Oncology and Therapy (Jul 2024)

Dynamic Changes in Circulating Tumor Fraction as a Predictor of Real-World Clinical Outcomes in Solid Tumor Malignancy Patients Treated with Immunotherapy

  • Ryan D. Gentzler,
  • John Guittar,
  • Akash Mitra,
  • Wade T. Iams,
  • Terri Driessen,
  • Regina Schwind,
  • Michelle M. Stein,
  • Kristiyana Kaneva,
  • Seung Won Hyun,
  • Yan Liu,
  • Adam J. Dugan,
  • Cecile Rose T. Vibat,
  • Chithra Sangli,
  • Jonathan Freaney,
  • Zachary Rivers,
  • Josephine L. Feliciano,
  • Christine Lo,
  • Kate Sasser,
  • Rotem Ben-Shachar,
  • Halla Nimeiri,
  • Jyoti D. Patel,
  • Aadel A. Chaudhuri

DOI
https://doi.org/10.1007/s40487-024-00287-2
Journal volume & issue
Vol. 12, no. 3
pp. 509 – 524

Abstract

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Abstract Introduction A dynamic molecular biomarker that can identify early efficacy of immune checkpoint inhibitor (ICI) therapy remains an unmet clinical need. Here we evaluate if a novel circulating tumor DNA (ctDNA) assay, xM, used for treatment response monitoring (TRM), that quantifies changes in ctDNA tumor fraction (TF), can predict outcome benefits in patients treated with ICI alone or in combination with chemotherapy in a real-world (RW) cohort. Methods This retrospective study consisted of patients with advanced cancer from the Tempus de-identified clinical genomic database who received longitudinal liquid-based next-generation sequencing. Eligible patients had a blood sample ≤ 40 days prior to the start of ICI initiation and an on-treatment blood sample 15–180 days post ICI initiation. TF was calculated via an ensemble algorithm that utilizes TF estimates derived from variants and copy number information. Patients with molecular response (MR) were defined as patients with a ≥ 50% decrease in TF between tests. In the subset of patients with rw-imaging data between 2 and 18 weeks of ICI initiation, the predictive value of MR in addition to rw-imaging was compared to a model of rw-imaging alone. Results The evaluable cohort (N = 86) was composed of 14 solid cancer types. Patients received either ICI monotherapy (38.4%, N = 33) or ICI in combination with chemotherapy (61.6%, N = 53). Patients with MR had significantly longer rw-overall survival (rwOS) (hazard ratio (HR) 0.4, P = 0.004) and rw-progression free survival (rwPFS) (HR 0.4, P = 0.005) than patients with molecular non-response (nMR). Similar results were seen in the ICI monotherapy subcohort; HR 0.2, P = 0.02 for rwOS and HR 0.2, P = 0.01 for rwPFS. In the subset of patients with matched rw-imaging data (N = 51), a model incorporating both MR and rw-imaging was superior in predicting rwOS than rw-imaging alone (P = 0.02). Conclusions xM used for TRM is a novel serial quantitative TF algorithm that can be used clinically to evaluate ICI therapy efficacy.

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