What are the recommended first-line and subsequent treatments for the management of metastatic renal cell carcinoma?

Management of Metastatic Renal Cell Carcinoma

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, 2, 3, 4

Risk Stratification (Essential First Step)

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, 5 Risk factors include: poor performance status, time from diagnosis to treatment <1 year, low hemoglobin, elevated calcium, elevated neutrophils, and elevated platelets. 1

First-Line Treatment by Risk Group

Favorable Risk Patients

• VEGFR TKI monotherapy remains acceptable: sunitinib, pazopanib, or cabozantinib are options 6
• ICI-based combinations may also be used, though data are less robust in this subgroup 6
• 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 6
• Pazopanib is noninferior to sunitinib with similar efficacy but better quality-of-life profile, particularly less fatigue and hand-foot syndrome 7, 8

Intermediate and Poor Risk Patients

• ICI combination therapy is strongly preferred 6, 1
• Nivolumab plus ipilimumab demonstrated superior overall survival versus sunitinib in intermediate and poor-risk patients, with 9.4% complete response rate 6
• Cabozantinib plus nivolumab: cabozantinib 40 mg daily combined with nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks 4
• Axitinib plus pembrolizumab or axitinib plus avelumab are FDA-approved first-line combinations 2
• Lenvatinib plus pembrolizumab is FDA-approved for first-line advanced RCC 3
• 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 6

Special Consideration: Observation

For patients with indolent disease, low metastatic burden, and favorable risk features, a period of observation before starting treatment may be considered, as some RCC have very indolent courses. 6 This approach is supported by prospective data showing non-inferiority to primary intervention in well-selected cohorts. 6

Second-Line Treatment

After VEGF-Targeted Therapy

• Axitinib is the preferred option with level IA evidence 6
• Everolimus has level IIA evidence 6
• Sorafenib has level IA evidence 6
• Pazopanib has level IIA evidence 6
• Nivolumab is recommended given its overall survival benefit and tolerability in refractory RCC 1

After Cytokine Therapy

• Axitinib has level IA evidence 6
• Sunitinib has level IIIA evidence 6
• Sorafenib and pazopanib are active options 1

Optimal Sequencing Strategy

Based on phase III data, the optimal sequence appears to be: sunitinib → axitinib → everolimus, with fourth-line sorafenib or sunitinib rechallenge as last-resort options. 9

Special Populations

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 6
• Cabozantinib-containing regimens may be preferred based on expert opinion 6

Brain Metastases

• Brain-directed local therapy with radiation therapy and/or surgery is essential 6
• Corticosteroids provide effective temporary relief of cerebral symptoms 6
• Whole-brain radiotherapy 20-30 Gy in 4-10 fractions, enhanced with stereotactic radiosurgery for single unresectable lesions 6
• ICI-based combination first-line treatment is preferred (ipilimumab plus nivolumab, or ICI plus TKI) 6

Sarcomatoid Features

• ICI-based combination therapy is strongly recommended 6, 1

Non-Clear Cell Histology

• Enrollment in specifically designed clinical trials is the preferred approach 6, 1
• In the absence of trials, sunitinib, sorafenib, or temsirolimus may provide benefit based on expanded access programs and retrospective data 6
• VEGF inhibitors are favored over mTORC1 inhibitors, though efficacy is less than for clear cell histology 6
• Most patients with metastatic non-clear cell RCC succumb within 18 months despite systemic treatment 6

Role of Surgery and Local Therapies

Cytoreductive Nephrectomy

• No longer standard of care for MSKCC intermediate and poor-risk patients with asymptomatic primary tumors requiring immediate medical treatment 6
• Upfront cytoreductive nephrectomy is associated with morbidity and mortality without proven superiority in these patients 6
• Still appropriate for: patients with low-volume metastatic disease, good performance status, favorable/intermediate risk who are candidates for initial observation 6
• Secondary cytoreductive nephrectomy remains an option for patients with local symptoms or near-complete responses to systemic therapy 6

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 6
• Consider for solitary or easily accessible pulmonary metastases, solitary resectable intra-abdominal metastases, or long disease-free interval after nephrectomy 1, 5

Metastasis-Directed Therapies

• For low-volume metastatic disease, definitive therapies including surgical resection, thermal ablation (radiofrequency, microwave, cryoablation), or stereotactic ablative radiotherapy may be offered 6, 1
• For patients on immunotherapy with limited disease progression, local therapy may be offered while continuing immunotherapy 1

Common Pitfalls to Avoid

• 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 6
• Treating non-clear cell histology the same as clear cell without considering clinical trial enrollment 6
• 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 6

Treatment Duration and Monitoring

All targeted agents are given continuously until disease progression in the absence of major toxicity. 6 Average duration of disease control is 8-9 months in first-line setting and 5-6 months in second-line setting. 6 Alternative schedules with elective treatment interruptions have not been validated in randomized controlled trials. 6