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Ross-Macdonald P, Walsh AM, Chasalow SD, et al. Molecular correlates of response to nivolumab at baseline and on treatment in patients with RCC. J Immunother Cancer. 2021;9(3)doi: 10.1136/jitc-2020-001506.
Ross-Macdonald, P., Walsh, A. M., Chasalow, S. D., Ammar, R., Papillon-Cavanagh, S., Szabo, P. M., Choueiri, T. K., Sznol, M., & Wind-Rotolo, M. (2021). Molecular correlates of response to nivolumab at baseline and on treatment in patients with RCC. Journal for immunotherapy of cancer, 9(3), . https://doi.org/10.1136/jitc-2020-001506
Ross-Macdonald, Petra, et al. "Molecular correlates of response to nivolumab at baseline and on treatment in patients with RCC." Journal for immunotherapy of cancer vol. 9,3 (2021). doi: https://doi.org/10.1136/jitc-2020-001506
Ross-Macdonald P, Walsh AM, Chasalow SD, Ammar R, Papillon-Cavanagh S, Szabo PM, Choueiri TK, Sznol M, Wind-Rotolo M. Molecular correlates of response to nivolumab at baseline and on treatment in patients with RCC. J Immunother Cancer. 2021 Mar;9(3). doi: 10.1136/jitc-2020-001506. PMID: 33658305; PMCID: PMC7931766.
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J Immunother Cancer. 2021 Mar;9(3). doi: 10.1136/jitc-2020-001506.

Molecular correlates of response to nivolumab at baseline and on treatment in patients with RCC.

Journal for immunotherapy of cancer

Petra Ross-Macdonald, Alice M Walsh, Scott D Chasalow, Ron Ammar, Simon Papillon-Cavanagh, Peter M Szabo, Toni K Choueiri, Mario Sznol, Megan Wind-Rotolo

Affiliations

  1. Translational Medicine, Bristol Myers Squibb, Princeton, New Jersey, USA.
  2. Department of Genitourinary Oncology, The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.
  3. Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA.
  4. Translational Medicine, Bristol Myers Squibb, Princeton, New Jersey, USA [email protected].

PMID: 33658305 PMCID: PMC7931766 DOI: 10.1136/jitc-2020-001506

Abstract

BACKGROUND: Nivolumab is an immune checkpoint inhibitor targeting the programmed death-1 receptor that improves survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). In contrast to other tumor types that respond to immunotherapy, factors such as programmed death ligand-1 (PD-L1) status and tumor mutational burden show limited predictive utility in ccRCC. To address this gap, we report here the first molecular characterization of nivolumab response using paired index lesions, before and during treatment of metastatic ccRCC.

METHODS: We analyzed gene expression and T-cell receptor (TCR) clonality using lesion-paired biopsies provided in the CheckMate 009 trial and integrated the results with their PD-L1/CD4/CD8 status, genomic mutation status and serum cytokine assays. Statistical tests included linear mixed models, logistic regression models, Fisher's exact test, and Kruskal-Wallis rank-sum test.

RESULTS: We identified transcripts related to response, both at baseline and on therapy, including several that are amenable to peripheral bioassays or to therapeutic intervention. At both timepoints, response was positively associated with T-cell infiltration but not associated with TCR clonality, and some non-Responders were highly infiltrated. Lower baseline T-cell infiltration correlated with elevated transcription of Wnt/β-catenin signaling components and hypoxia-regulated genes, including the Treg chemoattractant CCL28. On treatment, analysis of the non-responding patients whose tumors were highly T-cell infiltrated suggests association of the RIG-I-MDA5 pathway in their nivolumab resistance. We also analyzed our data using previous transcriptional classifications of ccRCC and found they concordantly identified a molecular subtype that has enhanced nivolumab response but is sunitinib-resistant.

CONCLUSION: Our study describes molecular characteristics of response and resistance to nivolumab in patients with metastatic ccRCC, potentially impacting patient selection and first-line treatment decisions.

TRIAL REGISTRATION NUMBER: NCT01358721.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Keywords: gene expression profiling; immunotherapy; kidney neoplasms; t-lymphocytes; tumor biomarkers

Conflict of interest statement

Competing interests: PR-M, SDC, SP-C, PMS, RA, AMW, and MW-R were employees of Bristol Myers Squibb at the time of their contribution. TKC has served as a consultant/advisor for Pfizer, GlaxoSmithKlin

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