Prognostic and Predictive Impact of Circulating Tumor DNA in Patients with Advanced Cancers Treated with Immune Checkpoint Blockade.

Journal Article (Journal Article)

The utility of circulating tumor DNA (ctDNA) as a biomarker in patients with advanced cancers receiving immunotherapy is uncertain. We therefore analyzed pretreatment (n = 978) and on-treatment (n = 171) ctDNA samples across 16 advanced-stage tumor types from three phase I/II trials of durvalumab (± the anti-CTLA4 therapy tremelimumab). Higher pretreatment variant allele frequencies (VAF) were associated with poorer overall survival (OS) and other known prognostic factors, but not objective response, suggesting a prognostic role for patient outcomes. On-treatment reductions in VAF and lower on-treatment VAF were independently associated with longer progression-free survival and OS and increased objective response rate, but not prognostic variables, suggesting that on-treatment ctDNA dynamics are predictive of benefit from immune checkpoint blockade. Accordingly, we propose a concept of "molecular response" using ctDNA, incorporating both pretreatment and on-treatment VAF, that predicted long-term survival similarly to initial radiologic response while also permitting early differentiation of responders among patients with initially radiologically stable disease. SIGNIFICANCE: In a pan-cancer analysis of immune checkpoint blockade, pretreatment ctDNA levels appeared prognostic and on-treatment dynamics predictive. A "molecular response" metric identified long-term responders and adjudicated benefit among patients with initially radiologically stable disease. Changes in ctDNA may be more dynamic than radiographic changes and could complement existing trial endpoints.This article is highlighted in the In This Issue feature, p. 1775.

Full Text

Duke Authors

Cited Authors

  • Zhang, Q; Luo, J; Wu, S; Si, H; Gao, C; Xu, W; Abdullah, SE; Higgs, BW; Dennis, PA; van der Heijden, MS; Segal, NH; Chaft, JE; Hembrough, T; Barrett, JC; Hellmann, MD

Published Date

  • December 2020

Published In

Volume / Issue

  • 10 / 12

Start / End Page

  • 1842 - 1853

PubMed ID

  • 32816849

Pubmed Central ID

  • PMC8358981

Electronic International Standard Serial Number (EISSN)

  • 2159-8290

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-20-0047

Language

  • eng

Conference Location

  • United States