Immunomodulatory Response to Neoadjuvant Nivolumab in Non-Metastatic Clear Cell Renal Cell Carcinoma

Surgery (partial or radical nephrectomy) performed with curative intent is the gold standard approach to treating localized, non-metastatic kidney cancer. Despite complete resection of all radiographically apparent disease, however, upwards of one-third of patients may exhibit recurrence, particularly those who initially present with locally advanced or high-risk features. The use of perioperative therapies (neoadjuvant and/or adjuvant approaches) has been explored throughout the targeted therapy era and is now increasingly in our contemporary era of immune checkpoint inhibition (ICI).

In the former era, the only trial that resulted in FDA approval of a perioperative therapy for localized clear cell renal cell carcinoma (ccRCC) was the S-TRAC trial, which demonstrated a disease-free survival (DFS) benefit with the use of adjuvant sunitinib compared to observation alone. The actuarial utilization of this agent has been low, however, based on the lack of demonstrable overall survival (OS) benefit. In the ICI era, the KEYNOTE-564 trial resulted in the FDA approval of adjuvant pembrolizumab for these high-risk patients based on a DFS benefit. Excitingly, for the first time, improvements in OS with the use of adjuvant pembrolizumab compared to observation alone were recently presented. Curiously, other ICI agents that have been investigated perioperatively for non-metastatic ccRCC have fallen short of reaching their primary endpoints in their index phase III trials, including IMmotion010 (adjuvant atezolizumab), CheckMate 914 (adjuvant ipilimumab and nivolumab), and PROSPER-RCC (combined neoadjuvant and adjuvant nivolumab). We continue to lack any approved agents for the neoadjuvant treatment of high-risk, non-metastatic ccRCC prior to nephrectomy.

Despite the relatively discouraging results from most perioperative ccRCC trials, there is pre-clinical rationale and evidence from other malignancies (e.g., melanoma) to support the use of neoadjuvant ICI or combination neoadjuvant and adjuvant approaches. In particular, PD-1 inhibition may theoretically enhance the anti-tumor T cell response induced by the primary tumor while the tumor still remains in situ. Furthermore, nephrectomy tissue following ICI offers a unique translational platform to study the effects of therapy on the primary tumor itself and in circulation.

We conducted a phase I trial of administering 3 cycles of neoadjuvant nivolumab prior to nephrectomy in 17 patients with non-metastatic, high-risk ccRCC. We present correlative analyses in 15 evaluable patients by leveraging matched primary tumor tissue and blood samples collected at various time points throughout the trial. Specifically, we performed bulk RNAseq and fluorescence-activated cell sorting (FACS) analyses on matched treatment-naïve tumor biopsies and nivolumab-treated nephrectomy specimen as well as FACS and circulating cytokine analyses on blood samples collected pre-nivolumab, post-nivolumab, and post-nephrectomy. The objective of our work was to elucidate the effects of PD-1 inhibition on primary tumor-infiltrating and circulating immune cell populations in ccRCC and to correlate the tumor microenvironment and circulating immune cell compositions with response to anti-PD-1 therapy.

We found that treatment with nivolumab promotes an inflammatory state within the primary tumor and that nivolumab remains durably bound to tumor-infiltrating lymphocytes (TIL). Using published gene signatures, we also found that immune infiltration at baseline predicts response to nivolumab, with more highly inflamed tumors exhibiting better response. Most strikingly, we found that neoadjuvant PD-1 inhibition may prime perioperative synergy for rational ICI combination strategies. In particular, we observed an increase in CTLA-4 expression on tumor-infiltrating CD8+ T cells following exposure to nivolumab, and we also found that circulating levels of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB were significantly increased 6 months following nephrectomy after neoadjuvant nivolumab. These are all notably targetable molecules. Hence, while 3 cycles of neoadjuvant nivolumab alone may be insufficient to elicit a pathologic complete response or demonstrate a conceivable oncologic benefit, there may be a potential role in combining neoadjuvant PD-1 inhibition with adjuvant strategies.

Indeed, our study is limited by several factors, including the small sample size and lack of response by RECIST v1.1 criteria among others that we have enumerated, and our observations must be interpreted with caution in the context of these limitations. However, our study provides important hypothesis-generating insights into the biology underlying response and resistance to anti-PD-1 therapy in primary ccRCC tumors. These findings will be crucial to better justify and understand the synergistic effects of perioperative combination drug therapies for high-risk, non-metastatic ccRCC.

Written by: Nirmish Singla, MD, MSCS, FACS, Associate Professor, Departments of Urology and Oncology, The James Buchanan, Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD

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