Neoadjuvant Cabozantinib for Locally Advanced Nonmetastatic Clear Cell Renal Cell Carcinoma: A Phase 2 Trial

Urology Oncology Nephrology Immunology Life Sciences Medicine
renal cell carcinoma cabozantinib neoadjuvant therapy locally advanced clinical trial

Academic Background

Renal Cell Carcinoma (RCC) is one of the cancers with a rapidly rising incidence globally, particularly among young patients and minorities. In the United States, an estimated 81,610 new cases of RCC will be diagnosed in 2024, with approximately 30% progressing to metastatic RCC. For locally advanced RCC, the initial treatment is typically partial or radical nephrectomy. However, although surgery can cure many patients, about 50% of patients experience recurrence within 5 years. Due to the high recurrence rate, researchers have recently begun exploring intensified therapies to improve patient outcomes. For example, adjuvant anti-PD-1 therapy after surgery has been shown to provide a small but significant improvement in overall survival. Nevertheless, the potential additional benefits of neoadjuvant therapy (treatment administered before surgery) remain under investigation.

The original intent of neoadjuvant therapy was to reduce tumor size, making previously unresectable tumors operable or enabling partial nephrectomy (nephron-sparing surgery) for some patients, thereby preserving renal function and reducing the long-term risk of renal insufficiency. However, researchers have increasingly recognized that certain neoadjuvant therapies, particularly immunotherapies, may improve long-term survival by stimulating a lasting anti-tumor immune response.

Cabozantinib is a multi-target tyrosine kinase inhibitor (TKI) that inhibits targets such as MET, AXL, RET, and VEGFR2, thereby suppressing tumor growth, metastasis, and angiogenesis. Cabozantinib has been approved for the treatment of metastatic RCC and has been shown in several preclinical models to enhance anti-tumor immune responses. As such, Cabozantinib is considered a promising candidate for neoadjuvant therapy.

Source of the Paper

This study was conducted by researchers including Mehmet A. Bilen, Viraj A. Master, and Haydn T. Kissick from Emory University and was published in the March 2025 issue of Nature Cancer. The study is a single-arm, non-randomized phase II clinical trial (NCT04022343) aimed at evaluating the neoadjuvant efficacy of Cabozantinib in patients with locally advanced non-metastatic clear cell renal cell carcinoma (ccRCC).

Study Process and Results

Study Design

The study enrolled 17 patients with biopsy-confirmed locally advanced non-metastatic ccRCC who received 12 weeks of Cabozantinib treatment prior to surgical resection. The primary endpoint was the objective response rate (ORR) at 12 weeks, including complete response (CR) and partial response (PR). Secondary endpoints included safety, tolerability, clinical and surgical outcomes, and quality of life.

Treatment Outcomes

The results showed that 6 patients (35%) achieved partial response (PR), while 11 patients (65%) had stable disease (SD). All patients experienced tumor shrinkage, with a clinical benefit rate of 100%, and no patients showed disease progression during treatment. The median reduction in primary renal tumor size was 26% (range: 8%-42%). One patient deemed initially unresectable became eligible for surgery after treatment, and two patients were converted from radical nephrectomy to partial nephrectomy.

Safety

The most common adverse events included diarrhea (70.6%), anorexia, fatigue, and hypertension (58.8%), as well as nausea and palmar-plantar erythrodysesthesia syndrome (52.9%). No grade 4 or 5 adverse events related to Cabozantinib or surgery occurred.

Immune Activation

The study found that Cabozantinib treatment activated CD8+ T cells in the peripheral blood of patients, depleted myeloid cell populations, and induced immune niches for TCF1+ stem-like CD8+ T cells. These results suggest that Cabozantinib not only has direct anti-tumor effects but may also improve long-term outcomes by enhancing immune responses.

Plasma Biomarkers and Tumor Response

The study also analyzed the relationship between plasma cell-free DNA (cfDNA) and cytokines with tumor response. The results showed that cfDNA concentrations significantly increased during treatment and correlated with changes in tumor size. Additionally, plasma concentrations of VEGF, c-MET, GAS6, and AXL significantly increased during Cabozantinib treatment, while VEGFR2 concentrations significantly decreased. These biomarkers may serve as early indicators of treatment efficacy.

Imaging Features

Magnetic resonance imaging (MRI) was used to monitor tumor response to Cabozantinib. The study found that tumors in patients with partial response (PR) significantly shrank at 12 weeks, while tumors in patients with stable disease (SD) remained largely unchanged. Furthermore, by calculating imaging features (such as Haralick and gradient features), researchers found that PR patients had higher tumor heterogeneity at baseline.

Tumor Immune Microenvironment

The researchers also analyzed the impact of Cabozantinib on the tumor immune microenvironment. The results showed that Cabozantinib significantly increased CD8+ T cell infiltration in tumors and induced the formation of TCF1+ stem-like CD8+ T cells. These cells, along with antigen-presenting cells (APCs), formed immune niches that may be associated with long-term survival and response to immunotherapy.

Conclusions and Significance

This study demonstrates that Cabozantinib is safe and effective as a neoadjuvant treatment for patients with locally advanced non-metastatic ccRCC. It not only significantly reduces tumor size, making some initially unresectable patients eligible for surgery, but may also improve long-term outcomes by activating immune responses. The findings support further exploration of Cabozantinib in combination with immunotherapy and provide important biomarkers and imaging features for future clinical trials.

Highlights of the Study

  1. Significant Tumor Shrinkage: Cabozantinib treatment led to tumor shrinkage in all patients, with some patients transitioning from unresectable to resectable.
  2. Immune Activation Effects: Cabozantinib significantly activated CD8+ T cells and induced the formation of stem-like CD8+ T cells, providing a potential foundation for immunotherapy.
  3. Discovery of Biomarkers: Changes in plasma cfDNA and cytokines were closely related to tumor response, potentially serving as early indicators of treatment efficacy.
  4. Predictive Value of Imaging Features: By calculating imaging features, researchers found that tumor heterogeneity correlated with treatment response, offering new insights for personalized therapy.

Additional Valuable Information

The study also detailed patient quality of life and postoperative complications, further demonstrating the safety of Cabozantinib in neoadjuvant therapy. Additionally, researchers analyzed transcriptional changes in the tumor microenvironment through RNA sequencing, revealing Cabozantinib’s regulatory effects on immune-related pathways.

This study provides new insights and evidence for neoadjuvant therapy in patients with locally advanced non-metastatic ccRCC, holding significant scientific value and clinical application prospects.