What are the treatment options for metastatic Renal Cell Carcinoma (RCC)?

Treatment Options for Metastatic Renal Cell Carcinoma

First-Line Treatment for Clear Cell RCC

For intermediate and poor-risk metastatic clear cell RCC, immune checkpoint inhibitor (ICI) combination therapy is the standard of care, with preferred options including cabozantinib plus nivolumab, pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, or nivolumab plus ipilimumab. 1, 2

Risk Stratification (Required First Step)

Before selecting therapy, stratify all patients using the International Metastatic RCC Database Consortium (IMDC) criteria 1, 2:

• Favorable risk (0 factors): Hemoglobin normal, calcium normal, neutrophils normal, platelets normal, performance status 0, time from diagnosis to treatment ≥1 year 2
• Intermediate risk (1-2 factors) 2
• Poor risk (3+ factors) 2

Treatment by Risk Group

Intermediate and Poor Risk (Preferred Approach):

• Cabozantinib plus nivolumab [Level 1b evidence] 1
• Pembrolizumab plus axitinib [Level 1b evidence] 1
• Pembrolizumab plus lenvatinib [Level 1b evidence] 1
• Nivolumab plus ipilimumab [Level 1b evidence] - demonstrated 9.4% complete response rate and superior overall survival versus sunitinib 1, 2

Favorable Risk:

• VEGFR TKI monotherapy remains acceptable: Sunitinib 50 mg daily (4 weeks on/2 weeks off), pazopanib, or cabozantinib 1, 2, 3
• ICI combinations may also be used but data are less robust in this subgroup 2

Poor Risk Specific Alternative:

• Temsirolimus as monotherapy has Level 1 evidence demonstrating overall survival improvement when ICI combinations cannot be given 1, 2

Treatment Duration

• Continue ICI therapy until progression; consider cessation after 2 years 1
• VEGFR TKI therapy breaks do not appear detrimental to efficacy 1

Second-Line Treatment

After progression on first-line PD-1-targeted therapy plus VEGFR TKI:

• Cabozantinib is the preferred agent [Level II, B] 1
• Alternative options: Axitinib, lenvatinib plus everolimus, pazopanib, sunitinib, or tivozanib [all Level III, B] 1

After progression on first-line VEGFR TKI therapy:

• Nivolumab [Level I, A] - associated with overall survival benefit 1
• Cabozantinib [Level I, A] - associated with overall survival benefit 1
• Alternative options: Axitinib [Level II, B], everolimus [Level II, B], or lenvatinib plus everolimus [Level II, B] 1

After progression on cytokine therapy:

• Axitinib [Level IA] or pazopanib [Level IIA] 1

Further-Line Treatment

After progression on both PD-1 and VEGFR-targeted therapy:

• Belzutifan should be considered instead of everolimus in heavily pretreated patients [Level I, B; FDA approved, not EMA approved] 1
• Sequencing additional VEGFR TKI therapy [Level III, B] 1
• Everolimus remains an option but other approaches are preferable [Level II, C] 1
• Do not use further PD-(L)1-targeted therapy after progression on first-line PD-1-targeted therapy [Level I, D] 1

Non-Clear Cell RCC

Papillary RCC:

• Cabozantinib is the preferred first-line monotherapy [Level II, B] 1
• Lenvatinib plus pembrolizumab and cabozantinib plus nivolumab have impressive response rates but are not proven superior to single-agent therapy [Level III, B] 1
• Alternative single-agent options: Sunitinib [Level II, B], pembrolizumab [Level III, B; not EMA or FDA approved] 1

Chromophobe RCC:

• Sunitinib [Level II, C], pazopanib [Level IV, C], lenvatinib plus everolimus [Level II, C], or lenvatinib plus pembrolizumab [Level III, C] 1

Collecting Duct and SMARCB1-Deficient RCC:

• Cisplatin-based chemotherapy is recommended [Level III, C] 1
• Alternative options: Sunitinib [Level V, C], pazopanib [Level V, C], cabozantinib [Level III, C] 1

Sarcomatoid (Predominant) Histology:

• ICI-based therapies are strongly preferred: Ipilimumab plus nivolumab [Level III, A], axitinib plus pembrolizumab [Level III, A], cabozantinib plus nivolumab [Level III, A], or lenvatinib plus pembrolizumab [Level III, A] 1
• Alternative options for patients with contraindications to ICI: Sunitinib [Level II, B], pazopanib [Level V, C] 1

General Recommendation for Non-Clear Cell:

• Enrollment into clinical trials is strongly recommended [Level IV, A] 1

Local and Surgical Therapies

Cytoreductive Nephrectomy

• Immediate cytoreductive nephrectomy should no longer be standard of care for intermediate and poor-risk patients requiring immediate medical treatment 1, 2
• May still be appropriate for favorable/intermediate risk patients with low-volume metastatic disease, good performance status, and candidates for initial observation 2

Metastasectomy

• May provide survival benefit for highly selected patients with: lung metastases only, metachronous disease-free interval ≥2 years, and response to immunotherapy/targeted therapy before resection 1, 2

Radiotherapy

• Stereotactic RT is recommended for brain metastases [Level III, B] 1
• Whole-brain RT should be avoided due to cognitive dysfunction [Level III, D] 1
• Stereotactic radiotherapy is safe and efficacious for oligometastases with 1-year local control at 90% 1

Bone-Directed Therapy

• Zoledronic acid or denosumab can be considered in patients with bone metastases after individualized risk assessment [Level IV, C] 1
• Radiotherapy for symptomatic bone lesions 1, 2

Critical Pitfalls to Avoid

• Never skip IMDC risk stratification - this determines optimal treatment selection 1, 2
• Never perform upfront cytoreductive nephrectomy in intermediate/poor-risk patients with high metastatic burden requiring immediate systemic therapy 1, 2
• Never use further PD-(L)1 therapy after progression on first-line PD-1-targeted therapy 1
• Never treat non-clear cell histology the same as clear cell without considering clinical trial enrollment 1
• Never use whole-brain radiotherapy when stereotactic options are available for brain metastases 1