excluded from treatment so we treated eligible patients without these resistance conferring mutations. Out of 52 patients 27 patients displayed this clearance of mutated clones. Patients were treated with panitumumab and we observed a 30% response rate in this selected population without resistance conferring mutations. Also an additional 30% of patients displayed stable disease that was sustained beyond four months, so sustained progression free disease, accounting overall for a 60% of control of disease.
How can there results impact the future treatment of colorectal cancer?
The results of CHRONOS are important because it’s the first study with an interventional liquid biopsy driving decision making for treatment in stage 4 disease. Also clinicians do use re-challenge with anti-EGFR monoclonal antibodies in clinical practice, however, this is mainly based on the clinical characteristics of patients, that is previous response and an appropriate time interval between previous anti-EGFR administration and re-challenge. Now with CHRONOS we provide a valuable tool, that is liquid biopsy, for monitoring ctDNA for resistance conferring mutations that actually is reflecting the real status of the tumour at the very moment of re-challenge.
So this approach has got several advantages over a clinical based re-challenge. First of all is to exclude those around 30% of patients still displaying resistance conferring mutations. Then we observed a response rate that is in the range of 30% that is higher than previously described and it also favourably compares with other therapeutic options in this line of treatment. Overall these observations suggest that liquid biopsy can be fruitfully incorporated in the clinical management of metastatic colorectal cancer.
