A Phase I clinical trial has shown promising results for the combination of sitravatinib, nivolumab, and ipilimumab for patients with advanced clear cell renal cell carcinoma (ccRCC). The study involved 22 previously untreated patients and aimed to evaluate the optimal dosing of this triplet therapy. Results indicated an overall response rate (ORR) of 45.5%, a disease control rate (DCR) of 86.4%, and a median progression-free survival (PFS) of 14.5 months, providing hope for patients resistant to standard treatments.
Conducted at The University of Texas MD Anderson Cancer Center, the trial enrolled patients between September 2020 and July 2022, with results reported as of August 25, 2023. The main objective was to assess the safety and preliminary efficacy of combining the tyrosine kinase inhibitor sitravatinib with the immune checkpoint inhibitors nivolumab and ipilimumab.
Despite the high expectations, researchers found significant immune-related adverse events (AEs) during the trial. Initial dosing included sitravatinib at 35 mg daily, nivolumab at 3 mg/kg, and ipilimumab at 1 mg/kg, which led to several dose modifications due to these AEs. Notably, the dosing of ipilimumab was successfully reduced to 0.7 mg/kg to improve the regimen's safety profile without compromising its efficacy.
The study revealed important correlations between treatment response and the tumor microenvironment (TME). It indicated the presence of dynamic shifts within the TME, including increased T cell counts and decreased myeloid and endothelial cells, with improved clinical outcomes linked to higher T cell abundance.
Though the combination treatment demonstrated efficacy, concerns around treatment resistance emerged. Researchers noted characteristics like epithelial-mesenchymal transition (EMT) associated with poor patient outcomes, highlighting the need for research on improving patient responses to treatment.
The combination therapy is particularly promising as it aims to overcome the limitations of existing treatments for ccRCC. Traditional therapies, including immune checkpoint therapies, have yielded mixed results, making the exploration of new combinations urgent.
Notably, the pharmacokinetics showed increased exposure to sitravatinib corresponding to dose escalation, reinforcing its viability as part of this triplet therapy. These findings could inform future treatment strategies and provide insights for optimizing immunotherapy efficacy.
Overall, the early results from this Phase I trial pave the way for larger studies to validate these observations. Continuous research will be imperative to determine the long-term outcomes of patients treated with this combination and whether these approaches can set new standards of care in advanced ccRCC.