From the Guidelines
For a patient with stage 4 kidney cancer (renal cell carcinoma) in the intermediate risk Heng group, I recommend starting treatment with nivolumab plus ipilimumab, administered as nivolumab 3 mg/kg and ipilimumab 1 mg/kg intravenously once every 3 weeks for four cycles, followed by nivolumab 3 mg/kg once every 2 weeks. This recommendation is based on the most recent and highest quality study, which demonstrated that nivolumab plus ipilimumab improved overall survival (OS) and progression-free survival (PFS) compared to sunitinib in intermediate- and poor-risk patients 1. The study found that at a minimum study follow-up of 42 months, nivolumab plus ipilimumab improved OS probability (52% vs 39%) and PFS probability (33% vs 16%) compared to sunitinib. Additionally, the study reported higher objective response rates (42% vs 26%) and complete response rates (10.1% vs 1.4%) with nivolumab plus ipilimumab compared to sunitinib. Other options, such as pembrolizumab plus axitinib or nivolumab plus cabozantinib, may also be considered, but the evidence from the study 1 supports nivolumab plus ipilimumab as a preferred regimen for intermediate-risk patients. It is essential to regularly monitor for immune-related adverse events, including thyroid function tests, liver enzymes, and renal function, and to continue treatment until disease progression or unacceptable toxicity. The dual approach of targeting both immune checkpoints and angiogenesis pathways provides synergistic effects, enhancing anti-tumor activity by both directly attacking cancer cells and stimulating the immune system to recognize and destroy tumor cells. Other guidelines, such as those from the ESMO 1 and NCCN 1, also support the use of immunotherapy-based combination therapy for intermediate-risk patients, but the study 1 provides the most recent and highest quality evidence for this recommendation.
From the FDA Drug Label
The efficacy of YERVOY with nivolumab was evaluated in CHECKMATE-214 (NCT02231749), a randomized (1:1), open-label study in patients with previously untreated advanced RCC. Patients were included regardless of their PD-L1 status CHECKMATE-214 excluded patients with any history of or concurrent brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression Patients were randomized to nivolumab 3 mg/kg and YERVOY 1 mg/kg administered intravenously every 3 weeks for 4 doses followed by nivolumab 3 mg/kg every two weeks or to sunitinib administered orally 50 mg daily for the first 4 weeks of each 6-week cycle. In intermediate/poor risk patients, the trial demonstrated statistically significant improvement in OS and ORR for patients randomized to YERVOY and nivolumab arm as compared with sunitinib arm.
The patient has stage 4 kidney cancer and an intermediate risk group according to Heng, so the treatment should be started with nivolumab 3 mg/kg and ipilimumab 1 mg/kg administered intravenously every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every two weeks 2.
From the Research
Treatment Options for Stage 4 Kidney Cancer
According to the Heng criteria, patients with intermediate-risk metastatic renal cell carcinoma (mRCC) have a poorer prognosis compared to those with favorable-risk disease. The treatment options for these patients are:
- Sunitinib, a multi-targeted tyrosine kinase inhibitor, which has been shown to improve overall survival in patients with mRCC 3
- Nivolumab-ipilimumab, an immunotherapy combination that has demonstrated a survival benefit over sunitinib in the first-line setting for patients with intermediate or poor risk prognosis 4
- Pazopanib, another tyrosine kinase inhibitor that has been shown to have a higher objective response rate and longer progression-free survival compared to sunitinib in the pre-nivolumab setting 5
First-Line Treatment Options
The current and emerging therapies for first-line treatment of metastatic clear cell renal cell carcinoma include:
- Single agent vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs): sunitinib, pazopanib, and cabozantinib
- Combination of lenvatinib and everolimus (mTOR inhibitor)
- Nivolumab anti-programmed cell death (PD-1)/ipilimumab (anti-cytotoxic T lymphocyte-associated antigen 4) combination
- Emerging front-line data with nivolumab and pembrolizumab (anti-PD-1) monotherapy 6
Considerations for Treatment Selection
Treatment selection will depend on the goals of therapy (endpoints) and the identification and validation of clinical and tumor-based predictive biomarkers that are linked to the desired treatment endpoints. The lack of head-to-head comparisons between different treatment options makes it challenging to determine the optimal treatment sequence or combination for metastatic disease 6.
Sunitinib as a Treatment Option
Sunitinib has been shown to be effective in the treatment of advanced renal cell carcinoma, with a high level of efficacy and acceptable tolerability 7. However, the dosage and scheduling of sunitinib remains a major challenge, and combination therapies appear to be toxic 3.