MD Anderson Cancer Center researchers have reported promising results from a phase 1 trial investigating a novel triplet combination therapy for advanced clear cell renal cell carcinoma (ccRCC), marking a potential advancement in first-line treatment options for this aggressive cancer.
The study, published in Nature Communications, evaluated the combination of sitravatinib, a tyrosine kinase inhibitor, with the immunotherapy agents nivolumab and ipilimumab in 22 previously untreated patients with advanced ccRCC.
Safety and Dosing Optimization
Initial testing revealed that sitravatinib at 35 mg daily combined with standard doses of nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) resulted in a high frequency of immune-related adverse events. Investigators successfully optimized the regimen by reducing ipilimumab to 0.7 mg/kg, which allowed for safe escalation of sitravatinib to 100 mg daily.
Efficacy Outcomes
The triplet combination demonstrated substantial clinical activity with:
- Objective response rate: 45.5%
- Disease control rate: 86.4%
- Median progression-free survival: 14.5 months
- One-year survival probability: 80.8%
Notably, the median overall survival and duration of response had not been reached at the time of analysis, suggesting durable treatment benefits. Pharmacokinetic analysis confirmed dose-dependent increases in sitravatinib exposure.
Molecular Insights into Treatment Response
The research team conducted sophisticated molecular analyses using single-cell RNA sequencing on tumor biopsies from 12 patients throughout their treatment course. This investigation revealed critical insights into treatment resistance mechanisms:
- Identification of a tumor cell-specific epithelial-mesenchymal transition-like program associated with poor outcomes
- Observation of T cell state transitions from cytotoxic to exhausted phenotypes
- Enrichment of M2-like myeloid cells in resistant tumors
Clinical Implications
Dr. Pavlos Msaouel, lead investigator from MD Anderson Cancer Center, emphasized the significance of these molecular findings: "Understanding the dynamic changes in cellular states during treatment provides crucial insights for developing strategies to overcome resistance and optimize immunotherapy efficacy."
The study, registered as NCT04518046, represents a significant step forward in understanding combination immunotherapy approaches for advanced renal cell carcinoma. The molecular insights gained may inform future therapeutic strategies and biomarker development for patient selection.
