Titrating Cabozantinib in Metastatic Renal Cell Carcinoma Patients Using Goldilocks Principle: A Real-World Evidence Study

Abstract

Introduction

The incidence of renal cell carcinoma (RCC) continues to rise worldwide, and this malignancy has demonstrated substantial sensitivity to both immunotherapies and targeted agents, particularly tyrosine kinase inhibitors (TKIs). Cabozantinib, a commonly utilized TKI, has shown promising efficacy across multiple clinical trials. This study aims to evaluate the real-world effectiveness of individualized cabozantinib dosing as a later-line treatment in patients with metastatic RCC (mRCC).

Patients and methods

Patients with mRCC treated at the Department of Oncology, Aarhus University Hospital, Denmark, were identified to estimate the median progression free survival (mPFS) and median overall survival (mOS) from treatment initiation. Best radiological response was evaluated using RECIST 1.1. Multivariable cox regression analyses were performed, including covariates such as brain metastasis, first-line treatment, line of treatment, ECOG Performance Status, IMDC risk group, nephrectomy status, and toxicity.

Results

A total of 179 patients were included, of which 139 patients received second-line (2L) treatment, and 40 patients received third+-line (3+L) treatment. We found a mPFS of 11.2 months for 2L treatment and 11.6 months for 3+L treatment. The mOS was 15.6 months for the 2L group and 17.1 months for the 3+L group. The mPFS and mOS in the IMDC favourable risk group were 28.5 and 52.1 months, respectively. No significant differences in mPFS or mOS were observed based on prior 1L treatment or the presence of brain metastases. The mOS and mPFS found in this study are comparable to, and in some cases exceed, those reported in other real-world cohorts. Interestingly, we found treatment-related toxicity to correlate significantly with an increased survival (mOS 66.8 vs. 32.8 months, P = .016) (mPFS 14,7 vs. 8,5 months, P = .013).

Conclusion

This study reinforces the existing data on effectiveness of cabozantinib as a later-line treatment for mRCC in real-world settings. We report 40 mg as the preferred landing zone. Furthermore we identify patients needing dose reductions due to toxicity as a subgroup carrying a significantly better prognosis. The results emphasize the importance of individual dosage for optimizing treatment outcomes and points out treatment-related toxicity as a surrogate marker for sufficient serum concentration of the active substance.