Circulating and Intratumoral Immune Determinants of Response to Atezolizumab plus Bevacizumab in Patients with Variant Histology or Sarcomatoid Renal Cell Carcinoma

Author:

Saliby Renee Maria1ORCID,El Zarif Talal1ORCID,Bakouny Ziad12ORCID,Shah Valisha1ORCID,Xie Wanling3ORCID,Flippot Ronan4ORCID,Denize Thomas5ORCID,Kane M. Harry6ORCID,Madsen Katrine N.6ORCID,Ficial Miriam5ORCID,Hirsch Laure1ORCID,Wei Xiao X.1ORCID,Steinharter John A.17ORCID,Harshman Lauren C.18ORCID,Vaishampayan Ulka N.9ORCID,Severgnini Mariano10ORCID,McDermott David F.11ORCID,Lee Gwo-Shu Mary1ORCID,Xu Wenxin1ORCID,Van Allen Eliezer M.1ORCID,McGregor Bradley A.1ORCID,Signoretti Sabina5ORCID,Choueiri Toni K.1ORCID,McKay Rana R.12ORCID,Braun David A.16ORCID

Affiliation:

1. 1Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

2. 2Department of Internal Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

3. 3Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts.

4. 4Department of Cancer Medicine, Gustave Roussy, Paris Saclay University, Villejuif, France.

5. 5Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

6. 6Yale Center of Cellular and Molecular Oncology, Yale School of Medicine, New Haven, Connecticut.

7. 7Larner College of Medicine, University of Vermont, Burlington, Vermont.

8. 8Surface Oncology, Cambridge, Massachusetts.

9. 9University of Michigan/Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.

10. 10Center for Immuno-Oncology Immune Assessment Laboratory at the Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

11. 11Division of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.

12. 12Moores Cancer Center, University of California San Diego, La Jolla, California.

Abstract

Abstract Renal cell carcinoma (RCC) of variant histology comprises approximately 20% of kidney cancer diagnoses, yet the optimal therapy for these patients and the factors that impact immunotherapy response remain largely unknown. To better understand the determinants of immunotherapy response in this population, we characterized blood- and tissue-based immune markers for patients with variant histology RCC, or any RCC histology with sarcomatoid differentiation, enrolled in a phase II clinical trial of atezolizumab and bevacizumab. Baseline circulating (plasma) inflammatory cytokines were highly correlated with one another, forming an “inflammatory module” that was increased in International Metastatic RCC Database Consortium poor-risk patients and was associated with worse progression-free survival (PFS; P = 0.028). At baseline, an elevated circulating vascular endothelial growth factor A (VEGF-A) level was associated with a lack of response (P = 0.03) and worse PFS (P = 0.021). However, a larger increase in on-treatment levels of circulating VEGF-A was associated with clinical benefit (P = 0.01) and improved overall survival (P = 0.0058). Among peripheral immune cell populations, an on-treatment decrease in circulating PD-L1+ T cells was associated with improved outcomes, with a reduction in CD4+PD-L1+ [HR, 0.62; 95% confidence interval (CI), 0.49–0.91; P = 0.016] and CD8+PD-L1+ T cells (HR, 0.59; 95% CI, 0.39–0.87; P = 0.009) correlated with improved PFS. Within the tumor itself, a higher percentage of terminally exhausted (PD-1+ and either TIM-3+ or LAG-3+) CD8+ T cells was associated with worse PFS (P = 0.028). Overall, these findings support the value of tumor and blood-based immune assessments in determining therapeutic benefit for patients with RCC receiving atezolizumab plus bevacizumab and provide a foundation for future biomarker studies for patients with variant histology RCC receiving immunotherapy-based combinations.

Funder

Genentech

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Immunology

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