Article Text

Download PDFPDF

266 Tumour mutation burden (TMB) and efficacy outcomes in the phase III DANUBE study of advanced urothelial carcinoma (UC)
  1. Sophie Wildsmith1,
  2. Jill Walker1,
  3. Anne L’Hernault1,
  4. Weimin Li1,
  5. Hannah Bye1,
  6. Philip He1,
  7. Feng Xiao1,
  8. Qu Zhang1,
  9. Ross Stewart1,
  10. Melissa de los Reyes1,
  11. Rajiv Raja1,
  12. Wendy Levin1,
  13. Ashok Gupta1,
  14. Thomas Powles2,
  15. Joaquim Bellmunt3,
  16. Matthew Galsky4,
  17. Alexandra Drakaki5 and
  18. Michiel van der Heijden6
  1. 1AstraZeneca, Cambridge, UK
  2. 2Barts Cancer Institute, London, UK
  3. 3Harvard Medical School, Boston, MA, USA
  4. 4Mount Sinai Hospital, New York, NY, USA
  5. 5University of California, Los Angeles, CA, USA
  6. 6Netherlands Cancer Institute, Amsterdam, 1066 CX, Netherlands


Background The phase III DANUBE study assessed the efficacy of the PD-L1 inhibitor durvalumab (D), alone or in combination with the CTLA-4 inhibitor tremelimumab (T), versus standard of care chemotherapy (SoC) for the first-line treatment of unresectable, locally advanced or metastatic UC. The study did not meet its co-primary endpoints of improving overall survival (OS) for D monotherapy vs SoC in patients with high tumor PD-L1 expression or for D+T vs SoC in the intention-to-treat population.1 TMB measurement in blood (bTMB) or tumour (tTMB) has been linked to improved efficacy with PD-1/PD-L1 inhibitors in UC and with D+T in non-small cell lung cancer,2 thus providing a rationale to explore TMB in the DANUBE trial.

Methods Baseline plasma samples from DANUBE were assessed for bTMB using the Guardant OMNI platform, while baseline tTMB was measured in formalin-fixed paraffin-embedded (FFPE) tumour samples using the FoundationOne CDx gene panel. Associations between progression-free survival (PFS) and median and landmark OS with bTMB and tTMB levels at various cutoffs were assessed as part of a pre-specified exploratory analysis. The data cutoff occurred on January 27, 2020.

Results Among 1032 patients randomised in DANUBE, 536 (51.9%) were evaluable for bTMB and 623 (60.4%) were evaluable for tTMB. For D vs SoC, bTMB and tTMB were not associated with OS or PFS at any cutoff. For D+T, stronger associations between bTMB and OS as well as PFS were observed with increasing bTMB cutoffs (table 1). At the bTMB cutoff ≥ 24 mut/Mb, 12-month OS rates were 76.7% for D+T and 54.3% for SoC, whereas for bTMB < 24 mut/Mb, 12-month OS rates were 53.4% for D+T and 51.2% for SoC. Similar trends for both OS and PFS were observed with tTMB (table 1).

Abstract 266 Table 1

Association between TMB and survival outcomes with D+TAssociation between TMB and survival outcomes with D+T

Conclusions Both bTMB and tTMB are potentially useful biomarkers for enriching responses to D+T in previously untreated, advanced UC. Neither bTMB nor tTMB was associated with better outcomes for D monotherapy. Cutoffs of 24 mut/Mb for bTMB and 10 mut/Mb for tTMB appear optimal for D+T in the setting of previously untreated, advanced UC.

Trial Registration The trial is registered with, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24.


  1. AstraZeneca. Update on phase III DANUBE trial for IMFINZI and tremelimumab in unresectable, stage IV bladder cancer [press release] March 6, 2020. []

  2. Rizvi NA, Cho BC, Reinmuth N, et al. Durvalumab with or without tremelimumab vs standard chemotherapy in first-line treatment of metastatic non-small cell lung cancer: The MYSTIC phase 3 randomized clinical trial. JAMA Oncol. 2020:6:661–674.

Ethics Approval The study protocol was approved by the Ethics Board at each investigator’s institution.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.