Integrative Analyses of Tumor and Peripheral Biomarkers in the Treatment of Advanced Renal Cell Carcinoma

Author:

Choueiri Toni K.1ORCID,Donahue Amber C.2ORCID,Braun David A.3ORCID,Rini Brian I.4ORCID,Powles Thomas5ORCID,Haanen John B.A.G.6ORCID,Larkin James7ORCID,Mu Xinmeng Jasmine2ORCID,Pu Jie2ORCID,Teresi Rosemary E.8ORCID,di Pietro Alessandra9ORCID,Robbins Paul B.2ORCID,Motzer Robert J.10ORCID

Affiliation:

1. 1The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

2. 2Pfizer, La Jolla, California.

3. 3Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

4. 4Hematology Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.

5. 5Department of Genitourinary Oncology, Barts Cancer Institute, Experimental Cancer Medicine Centre, Queen Mary University of London, St Bartholomew's Hospital, London, United Kingdom.

6. 6Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.

7. 7Department of Medical Oncology, Royal Marsden NHS Foundation Trust, London, United Kingdom.

8. 8Pfizer, New York, New York.

9. 9Pfizer, Milan, Italy.

10. 10Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Abstract

Abstract The phase III JAVELIN Renal 101 trial demonstrated prolonged progression-free survival (PFS) in patients (N = 886) with advanced renal cell carcinoma treated with first-line avelumab + axitinib (A+Ax) versus sunitinib. We report novel findings from integrated analyses of longitudinal blood samples and baseline tumor tissue. PFS was associated with elevated lymphocyte levels in the sunitinib arm and an abundance of innate immune subsets in the A+Ax arm. Treatment with A+Ax led to greater T-cell repertoire modulation and less change in T-cell numbers versus sunitinib. In the A+Ax arm, patients with tumors harboring mutations in ≥2 of 10 previously identified PFS-associated genes (double mutants) had distinct circulating and tumor-infiltrating immunologic profiles versus those with wild-type or single-mutant tumors, suggesting a role for non–T-cell–mediated and non–natural killer cell–mediated mechanisms in double-mutant tumors. We provide evidence for different immunomodulatory mechanisms based on treatment (A+Ax vs. sunitinib) and tumor molecular subtypes. Significance: Our findings provide novel insights into the different immunomodulatory mechanisms governing responses in patients treated with avelumab (PD-L1 inhibitor) + axitinib or sunitinib (both VEGF inhibitors), highlighting the contribution of tumor biology to the complexity of the roles and interactions of infiltrating immune cells in response to these treatment regimens. This article is featured in Selected Articles from This Issue, p. 384

Funder

N/A

Publisher

American Association for Cancer Research (AACR)

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