FOLFIRI plus panitumumab as second-line treatment in mutated RAS metastatic colorectal cancer patients who converted to wild type RAS after receiving first-line FOLFOX/CAPOX plus bevacizumab-based treatment: Phase II CONVERTIX trial

Abstract

Introduction: Genomic studies of liquid biopsies in metastatic colorectal cancer (mCRC) have shown the evolutionary trajectory of wild type (WT) RAS colorectal tumours to mutant clones (mut). Recently, the disappearance of RAS mut has been reported supporting an unexpected negative selection of RAS mutations. Our objective is to evaluate the efficacy and safety of FOLFIRI plus panitumumab (P) as second-line treatment in mCRC patients who are RAS WT at treatment initiation (according to liquid biopsy) but were RAS mut at first-line initiation with FOLFOX/CAPOX plus bevacizumab-based treatment.

Methods: CONVERTIX is a multicentric, single arm, phase II clinical trial (EudraCT number: 2017-003242-25). Eligible patients are those with unresectable mCRC who had RAS mut status in solid biopsies prior to receiving a first-line chemotherapy regimen based on FOLFOX/CAPOX plus bevacizumab and with WT RAS status in liquid biopsy prior to second-line initiation of FOLFIRI + P (every 14 days until disease progression, unacceptable toxicity, or patient/physician’s request to discontinue). The primary objective is progression-free survival (PFS) in second-line treatment. Other objectives include determining WT to mut RAS conversion rate, overall response rate (ORR), disease control rate (DCR), estimated proportion of subjects with early tumour shrinkage (ETS), depth and duration of response (DpR, DoR), time to response (TTR) and treatment failure (TTF), overall survival (OS), safety and tolerability, as well as biomarker analysis of the liquid biopsies. Tumour response will be evaluated every 8 weeks until disease progression. Patient follow-up will be at 36 months.

Results: Sample size has been estimated according to clinical criteria: 40 total patients (36 events assuming a 10% censoring and a mean PFS of 6 months) will produce a two-sided 95% confidence interval with a width of 4 months for the estimation of the PFS. Due to the lack of information regarding RAS mut conversion to WT, the RAS mutational status will be evaluated in liquid biopsies in 20 patients. An early stop is planned if less than 2 of these mCRC patients have WT RAS in liquid biopsy analysis. The recruitment of patients from 8 centres began in July 2018.

Conclusion: An interim analysis will take place once 10 patients have either had a PFS event or gone 6 months progression-free. If less than 5 have PFS > 6 months, the study will be stopped early. This work was supported by Amgen.