Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Poster Display session 3

3594 - Tumor mutation burden (TMB), PD-L1, IFN-γ signaling identify subgroups of patients (pts) who benefit from durvalumab (D, anti-PDL1) or D and tremelimumab (T, anti-CTLA4) treatment in urothelial bladder cancer (UC)

Date

30 Sep 2019

Session

Poster Display session 3

Topics

Immunotherapy

Tumour Site

Urothelial Cancer

Presenters

Christophe Massard

Citation

Annals of Oncology (2019) 30 (suppl_5): v475-v532. 10.1093/annonc/mdz253

Authors

C. Massard1, H. Si2, Q. Zhang3, B. Higgs3, R. Raja4, S.E. Abdullah5, A. Gupta5, W. Li6, M.S. Van der Heijden7

Author affiliations

  • 1 Ditep, Gustave Roussy - Cancer Campus, 94805 - Villejuif/FR
  • 2 Oncology Research, AstraZeneca, 20878 - Gaithersburg/US
  • 3 Translational Bioinformatics, AstraZeneca, 20878 - Gaithersburg/US
  • 4 Translational Medicine Oncology And Pharmacogenics, AstraZeneca, 20878 - Gaithersburg/US
  • 5 Clinical Development, AstraZeneca, 20878 - Gaithersburg/US
  • 6 Translational Sciences, AstraZeneca, 20878 - Gaithersburg/US
  • 7 Urogenital Carcinogenesis, Netherlands Cancer Institute (NKI), 1066 - Amsterdam/NL

Resources

Login to get immediate access to this content.

If you do not have an ESMO account, please create one for free.

Abstract 3594

Background

We conducted NGS of baseline UC tumors to elucidate molecular predictors of clinical outcomes on D/D+T.

Methods

CP1108/NCT01693562 was a nonrandomized phase I/II trial including 201 2L UC pts who were treated with D (10 mg/kg Q2W). Study 10/NCT02261220 was a phase I trial including 190 2L UC pts treated with D (20 mg/kg Q4W) +T (1 mg/kg Q4W). Pts with ≥25% PD-L1 expression in tumor or immune cells were scored as PD-L1+ by IHC. RNA-seq (n = 62) and whole exome sequencing (WES; n = 37) were used in CP1108. The IFN-γ gene signature (IFNGS) was calculated as described (Higgs B et al., 2018). TMB was calculated as somatic coding mutation count per mega base from WES data with TMB≥top tertile as TMB high. FMI assay (n = 62) was conducted in Study 10 with TMB≥top tertile as TMB high. ctDNA dynamics using Guardant360 were calculated using an established method (Raja R, et al., 2018). Wilcoxon, log-rank tests and COX-PH model were used in relevant statistical tests.

Results

Among ITT pts, 55% and 44.5% pts were PD-L1+ in CP1108 and Study 10 respectively. PD-L1 status correlated with IFNGS (p < 0.001), whereas PD-L1 did not correlate with TMB. PD-L1+ correlated with better OS in CP1108 (HR = 0.46, p < 0.001) but not in Study 10 (HR = 0.75, p = 0.2). IFNGS significantly correlated with better PFS in CP1108 (HR = 0.5, p = 0.02). Higher TMB in CP1108 using the median cutoff trended towards better OS (HR = 0.51, p = 0.18), but no clear trend using the top tertile cutoff due to small sample size. Higher TMB in Study 10 correlated with improved OS (HR = 0.34, p = 0.01). In Study 10, TMB and PD-L1 double positive pts (n = 14, 24%) had best OS and pts low in both had worst (n = 19, 32%, HR = 0.23, p = 0.01). Clearance of ctDNA after treatment correlated with better OS (HR = 0.23, p = 0.006) and PFS (HR = 0.33, p = 0.01) in combined UC pts from the 2 studies.

Conclusions

Both PD-L1 and TMB predict for survival benefit in UC pts treated with D/D+T. They identify overlapping but generally distinct patient populations. Double highs perform the best. ctDNA loss following treatment can be predictive for better survival.

Clinical trial identification

NCT01693562; NCT02261220.

Editorial acknowledgement

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

C. Massard: Advisory / Consultancy: Amgen; Advisory / Consultancy: Astellas; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Celgene; Advisory / Consultancy: Genentech; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy: Janssen; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Orion. H. Si: Full / Part-time employment: AstraZeneca. Q. Zhang: Full / Part-time employment: AstraZeneca. B. Higgs: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. R. Raja: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. S.E. Abdullah: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. A. Gupta: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options, Licensing / Royalties, Use of immunotherapy in the treatment of cancer-patent: Bristol-Myers Squibb. W. Li: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. M. van der Heijden: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy: Seattle Genetics.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.