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Pathologic scoring of pre-treatment H&E biopsies predicts overall survival in patients with metastatic clear cell renal cell carcinoma receiving nivolumab monotherapy

Date

30 Sep 2019

Session

Poster Display session 3

Presenters

Julie Stein

Citation

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

Authors

J.E. Stein1, S. Signoretti2, M. Sznol3, Y. Ishii4, D.F. McDermott5, T.K. Choueiri6, J.M. Taube1

Author affiliations

  • 1 Dermatology, Johns Hopkins University, 21287 - Baltimore/US
  • 2 Pathology, Brigham and Women's Hospital, 02215 - Boston/US
  • 3 Medical Oncology, Yale University School of Medicine, 06520-8028 - New Haven/US
  • 4 Medical Oncology, Bristol-Myers Squibb, 08648 - Princeton/US
  • 5 Hematology/oncology, Beth Israel Deaconess Med. Center, 2215 - Boston/US
  • 6 Medical Oncology, Dana-Farber Cancer Institute, 02215 - Boston/US
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Background

Anti-PD-1 therapy is effective and durable in a subset of patients with metastatic clear cell renal cell carcinoma (mCCRCC). Previous studies have suggested that PBRM1 mutations associate with response to anti-PD-1. Here, we assessed routine, pre-treatment hematoxylin and eosin-stained (H&E) slides for features of a pre-existing immune response to tumor and tested them for an association with overall survival (OS).

Methods

We studied prospectively-collected pre-treatment biopsies from 56 patients (n = 15 treatment naïve; n = 41 previously failed at least 1 prior anti-angiogenic agent) as part of the CheckMate 009 trial (NCT01358721). H&E-stained slides were scored by two pathologists blinded to patient outcome for features of immune-related pathologic response (irPR, Cottrell, Ann Oncol 2018; Stein, Ann Oncol 2019) and necrosis. Specifically, the co-localization of moderate-high tumor infiltrating lymphocytes, plasma cells, lymphoid aggregates, neovascularization, and proliferative fibrosis was scored and compared to OS. 23 patients also had genomic data available for study.

Results

H&E evidence of a pre-existing immune response to tumor (irPR score=1 or 2) associated with improved 5-year OS (median survival undefined at 5 years vs. 16.0 months, log-rank, p = 0.006). Necrosis score alone did not associate with OS, however, a composite score (irPR minus necrosis) distinguished a population of patients with particularly poor OS following anti-PD-1 therapy (median survival 40.5 months vs. 12.3 months, log-rank, p = 0.01). Prior systemic therapy did not affect irPR or necrosis scores (p > 0.05, Fisher’s exact test). Patients positive for both an irPR score of 1 or 2 and PBRM1 mutation had significantly improved OS as compared to patients negative for both (median survival undefined vs. 7.9 months, log-rank p = 0.002).

Conclusions

Pre-treatment H&E slides can be used to predict OS in patients with mCCRCC treated with anti-PD-1 using a routine surgical pathology workflow. Early evidence suggests that the combination of irPR scoring with genomic testing for PBRM1 may further stratify the predictive ability of these assessments beyond either individual approach alone.

Clinical trial identification

NCT01358721.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

NIH T32 CA193145.

Disclosure

S. Signoretti: Advisory / Consultancy: AstraZeneca/MedImmune, Merck, AACR, NCI; Research grant / Funding (self): AstraZeneca, Exelixis, Bristol-Myers Squibb; Licensing / Royalties: Biogenex Laboratories. M. Sznol: Advisory / Consultancy: Bristol-Myers Squibb, Genentech/Roche, AstraZeneca-MedImmune, Novartis, Seattle Genetics, Nektar, Lilly, Biodesix, Modulate Therapeutics, Newlink Genetics, Molecular Partners, Innate Pharma, AbbVie, Immunocore, Genmab, Almac, Hinge, Anaeropharma, Array, G; Shareholder / Stockholder / Stock options: Amphivena, Intensity Therapeutics, Adaptive Biotechnologies, Nextcure, Actym, Torque . Y. Ishii: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. D.F. McDermott: Advisory / Consultancy: Bristol-Myers Squibb, Merck, Pfizer, Novartis, Eisai, Exelixis, Array BioPharma, Alkermes, Inc., Jounce Therapeutics, X4 Pharmaceuticals, Peloton Therapeutics, EMD Serono and Genentech BioOncology, Eli Lilly; Research grant / Funding (self): Bristol-Myers Squibb, Prometheus Laboratories, Merck, Genentech, Pfizer, Exelixis, Novartis, X4 Pharmaceuticals, Alkermes, Inc. and Peloton. T.K. Choueiri: Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca, Bayer, BMS, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Takeda; Honoraria (self), Honoraria (institution): AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN,; Advisory / Consultancy: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Heron Therapeutics, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, A. J.M. Taube: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck; Advisory / Consultancy: Amgen. All other authors have declared no conflicts of interest.

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