Abstract 90P
Background
Noninvasive biomarkers for immune checkpoint inhibitors remain a compelling unmet medical need. POLARIS-03 is a multicenter phase II trial to evaluate the safety and efficacy of toripalimab (anti-PD-1) in refractory metastatic urothelial carcinoma (mUC). We assessed the predictive utility of longitudinal circulating tumor DNA (ctDNA) analysis from a single-institution biomarker cohort.
Methods
Twenty-seven mUC patients receiving toripalimab (3 mg/kg Q2W) at Ren Ji Hospital were enrolled and consented to Institutional Review Board-approved protocol. Serial plasma specimens were obtained at baseline and then every two cycles during treatment. The 600-gene panel (PredicineATLAS) liquid biopsy assay was applied to probe somatic variants and tumor mutational burden (TMB) by sequencing paired tissue and blood samples. Genomic aberrations were correlated with clinical outcomes.
Results
TMB inferred by ctDNA in blood (bTMB) was in concordance with that measured by matched tumor samples (tTMB). High pretreatment bTMB predicted toripalimab response and correlated with prolonged progression-free survival (Hazard ratio = 0.38, P = 0.07). One patient with an exceptionally high bTMB (60.4 mutations/Mb) and genomic features of microsatellite instability experienced a rapid disease improvement. Early ctDNA clearance identified anti-PD-1 responders. Interestingly, two out of three patients with FGFR3-TACC3 gene fusions achieved partial response. Gene-level alterations in ZFHX3 or CYLD enriched for a clinical benefit.
Conclusions
This study demonstrates the feasibility and effectiveness of bTMB as a potential biomarker for mUC patients undergoing immunotherapy, and supports clinical application of PredicineATLAS liquid biopsy assay as a minimally invasive tool for treatment stratification and therapy monitoring in mUC.
Clinical trial identification
NCT03113266.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Shanghai Junshi BioSciences; Huidu Shanghai Medical Sciences Ltd.
Disclosure
All authors have declared no conflicts of interest.