Residency · Residency · Urology

Systemic Therapy for Metastatic Renal Cell Carcinoma

Overview

The management of metastatic renal cell carcinoma (RCC) has evolved significantly with the introduction of vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs), immune checkpoint inhibitor combinations such as ipilimumab/nivolumab and pembrolizumab/axitinib, and the role of cytoreductive nephrectomy in the immunotherapy era. Risk stratification using the International Metastatic RCC Database Consortium (IMDC) criteria is fundamental to guiding treatment decisions.

RCC Subtypes and Molecular Biology

Clear cell RCC (ccRCC) accounts for approximately 70-80% of RCC cases and is characterized by inactivation of the von Hippel-Lindau (VHL) gene. This inactivation leads to accumulation of hypoxia-inducible factors (HIF), which in turn cause overexpression of angiogenic factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). Papillary RCC comprises 10-15% of cases and is subdivided into type 1, associated with MET alterations, and type 2, linked to fumarate hydratase (FH) and NRF2 pathway changes. Chromophobe RCC represents about 5% of cases, tends to be indolent, and has limited systemic therapy options. Collecting duct and medullary RCC are rare but aggressive subtypes, for which cisplatin-based chemotherapy is often considered. Sarcomatoid differentiation can occur in any RCC subtype and is associated with aggressive behavior but shows responsiveness to immunotherapy combinations. Most systemic therapy data derive from studies in ccRCC, with limited evidence available for non-clear cell subtypes.

IMDC (International Metastatic RCC Database Consortium) Risk Stratification

The IMDC risk stratification system incorporates six clinical and laboratory risk factors: a Karnofsky performance status below 80%, time from diagnosis to systemic therapy less than one year, hemoglobin levels below the lower limit of normal, corrected serum calcium above the upper limit of normal, neutrophil count above the upper limit of normal, and platelet count above the upper limit of normal. Patients are categorized into three risk groups based on the number of these factors present. Those with no risk factors are classified as favorable risk, with a median overall survival (OS) exceeding 40 months in the immunotherapy era. Intermediate risk includes patients with one or two factors, with median OS around 25 to 30 months. Poor risk comprises three to six factors, with median OS approximately 10 to 15 months. This risk stratification guides first-line therapy selection and has replaced the older Memorial Sloan Kettering Cancer Center (MSKCC) or Motzer criteria.

First-Line Systemic Therapy

IO/IO Combination

The combination of ipilimumab and nivolumab, evaluated in the CheckMate 214 trial, pairs an anti-CTLA-4 antibody (ipilimumab) with an anti-PD-1 antibody (nivolumab). The regimen involves ipilimumab at 1 mg/kg and nivolumab at 3 mg/kg every three weeks for four cycles, followed by nivolumab maintenance every four weeks. In patients with intermediate or poor risk disease, this combination demonstrated superior objective response rates (42% versus 27%), overall survival benefit, and a complete response (CR) rate of 11% compared to sunitinib. However, in favorable risk patients, sunitinib performed comparably or better in progression-free survival (PFS), making the use of ipilimumab/nivolumab controversial in this group. Notably, complete responses with ipilimumab/nivolumab can be durable, lasting over five years in some patients. Grade 3-4 immune-related adverse events (irAEs) occur in about 45% of patients, with hepatitis, colitis, and endocrinopathies being the most common. The National Comprehensive Cancer Network (NCCN) guidelines prefer this combination for intermediate and poor risk ccRCC.

IO/TKI Combinations

Pembrolizumab combined with axitinib, as studied in the KEYNOTE-426 trial, pairs an anti-PD-1 antibody with a VEGF-TKI. Pembrolizumab is administered at 200 mg every three weeks alongside axitinib 5 mg twice daily. This combination improved overall survival and progression-free survival across all risk groups, including favorable risk patients, with an objective response rate of 60% and a complete response rate of 9%. It is preferred by NCCN for all risk groups.

Nivolumab plus cabozantinib, evaluated in the CheckMate 9ER trial, combines an anti-PD-1 antibody with a multi-target VEGF-TKI that also inhibits MET and AXL. This regimen improved progression-free survival and objective response rates across all risk groups, achieving an ORR of 56% and a CR rate of 12%. Cabozantinib is associated with gastrointestinal toxicities such as diarrhea, hand-foot syndrome, and hypertension.

