Neoadjuvant Cabozantinib in an Unresectable Locally Advanced Renal Cell Carcinoma Patient Leads to Downsizing of Tumor Enabling Surgical Resection: A Case Report

Abstract

Introduction: Cabozantinib (XL-184) is a small molecule inhibitor of the tyrosine kinases c-Met, AXL, and VEGFR2 that has been shown to reduce tumor growth, metastasis, and angiogenesis. After the promising results from the METEOR and CABOSUN trials, cabozantinib was approved for use in the first- and second-line setting in patients with advanced RCC. Previously, targeted therapies have been used in the neoadjuvant setting for tumor size reduction and facilitating nephrectomies. The increased response rates with cabozantinib in metastatic renal cell carcinoma (mRCC), along with the other neoadjuvant TKI data, strongly support an expanded role for cabozantinib in the neoadjuvant setting.

Case description: We report on a 59-year-old gentleman presenting with an unresectable 21.7 cm left renal cell carcinoma (RCC) with extension to soft tissue and muscles of the thoracic cage, psoas muscle, posterior abdominal wall, tail of pancreas, splenic flexure of colon, and inferior margin of spleen. Presurgical, neoadjuvant systemic therapy with cabozantinib was initiated for 11 months in total. Initially after 2 months of cabozantinib, magnetic resonance imaging (MRI) revealed a significant reduction (44.2%) in tumor diameter from 21.7 to 12.1 cm with decreased extension into adjacent structures. After 11 months total of cabozantinib, the corresponding MRI showed grossly stable size of the tumor and significant resolution of invasion of adjacent structures. After washout of cabozantinib, radical resection, including nephrectomy, was successfully performed without any major complications, either intra-operative or perioperative. Negative margins were achieved.

Conclusions: This is a report of neoadjuvant cabozantinib downsizing a tumor and enabling surgical resection in this patient with locally advanced RCC. Our findings demonstrate that neoadjuvant cabozantinib to facilitate subsequent surgical resection may be a feasible option for patients presenting with unresectable RCC.

Keywords: cabozantinib; case report; neoadjuvant therapy; radical nephrectomy; renal cell carcinoma.

Figure 1

Coronal T2 weighted MRI at baseline (A) demonstrates a large 21.7 cm mass (white arrows) replacing the entire left kidney with central areas of necrosis. After just 2 months of cabozantinib therapy (B), the mass had decreased to 12.1 cm (white arrows). After 12 months of cabozantinib (C), the mass was stable in size.

Figure 2

Axial T1 weighted MR with contrast at baseline (A) demonstrates tumor invasion into the intercostal space (red arrowhead) and neovascularity (white arrow). By 2 months of therapy (B), the invasion has retracted (red arrowhead). By 12 months (C), the invasion has resolved and vascularity has decreased significantly.

Figure 3

Trend of tumor diameters, from MRIs, during cabozantinib therapy.

Figure 4

Clear cell renal cell carcinoma (white arrow) infiltrating into skeletal muscle (black arrow), representing psoas muscle and diaphragm. The background is fibrotic with extensive hemosiderin laden macrophages, possibly representing therapy related changes (H&E-10x).

Figure 5

(A) Flow cytometry gating scheme. Samples were gated to exclude doublets and cell aggregates and to include only single cells for further analysis. This single cell population was then gated to include only live, CD3+ cells, then to include only lymphocyte sized cells. These gates insured as pure of a T lymphocyte population as possible for further analysis. T lymphocytes were then divided into CD4+ and CD8+ populations. (B) Distribution of %CD8 of total cells by flow cytometry among a cohort of renal cell carcinoma patients, n = 198. (C) Distribution of pre-operative neutrophil to lymphocyte ratio among a cohort of renal cell carcinoma patients (n=74). (D) Distribution of pre-operative C-reactive protein level (mg/L) among a cohort of renal cell carcinoma patients (n=74). (E) Distribution of pre-operative albumin level (g/dl) among a cohort of renal cell carcinoma patients (n=76). (B–E) Patient of interest highlighted in red. Box plots show middle 50% with the median at the center and the whiskers extending to minimum and maximum values.

Figure 6

(A, B) Immunofluorescence imaging illustrating sparse CD8 T cell infiltration (A, B, left) and presence of CD31+ endothelium (A, B, right) in resected tumor specimens (A representative. Mass, B mass to Gerota’s fascia). (C, D) Hematoxylin and eosin staining shows presence of tertiary lymphoid structures (highlighted in insets) (C representative mass, D mass to Gerota’s fascia).