Use of on-therapy ctDNA monitoring in a patient with KIF5B-RET fusion positive advanced non-small cell lung cancer: a case report

Molecular characterization of non-small cell lung cancer (NSCLC) has led to marked improvements in the treatment of patients with advanced disease who harbor driver mutations, including those with alterations in the RET proto-oncogene. Liquid biopsy to detect circulating tumor DNA (ctDNA) is a clinically validated tool to identify genomic alterations in advanced NSCLC at diagnosis and disease progression. Whether ctDNA assessment can be integrated into other aspects of patient care is an area of ongoing active research. Here, we present the case of a 65-year-old female with KIF5B-RET fusion-positive advanced NSCLC who underwent on-therapy ctDNA surveillance while being treated on a phase 1b trial with the oral RET inhibitor RXDX-105. The patient initially presented with right-sided flank discomfort, with a CT scan identifying a large right lower lobe (RLL) lung mass and right-sided pleural effusion. CT-guided biopsy confirmed thyroid transcription factor 1 (TTF-1) positive lung adenocarcinoma. Subsequent video-assisted thoracoscopic surgery to assess resectability identified pleural studding, with pleural biopsy confirming advanced unresectable disease. Next-generation sequencing (NGS) of tumor tissue and peripheral blood confirmed the presence of a KIF5B-RET fusion, prompting initiation of trial therapy RXDX-105. After 1 year on therapy, ctDNA became detectable prompting early scans which identified disease progression. The patient was subsequently enrolled onto a phase II trial of the RET inhibitor pralsetinib, on which she continues to this day (2+ years) without detectable KIF5B-RET ctDNA and with an ongoing minor response [stable disease per response evaluation criteria in solid tumors (RECIST) v1.1] on imaging. This case illustrates a potential role for on-therapy ctDNA monitoring as a non-invasive method to evaluate treatment response and detect early relapse in patients with advanced NSCLC. Prospective investigation is required to clearly define the optimal integration of ctDNA testing into on-treatment surveillance in patients with advanced NSCLC.