Pembrolizumab combined with lenvatinib, assessed in the CLEAR/KEYNOTE-581 trial, demonstrated the highest objective response rate of approximately 71% and superior progression-free survival among first-line combinations. However, this regimen carries a significant toxicity burden, with grade 3-4 adverse events occurring in about 73% of patients. Dose reductions of lenvatinib are common due to diarrhea, hypertension, and fatigue. NCCN guidelines also prefer this combination for all risk groups.

Avelumab plus axitinib, studied in the JAVELIN Renal 101 trial, combines an anti-PD-L1 antibody with a VEGF-TKI. While it improved progression-free survival, overall survival was not significantly different from sunitinib. This combination is less commonly used compared to other IO/TKI regimens.

TKI Monotherapy

Sunitinib and pazopanib were previously standard first-line therapies but are now generally reserved for patients who cannot receive immunotherapy due to contraindications such as autoimmune disease or organ transplantation. Cabozantinib monotherapy remains an option for all risk groups, particularly when immunotherapy is contraindicated.

Second-Line and Subsequent Therapy

After progression on ipilimumab/nivolumab, VEGF-TKIs such as cabozantinib, axitinib, or lenvatinib combined with everolimus are commonly used. Cabozantinib is preferred based on data from the METEOR trial.

Following progression on IO/TKI combinations, cabozantinib is recommended if not previously administered, supported by METEOR trial evidence. Lenvatinib plus everolimus, as studied in the HOPE-205 trial, is another option. Alternative TKIs such as axitinib, sunitinib, or pazopanib may be considered. Nivolumab monotherapy can be used if a PD-1 inhibitor has not been previously given. Participation in clinical trials is encouraged in this setting.

Specific agents include cabozantinib, which targets VEGFR, MET, and AXL and demonstrated superior progression-free and overall survival compared to everolimus post-TKI therapy in the METEOR trial. Everolimus, an mTOR inhibitor, is used in combination or later lines of therapy. The combination of lenvatinib and everolimus improved progression-free survival compared to everolimus alone in the HOPE-205 trial. Tivozanib, evaluated in the TIVO-3 trial, showed improved progression-free survival in the third- or fourth-line setting.

Belzutifan is a novel agent that directly inhibits HIF-2 alpha, a downstream target of VHL loss. In the LITESPARK-005 trial, belzutifan improved progression-free survival compared to everolimus in previously treated ccRCC. It is FDA-approved for ccRCC after prior anti-PD-1 and VEGF-TKI therapy and also for VHL disease-associated RCC, including associated tumors such as pheochromocytoma and pancreatic neuroendocrine tumors. A unique side effect of belzutifan is anemia, which is mechanism-based due to reduced erythropoietin production.

Management of Special Situations

In oligometastatic disease, complete surgical metastasectomy can provide prolonged disease-free intervals. The best candidates have a single or few metastases, a long disease-free interval, and good performance status. Pulmonary metastasectomy is the most studied approach, with five-year cancer-specific survival after complete metastasectomy ranging from 30 to 50%.

Non-clear cell RCC subtypes have limited level 1 evidence because most clinical trials have excluded these histologies. Papillary RCC may respond to cabozantinib, as demonstrated in the SWOG 1500 trial, and MET inhibitors like savolitinib are under investigation. Immune checkpoint inhibitor combinations are also being studied in this group. Chromophobe RCC is generally resistant to TKIs and immunotherapy; surgery and surveillance remain the mainstays when feasible. Collecting duct and medullary RCC are aggressive and treated with cisplatin-based chemotherapy and checkpoint inhibitors. Sarcomatoid differentiation responds well to immunotherapy-based regimens such as ipilimumab/nivolumab or IO/TKI combinations and should not be treated with TKI monotherapy.

For brain metastases, stereotactic radiosurgery (SRS) or whole-brain radiation is the mainstay of treatment. Systemic immunotherapy and TKIs have limited central nervous system penetration, although cabozantinib has some evidence of CNS activity.

Bone metastases are managed with bone-targeted agents such as denosumab or zoledronic acid to reduce skeletal-related events. Palliative radiation is used for symptomatic lesions, and calcium and renal function should be monitored during therapy.

Immune-Related Adverse Events (irAEs)

Common immune-related adverse events include fatigue, rash, pruritus, and diarrhea or colitis. Hepatitis, characterized by elevated transaminases, is most common with the ipilimumab/nivolumab combination. Endocrinopathies such as hypothyroidism, hypophysitis, adrenal insufficiency, and type 1 diabetes occur frequently, with hypothyroidism being the most common. Pneumonitis presents with cough and dyspnea and can be life-threatening. Nephritis is rare but important to recognize, especially in urology patients.

