American Association for Cancer Research
21598290cd200047-sup-cd-20-0047r2_supplementary_figure_1.pdf (1.17 MB)

CD-20-0047R2_Supplementary_Figure_1.pdf from Prognostic and Predictive Impact of Circulating Tumor DNA in Patients with Advanced Cancers Treated with Immune Checkpoint Blockade

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journal contribution
posted on 2023-04-03, 22:22 authored by Qu Zhang, Jia Luo, Song Wu, Han Si, Chen Gao, Wenjing Xu, Shaad E. Abdullah, Brandon W. Higgs, Phillip A. Dennis, Michiel S. van der Heijden, Neil H. Segal, Jamie E. Chaft, Todd Hembrough, J. Carl Barrett, Matthew D. Hellmann

Figure S1



Memorial Sloan Kettering Cancer Center

Damon Runyon Cancer Research Foundation

Parker Institute for Cancer Immunotherapy




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. 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

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