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Poster Discussion – Genitourinary tumours, non-prostate

4138 - ADAPTeR: A phase II study of anti-PD1 (nivolumab) therapy as pre- and post-operative therapy in metastatic renal cell carcinoma.

Date

29 Sep 2019

Session

Poster Discussion – Genitourinary tumours, non-prostate

Presenters

Lewis Au

Citation

Annals of Oncology (2019) 30 (suppl_5): v356-v402. 10.1093/annonc/mdz249

Authors

L. Au1, K. Litchfield1, A. Rowan1, S. Horswell1, F. Byrne1, D. Nicol2, N. Fotiadis3, R.F. Salgado4, S. Hazell5, J.I. Lopez6, E. Hatipoglu7, L. Del Rosario8, L. Pickering8, M. Gore8, B. Chain9, S. Quezada10, J.M.G. Larkin11, C. Swanton1, S. Turajlic12

Author affiliations

  • 1 Cancer Evolution And Genome Instability Laboratory, The Francis Crick Institute, NW1 1ST - London/GB
  • 2 Department Of Surgery, Royal Marsden Hospital NHS Foundation Trust, SW6 1EJ - London/GB
  • 3 Interventional Radiology Unit, Royal Marsden NHS Foundation Trust, SM2 5PT - Sutton/GB
  • 4 Department Of Pathology, St-Augustinus Ziekenhuis, 2580 - Wilrijk/BE
  • 5 Department Of Pathology, Royal Marsden Hospital NHS Foundation Trust, SW6 1EJ - London/GB
  • 6 Department Of Pathology, Cruces University Hospital, Bilbao/ES
  • 7 Cancer Immunology Unit, University College London Cancer Institute, London/GB
  • 8 Skin And Renal Unit, Royal Marsden Hospital NHS Foundation Trust, SW6 1EJ - London/GB
  • 9 Division Of Infection And Immunity, Imperial College London, EJ - London/GB
  • 10 Cancer Institute, University College London, WC1E 6DD - London/GB
  • 11 Medicine, Royal Marsden Hospital NHS Foundation Trust, SW6 1EJ - London/GB
  • 12 Cancer Evolution And Genome Instability Laboratory, The Francis Crick Institute, NW1 1AT - London/GB

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Abstract 4138

Background

ADATPeR is the first prospective study evaluating the role of anti-PD1 agents in the neoadjuvant setting prior to cytoreductive nephrectomy in treatment-naïve patients with metastatic clear cell renal cell carcinoma (mccRCC). We performed multi-omic analyses to resolve spatial heterogeneity and temporal dynamics in putative biomarkers of response to anti-PD1 blockade.

Methods

In a single center study, patients received nivolumab (3mg/kg every 2 weeks) pre- and post-operatively until progressive disease (PD). Primary endpoint was safety, secondary endpoints were response evaluation and exploratory biomarker analysis. Multiregion tumour biopsies were obtained at baseline, on-treatment (week 9) and at PD. Whole-exome sequencing was performed to infer somatic mutations and predict candidate neoantigens (NAs). Tumour immune microenvironment was evaluated using a RNA-seq-derived immune signature and by stromal and intraepithelial tumour infiltrating lymphocytes (TILs) assessments.

Results

15 patients were treated. At median follow-up of 12.5 months(m), nivolumab had an acceptable side-effect profile. Overall response rate was 37%. Preliminary transcriptome analyses of pre-treatment biopsies (33 samples from 14 patients; up to 4 regions per case) revealed enrichment for primary-resistance (defined as PD within 2m; n = 4) with immune ‘cold’ tumours, distinct from ’hot’ tumours. Histologic TILs scoring showed concordant immune phenotypic clusters. Primary-resistant cases demonstrated 0% on-treatment stromal- and IE-TILs (2 evaluable patients). In contrast, we observed heavy on-treatment stromal TILs (70-90%) and intraepithelial TILs (30-90%) across 7 regions at nephrectomy in an exceptional responder receiving ongoing treatment (>24 cycles).

Conclusions

ADATPeR is the first neoadjuvant immune checkpoint inhibitor study pre-cytoreductive nephrectomy, and incorporated multi-omic analyses of putative biomarkers. Baseline immune gene expression signature is distinct in responders compared with non-responders. On-treatment intraepithelial TILs were prominent in those deriving durable clinical benefit. Integrative analyses are ongoing.

Clinical trial identification

NCT02446860.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Bristol-Myers Squibb; The National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research; Cancer Research UK (CRUK).

Disclosure

All authors have declared no conflicts of interest.

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