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 (IMDC)-poor risk patients and was associated with worse progression-free survival (PFS) (p=0.028). At baseline, an elevated circulating 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[0.49-0.91], p=0.016) and CD8+PD-L1+ T cells (HR:0.59[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.
Cancer immunology research. 2023 Jun 06 [Epub ahead of print]
Renee Maria Saliby, Talal El Zarif, Ziad Bakouny, Valisha Shah, Wanling Xie, Ronan Flippot, Thomas Denize, M Harry Kane, Katrine N Madsen, Miriam Ficial, Laure Hirsch, Xiao X Wei, John A Steinarter, Lauren C Harshman, Ulka N Vaishampayan, Mariano Severgnini, David F McDermott, Gwo-Shu Mary Lee, Wenxin Xu, Eliezer M Van Allen, Bradley A McGregor, Sabina Signoretti, Toni K Choueiri, Rana R McKay, David A Braun
Dana-Farber/Brigham and Women's Cancer Center, Boston, United States., Dana-Farber Cancer Institute, Boston, MA, United States., Brigham and Women's Hospital, Boston, MA, United States., Dana-Farber Cancer Institute, Boston, Massachusetts, United States., Institut Gustave Roussy, France., Brigham and Women's Hospital, Boston, United States., Yale Cancer Center, United States., Yale Cancer Center, New Haven, United States., Dana-Farber Cancer Institute, Boston, United States., Dana-Farber Cancer Institute, United States., University of Michigan Medical School, Ann Arbor, Michigan, United States., Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States., Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States., University of California, San Diego, La Jolla, CA, United States., Yale School of Medicine, New Haven, CT, United States.