Molecular residual disease (MRD) detection with a tissue comprehensive genomic profiling (CGP)-informed personalized monitoring assay: An exploratory analysis of the IMvigor-010 observation arm.

Abstract

448 Background: There is compelling rationale that detection of MRD following curative therapy may identify patients at high risk of relapse requiring intensified adjuvant therapy. Combining MRD detection with CGP creates an opportunity to offer MRD-guided treatment with precision cancer therapeutics. Here we analyze the observation arm of the IMvigor-010 study to understand the genomics of resected early stage bladder cancer and to validate CGP-informed personalized MRD detection in circulating tumor DNA (ctDNA). Methods: Using the resected tumor, tissue CGP was performed retrospectively with a 300+ gene assay, followed by MRD detection using FoundationOne Tracker (F1T). Briefly, coding, synonymous, and non-coding variants were selected from tumor tissue sequencing using an optimized algorithm that filters out non-tumor derived variants (germline, clonal hematopoiesis derived, sequencing artifacts). Tumor-informed personalized multiplex PCR-next generation sequencing (Natera) assay was designed and used to detect and quantify variant allelic frequency (VAF) in ctDNA from 182 patients. ctDNA levels were reported in mean tumor molecules per mL of plasma. F1T, a tissue-informed personalized monitoring assay, was performed on plasma samples collected at an MRD timepoint a median of 11 weeks post-surgery. Results: At the MRD timepoint, ctDNA was detected in 66/182 (36%). Focusing on the 66 ctDNA-positive patients, 58 had relapsed (88% PPV) at time of analysis. Median disease-free survival (DFS) from randomization was 3 months in ctDNA-positive vs not reached in ctDNA-negative population (HR = 5.7, 95% CI: 3.8-8.6, p <.0001). Median overall survival (OS) was 13 months in ctDNA-positive vs not reached in ctDNA-negative (HR = 5.7, 95% CI: 3.4-9.7, p <.0001). Potentially actionable CGP findings included FGFR2/3 short variants (SVs) and fusions (13%), ERBB2 SVs and amplifications (13%), PIK3CA SVs (20%), CDKN2A SVs and losses (41%) and tumor mutational burden (TMB) ≥10 mutations/Mb (35%). Conclusions: Tissue CGP-informed personalized MRD detection can detect low levels of residual ctDNA in patients with resected early stage bladder cancer, identifying a population with inferior DFS and OS. This technologic approach, synergizing regulatory-grade actionable CGP with ctDNA-based MRD detection, creates new opportunities for precision adjuvant therapy across a range of high-risk cancer types. Clinical trial information: NCT02450331.