Management of Metastatic Renal Cell Carcinoma

Introduction to Treatment

The American College of Cardiology is not relevant here, however, for first-line treatment of metastatic clear cell RCC, use immune checkpoint inhibitor (ICI) combination therapy with either a VEGFR tyrosine kinase inhibitor (TKI) or dual ICI therapy, stratified by risk group, with axitinib plus pembrolizumab, axitinib plus avelumab, lenvatinib plus pembrolizumab, cabozantinib plus nivolumab, or nivolumab plus ipilimumab as preferred options 1

Before selecting therapy, stratify patients using the International Metastatic RCC Database Consortium (IMDC) criteria into favorable (0 risk factors), intermediate (1-2 risk factors), or poor (3+ risk factors) risk groups 1, 2
Risk factors include: poor performance status, time from diagnosis to treatment <1 year, low hemoglobin, elevated calcium, elevated neutrophils, and elevated platelets 1

For favorable risk patients, VEGFR TKI monotherapy remains acceptable: sunitinib, pazopanib, or cabozantinib are options 3, 4, 5
ICI-based combinations may also be used for favorable risk patients, though data are less robust in this subgroup 5
Sunitinib 50 mg daily (4 weeks on/2 weeks off schedule) demonstrated superiority over interferon-alpha with improved response rate, progression-free survival, and overall survival 4
For intermediate and poor risk patients, ICI combination therapy is strongly preferred 6, 5, 1
Nivolumab plus ipilimumab demonstrated superior overall survival versus sunitinib in intermediate and poor-risk patients, with 9.4% complete response rate 5
For poor-risk patients specifically: temsirolimus as monotherapy has level 1 evidence demonstrating overall survival improvement and remains an option when ICI combinations cannot be given 7, 8, 9

After VEGF-targeted therapy, axitinib is the preferred option with level IA evidence 7, 8, 9
Everolimus has level IIA evidence 7, 8, 9
Sorafenib has level IA evidence 7, 8
Pazopanib has level IIA evidence 7, 8
Nivolumab is recommended given its overall survival benefit and tolerability in refractory RCC 1

For patients with bone metastases, bone-directed radiation therapy for symptomatic lesions 6
Bone resorption inhibitors (zoledronic acid or RANKL inhibitor like denosumab) to reduce skeletal-related events when clinical concern for fracture exists 7, 8, 9, 6
Cabozantinib-containing regimens may be preferred for patients with bone metastases based on expert opinion 6
For patients with brain metastases, brain-directed local therapy with radiation therapy and/or surgery is essential 7, 8, 9, 6
ICI-based combination first-line treatment is preferred for patients with brain metastases (ipilimumab plus nivolumab, or ICI plus TKI) 6
For patients with sarcomatoid features, ICI-based combination therapy is strongly recommended 6, 1
For patients with non-clear cell histology, enrollment in specifically designed clinical trials is the preferred approach 7, 8, 9, 1
In the absence of trials, sunitinib, sorafenib, or temsirolimus may provide benefit based on expanded access programs and retrospective data 7, 4, 8, 9

Cytoreductive nephrectomy is no longer standard of care for MSKCC intermediate and poor-risk patients with asymptomatic primary tumors requiring immediate medical treatment 5
Upfront cytoreductive nephrectomy is associated with morbidity and mortality without proven superiority in these patients 5
Cytoreductive nephrectomy is still appropriate for patients with low-volume metastatic disease, good performance status, favorable/intermediate risk who are candidates for initial observation 5
Metastasectomy may provide survival benefit for highly selected patients with: lung metastases only, long metachronous disease-free interval (≥2 years), and response to immunotherapy/targeted therapy before resection 7, 8, 9
Metastasis-directed therapies, including surgical resection, thermal ablation, or stereotactic ablative radiotherapy, may be offered for low-volume metastatic disease 6, 1

Failing to risk-stratify patients before selecting therapy - this is the critical first step that determines optimal treatment 1
Using high-dose IL-2 outside experienced high-volume centers 1
Performing upfront cytoreductive nephrectomy in intermediate/poor-risk patients with high metastatic burden requiring immediate systemic therapy 5
Treating non-clear cell histology the same as clear cell without considering clinical trial enrollment 7, 4, 8
Discontinuing effective therapy for limited progression when local therapy could be applied 1
Not considering bone-directed therapy in patients with bone metastases at risk for skeletal complications 7, 8, 9, 6

All targeted agents are given continuously until disease progression in the absence of major toxicity 4
Average duration of disease control is 8-9 months in first-line setting and 5-6 months in second-line setting 4