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Markers of inflammation are associated with clinical outcomes in patients with metastatic renal cell carcinoma treated with nivolumab
  1. Mario Sznol1,
  2. Mayer Fishman2,
  3. Bernard Escudier3,
  4. David F McDermott4,
  5. Harriet Kluger5,
  6. Walter M Stadler6,
  7. Jose Perez-Gracia7,
  8. Douglas G McNeel8,
  9. Brendan D Curti9,
  10. Michael R Harrison10,
  11. Elizabeth R Plimack11,
  12. Leonard Appleman12,
  13. Lawrence Fong13,
  14. Charles G Drake14,
  15. Tina C Young15,
  16. Scott D Chasalow15,
  17. Petra Ross-MacDonald15,
  18. Jason S Simon15,
  19. Dana Walker15 and
  20. Toni K Choueiri16
  1. Aff1 grid.433818.5Yale Comprehensive Cancer Center New Haven CT USA
  2. Aff2 grid.170693.a000000012353285XDepartment of Medical OncologyH. Lee Moffitt Cancer Center and Research Institute Tampa FL USA
  3. Aff3 grid.14925.3b0000000122849388Department of Medical OncologyInstitut Gustave Roussy Villejuif France
  4. Aff4 grid.239395.70000000090118547The Cytokine Working Group; Division of Hematology/OncologyBeth Israel Deaconess Medical Center Boston MA USA
  5. Aff5 grid.433818.5Department of Medical OncologyYale Cancer Center New Haven CT USA
  6. Aff6 grid.170205.10000000419367822University of Chicago Medicine Chicago IL USA
  7. Aff7 grid.412375.6Department of OncologyUniversity Clinic of Navarra Pamplona Spain
  8. Aff8 grid.14003.360000000099041312Department of MedicineUniversity of Wisconsin-Madison Madison WI USA
  9. Aff9 grid.240531.1000000040456863XProvidence Cancer CenterProvidence Portland Medical Center Portland OR USA
  10. Aff10 grid.189509.c0000000100241216Department of SurgeryDuke University Medical Center Durham NC USA
  11. Aff11 grid.412530.10000000404566466Department of Medical OncologyFox Chase Cancer Center Philadelphia PA USA
  12. Aff12 grid.412689.00000000106507433Department of MedicineUniversity of Pittsburgh Medical Center Cancer Pavilion Pittsburgh PA USA
  13. Aff13 grid.266102.10000000122976811Department of MedicineUniversity of California San Francisco Helen Diller Family Comprehensive Cancer Center San Francisco CA USA
  14. Aff14 grid.21107.350000000121719311Department of OncologySidney Kimmel Comprehensive Cancer Center at Johns Hopkins University Baltimore MD USA
  15. Aff15 grid.419971.3Bristol-Myers Squibb Princeton NJ USA
  16. Aff16 grid.65499.370000000121069910Department of MedicineDana-Farber Cancer Institute Boston MA USA

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Meeting abstracts

Background

In previously treated patients with metastatic renal cell carcinoma (mRCC), the programmed death-1 (PD-1) inhibitor antibody nivolumab demonstrated objective response rates of 20%–22% and median overall survival (OS) of 18.2– 25.5 months[1]. An exploratory biomarker analysis of baseline and on-therapy changes was conducted to investigate the relationship between the clinical and immunomodulatory activity of nivolumab.

Methods

Patients with 1–3 prior therapies for mRCC received nivolumab 0.3, 2, or 10 mg/kg IV every 3 weeks (Q3W); treatment-naïve patients received 10 mg/kg IV Q3W. Biopsies and peripheral blood mononuclear cells were obtained at baseline and cycle 2 day 8. Tumor burden reduction was defined as a ≥20% decrease. Gene expression data were obtained on Affymetrix U219. OS parameters were estimated by the Kaplan-Meier method or by Cox proportional hazards regression. PD-1 ligand 1 (PD-L1) expression was measured by tumor membrane immunohistochemical staining (28-8 antibody; Dako) in baseline biopsies. Serum-soluble factors were quantified using a Luminex multiplex panel (Myriad Rules-Based Medicine). T cell receptor sequencing was conducted with the immunoSEQ assay (Adaptive Biotechnologies).

Results

91 patients were treated. 59 baseline and 55 on-therapy biopsies were evaluable for gene expression, with 42 matched samples. Patients with tumor burden reduction had differential expression (>1.3-fold, P < 0.01, q-value < 0.16) of 311 genes at baseline (n = 13) and 779 genes on-therapy (n = 11) compared with patients without tumor burden reduction, including higher expression of transcripts associated with cell-mediated immunity. CTLA-4, TIGIT, and PD-L2 transcripts were present at higher levels on-therapy in patients with tumor burden reduction. Table 1 summarizes OS and OS by PD-L1 expression. 18/56 biopsies (32%) had ≥5% PD-L1 expression. Among serum-soluble factors, recognized prognostic markers (VEGF, ICAM1, VCAM1, TIMP1) were associated with OS. Based on T cell sequencing, increased tumor T cell counts and decreased blood T cell clonality at baseline were associated with longer OS.

Table 1

Conclusions

Immune markers at baseline and on-therapy suggest pre-existing adaptive immunity is associated with nivolumab-induced tumor regression. Upregulation of immune checkpoint molecules provides rationale for study of nivolumab and ipilimumab combination in mRCC. A minimal difference in OS by PD-L1 expression was observed for up to 2 years.

Trial registration

ClinicalTrials.gov identifier NCT01358721.

Acknowledgments

Dako, for collaborative development of the automated PD-L1 immunohistochemistry assay. Adaptive Biotechnologies, for T cell repertoire analysis.

References

  1. 1.

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