Relationship between dynamic changes in circulating tumor fraction and real-world imaging with real-world survival in patients with solid tumors treated with immunotherapy.
Authors: Wade Thomas Iams, Akash Mitra, John Guittar, Ryan D. Gentzler, Regina M. Schwind, Adam Joseph Dugan, Yan Liu, Seung Won Hyun, Michelle M. Stein, Kate Sasser, Rotem Ben-Shachar, Halla Nimeiri, Jyoti D. Patel, Aadel A Chaudhuri
Journal: Journal of Clinical Oncology (2024)

3046 Background: There is an unmet need for a sensitive biomarker that can determine which patients will confer long term benefit from immune checkpoint inhibitors (ICI). While radiologic imaging is the current standard of care for assessing ICI response, imaging can be difficult to interpret and is typically only assessed at 3 month intervals. Dynamic changes in circulating tumor fraction (TF) is a potential biomarker for monitoring ICI response. Here we evaluate the clinical benefit of a molecular biomarker, xM for treatment response monitoring (TRM), in addition to imaging, in a real-world (rw), pan-cancer cohort treated with ICIs. Methods: Using the Tempus liquid biopsy assay, ctDNA TF was computed by applying an ensemble algorithm incorporating copy number variant data and pathogenic variant allele frequencies. Deidentified patient records from the Tempus multimodal database were analyzed if patients had a baseline xF test ≤ 40 days prior to the start of ICI (alone or in combination with chemotherapy [CT], median = 13 days) and an on-treatment xF test 15-180 days post-ICI (median=93 days) and clinical response evaluated via imaging 15-126 days post ICI (median=77 days). Molecular responders (MR) were defined as patients with a ≥ 50% decrease in TF between tests. Rw-imaging, as documented by a provider in their clinical notes, was categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD), Rw overall survival (rwOS) was defined as time from the imaging date closest to on-treatment xF test to death. A likelihood ratio test at a two-sided 5% significance level was performed to assess if a Cox proportional hazards model incorporating both xM Monitor and rw-imaging as covariates (full model) had predictive power over a reduced model with only rw-imaging as a covariate. Results: The evaluable cohort (N=51) – 53% female, median age 64 yrs – had &gt;10 advanced solid tumors (NSCLC 29% and breast cancer 18%). The majority of patients (69%) received ICI + CT, while 31% received ICI alone. 24 patients achieved MR (79% on ICI monotherapy, 21% on ICI + CT). Concordance of response markers is shown in the table. In the full model, xM was a significant predictor of rwOS (HR=0.33 [0.13, 0.84], p=0.02). The added information provided from xM was significant and superior compared to the reduced model of only rw-imaging (p=0.02). For patients with nMR and CR/PR/SD predicted median survival was 10 months whereas for patients with MR and CR/PR/SD predicted median survival was 16 months. Conclusions: MRs achieved significantly longer rwOS than nMRs and provides significant power in predicting rwOS beyond rw-imaging response. xM used for TRM can help identify nMRS who can discontinue therapy and be spared ICI toxicity. [Table: see text]