Abstract 5145: Association of a ctDNA biomarker of treatment response with clinical outcomes in a real-world pan-cancer cohort treated with tyrosine kinase inhibitors
Authors: Mitra Akash , Guittar John , Schwind Regina , Driessen Terri , Berginski Matthew , Lo Christine , Stein Michelle M. , Freaney Jonathan , Hyun Seung Won , Sangli Chithra , Sasser Kate , Nimeiri Halla , Chaudhuri Aadel 
Published: March 2024

Clinical evidence suggests that early changes in circulating tumor DNA tumor fraction (ctDNA TF) is predictive of patient response to immune checkpoint inhibitors, but the extent to which this approach can be used for patients on Tyrosine Kinase Inhibitors (TKIs) is not known. Here, we use xF Monitor to estimate ctDNA TF in patients that received TKIs and show that changes in circulating TF correlate with outcomes in a real-world pan-cancer cohort.

Tempus xF Monitor is a ctDNA assay that measures quantitative molecular changes in ctDNA TF by utilizing diverse genomic events, dynamically weighting somatic variant allele frequencies and copy number variants, while using germline information to inform these estimates and providing single nucleotide variant (SNV) results on 105 genes. Molecular responders (MR) were defined as patients with ≥50% reduction in ctDNA TF between baseline and on-treatment time points, consistent with our previously established threshold. Deidentified patient records from the Tempus multimodal database were analyzed if patients had an xF test ≤ 15 weeks prior to the start of their first TKI regimen and an xF test 15 -180 days post-TKI initiation. Patients received TKI agents as classified in the Tempus Medical Ontology, which assigns a unique ID to key clinical concepts, validated and harmonized across industry standard terminologies. The TKI list was further validated using the NCI Metathesaurus (https://ncim.nci.nih.gov/ncimbrowser/) TKI concept (NCI Code C1967). Clinical endpoints were defined from TKI start to the first progression event or death (rwPFS) or death (rwOS), both censored on the last follow-up in event-free patients. Kaplan Meier analysis and Cox proportional hazard models were fitted to compare MR status and survival outcomes on TKI.

The evaluable pan-cancer cohort N=69, median age = 61.5 yo, advanced/metastatic disease = 72%, 65% were female, consisted of &gt; 10 cancer diagnoses (35% NSCLC, 26% BC), 41% 1L. In this cohort, 49% of patients received a TKI combination regimen, 21% with CT, 18% with ICI. 68% of patients with NGS testing received matched targeted mutation therapies based on NCCN guidelines. Patients classified as MR based on xF Monitor results had improved survival outcomes with a median rwOS of 951 days (vs 439 days for non-MRs). MR patients had significantly longer rwPFS (HR = 0.383, p = 0.005, CI = 0.12 - 0.75) and rwOS (HR = 0.205, p = 0.004, CI = 0.07 - 0.61) than non-MRs.

xF Monitor is a novel tumor naive serial quantitative ctDNA TF algorithm off the Tempus xF assay that has the potential to be used clinically as a monitoring biomarker to stratify patients who are likely to benefit from TKI therapy. xF monitor can be used as a strategy to identify patients at a high risk of progression who could benefit from early switch or intensifying therapy. Results need to be prospectively validated in a larger cohort.

Citation Format: Akash Mitra, John Guittar, Regina Schwind, Terri Driessen, Matthew Berginski, Christine Lo, Michelle M. Stein, Jonathan Freaney, Seung Won Hyun, Chithra Sangli, Kate Sasser, Halla Nimeiri, Aadel Chaudhuri. Association of a ctDNA biomarker of treatment response with clinical outcomes in a real-world pan-cancer cohort treated with tyrosine kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5145.