Abstract
Regorafenib, targeting a broad range of receptor tyrosine kinases (RTKs), is an oral multikinase inhibitor which improves the progression-free survival (PFS) and overall survival (OS) of patients diagnosed with chemorefractory metastatic colorectal cancer (mCRC), making an immunosuppressive tumour microenvironment. The correlation between PD-1/PD-L1 expression and RTKs inhibition has been studied in several tumour types but has not been analyzed extensively in mCRC in the era of regorafenib. In this study, using liquid biopsy, we evaluated the opportunity to reveal if PD-L1 expression on circulating tumour cells (CTCs) could serve as a predictive biomarker of response and clinical benefit in patients treated with regorafenib as the third line of treatment. We analyzed a cohort of forty chemorefractory metastatic colorectal cancer patients, of whom twenty-six KRAS mutated, treated with regorafenib, all as the third line of treatment. Blood samples were collected from patients prior to treatment and longitudinally four and eight weeks after initiation of therapy. CTCs were identified using multiparametric flow cytometry; therefore, PD-L1 expression was evaluated. Objective responses were defined following the RECIST criteria v.1.1. Moreover, focusing on peripheral blood biomarkers, we found that high platelet-to-lymphocyte ratio (PLR) was an independent prognostic indicator of poor OS. For the first time, our study showed the usefulness of sequential assessments of CTCs as a non-invasive real-time biopsy to evaluate PD-L1 expression in patients diagnosed with mCRC and treated with regorafenib. Our analysis suggests that by assessing PD-L1 expression on CTCs, we could predict who will benefit from regorafenib, offering highly individualized treatment plans.