Management depends on severity. Grade 1 irAEs are monitored while continuing immunotherapy. Grade 2 events warrant holding immunotherapy and considering corticosteroids. Grade 3-4 events require high-dose steroids (prednisone 1-2 mg/kg) and usually permanent discontinuation of immunotherapy for most grade 4 toxicities. Endocrinopathies typically require hormone replacement and can often continue immunotherapy. Colitis management includes ruling out infection such as Clostridioides difficile, initiating steroids, and using infliximab if steroid-refractory. Baseline laboratory tests including thyroid-stimulating hormone (TSH), liver function tests (LFTs), and cortisol should be documented before starting immunotherapy.

<image>A treatment algorithm flowchart for first-line systemic therapy in metastatic clear cell RCC, organized by IMDC risk group. Favorable risk branches to IO/TKI combinations (pembrolizumab/axitinib, pembrolizumab/lenvatinib) or TKI monotherapy. Intermediate-poor risk branches to IO/IO (ipilimumab/nivolumab) or IO/TKI combinations. Each arm includes key trial names, ORR, PFS, and OS data. A separate pathway shows contraindications to IO (autoimmune disease, transplant) leading to TKI monotherapy. Clinical algorithm format with trial data annotations.</image>

<image>A diagram illustrating the molecular biology of clear cell RCC and therapeutic targets. Central pathway shows VHL loss → HIF accumulation → downstream VEGF, PDGF, and mTOR signaling. Each therapeutic target is paired with its corresponding drug: VEGF-TKIs (sunitinib, cabozantinib, axitinib, lenvatinib), mTOR inhibitors (everolimus, temsirolimus), HIF-2 alpha inhibitor (belzutifan), and immune checkpoint inhibitors (PD-1, PD-L1, CTLA-4). Arrows show the signaling cascades and points of therapeutic intervention. Molecular biology illustration style.</image>

<image>An infographic showing the IMDC risk stratification system with the 6 risk factors listed in a visual checklist format. Three panels represent favorable (0 factors), intermediate (1-2 factors), and poor (3-6 factors) risk groups, each with associated median OS, recommended first-line regimens, and expected outcomes. Color-coded from green (favorable) to red (poor risk). Patient proportion percentages for each risk group are included. Clean clinical education infographic.</image>

Clinical Pearls

IMDC risk stratification is essential for selecting appropriate systemic therapy and should always be calculated before initiating treatment, as it directly determines the recommended first-line regimen. The ipilimumab/nivolumab combination produces the highest complete response rate and the most durable remissions in intermediate and poor risk ccRCC, with some complete responses lasting beyond five years. Immune checkpoint inhibitor and TKI combinations provide benefit across all risk groups, including favorable risk, with pembrolizumab/axitinib and pembrolizumab/lenvatinib being broadly applicable first-line options. Sequential use of TKIs after failure of IO/TKI combinations remains effective, with cabozantinib having the strongest evidence base in the second-line setting. Belzutifan introduces a new therapeutic class targeting HIF-2 alpha and is the first effective targeted therapy for VHL disease-associated RCC. Sarcomatoid differentiation in RCC responds well to immunotherapy-based regimens and should not be treated with TKI monotherapy. Vigilant monitoring for immune-related adverse events is critical; baseline thyroid function, liver enzymes, and cortisol should be assessed before starting immunotherapy, and endocrinopathies may be permanent, requiring lifelong hormone replacement.

References

• Motzer RJ, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma (CheckMate 214). N Engl J Med. 2018;378(14):1277-1290
• Rini BI, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma (KEYNOTE-426). N Engl J Med. 2019;380(12):1116-1127
• Motzer RJ, et al. Lenvatinib plus pembrolizumab versus sunitinib in advanced renal-cell carcinoma (CLEAR/KEYNOTE-581). N Engl J Med. 2021;384(14):1289-1300
• Choueiri TK, et al. Belzutifan versus everolimus for advanced renal-cell carcinoma (LITESPARK-005). Lancet. 2024;403(10441):2095-2106
• Heng DY, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma (IMDC model). J Clin Oncol. 2009;27(34):5794-5799
• NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer, Version 4.2024

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