Plasma versus Tissue Tumor Mutational Burden as Biomarkers of Durvalumab plus Tremelimumab Response in Patients with Metastatic Colorectal Cancer in the CO.26 Trial.

Autor:	Loree JM; BC Cancer, University of British Columbia, Vancouver, Canada., Titmuss E; BC Cancer, University of British Columbia, Vancouver, Canada., Topham JT; BC Cancer, University of British Columbia, Vancouver, Canada., Kennecke HF; Oregon Health & Science University, Portland, Oregon., Feilotter H; Canadian Clinical Trials Group, Kingston, Canada., Virk S; Canadian Clinical Trials Group, Kingston, Canada., Lee YS; AstraZeneca, Gaithersburg, Maryland., Banks K; Guardant Health, Redwood, California., Quinn K; Guardant Health, Redwood, California., Karsan A; BC Cancer, University of British Columbia, Vancouver, Canada., Renouf DJ; BC Cancer, University of British Columbia, Vancouver, Canada., Jonker DJ; The Ottawa Hospital, University of Ottawa, Ottawa, Canada., Tu D; Canadian Clinical Trials Group, Kingston, Canada., O'Callaghan CJ; Canadian Clinical Trials Group, Kingston, Canada., Chen EX; Princess Margaret Cancer Centre, Toronto, Canada.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Aug 01; Vol. 30 (15), pp. 3189-3199.
DOI:	10.1158/1078-0432.CCR-24-0268
Abstrakt:	Purpose: Tissue-derived tumor mutation burden (TMB) of ≥10 mutations/Mb is a histology-agnostic biomarker for the immune checkpoint inhibitor (ICI) pembrolizumab. However, the dataset in which this was validated lacked colorectal cancers (CRC), and there is limited evidence for immunotherapy benefits in CRC using this threshold. Patients and Methods: CO.26 was a randomized phase II study of 180 patients, comparing durvalumab and tremelimumab (D + T, n = 119 patients) versus best supportive care (BSC; n = 61 patients). ctDNA sequencing was available for 168 patients (n = 118 D + T; n = 50), of whom 165 had evaluable plasma TMB (pTMB). Tissue sequencing was available for 108 patients. Optimal thresholds for stratifying patients based on OS were determined using a minimal P value approach. This report includes the final OS analysis. Results: Tissue TMB ≥10 mutations/Mb was not predictive of benefit from D + T compared with BSC in microsatellite stable (MSS) metastatic CRC [HR, 0.71 (95% CI, 0.28-1.80); P = 0.47]. No tissue TMB threshold could identify a high TMB group that benefited from ICI. By contrast, plasma TMB (pTMB) ≥28 mutations/Mb was predictive of benefit from D + T [HR, 0.34 (95% CI, 0.13-0.85); P = 0.022], as was clonal pTMB ≥10.6 mutations/Mb [HR, 0.10 (95% CI, 0.014-0.79); P = 0.029] and subclonal pTMB ≥25.9/Mb [HR, 0.20 (95% CI, 0.061-0.69); P = 0.010]. Higher pTMB was associated with length of time on cytotoxic agents (P = 0.021) and prior anti-EGFR exposure (P = 2.44 × 10-06). Conclusions: pTMB derived from either clonal or subclonal mutations may identify a group likely to benefit from immunotherapy, although validation is required. Tissue TMB provided no predictive utility for immunotherapy in this trial. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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