What is the optimal first‑line management for a 60‑year‑old man with metastatic PAX8‑positive renal cell carcinoma involving a left renal nodule, left pleural‑based mass, and pleural effusion, who has good functional capacity?

First-Line Management of Metastatic PAX8-Positive Renal Cell Carcinoma

For this 60-year-old man with metastatic clear cell RCC and good functional capacity, initiate combination immunotherapy with a PD-1 inhibitor plus VEGFR tyrosine kinase inhibitor as first-line systemic therapy, specifically lenvatinib-pembrolizumab, axitinib-pembrolizumab, or cabozantinib-nivolumab. 1

Risk Stratification Required

Before selecting therapy, you must determine the IMDC (International Metastatic RCC Database Consortium) risk category by assessing:

• Performance status (Karnofsky or ECOG)
• Time from diagnosis to treatment (<1 year vs ≥1 year)
• Hemoglobin level (below normal)
• Corrected calcium (above normal)
• Neutrophil count (above normal)
• Platelet count (above normal)

Patients are classified as favorable (0 risk factors), intermediate (1-2 risk factors), or poor (3+ risk factors). 1, 2

Recommended First-Line Systemic Therapy

For All Risk Groups (Favorable, Intermediate, and Poor):

The 2024 ESMO guidelines establish PD-1 inhibitor plus VEGFR TKI combinations as the standard of care across all risk categories 1:

• Lenvatinib-pembrolizumab [Level I, A; ESMO-MCBS score: 4] 1
• Axitinib-pembrolizumab [Level I, A; ESMO-MCBS score: 4] 1, 3
• Cabozantinib-nivolumab [Level I, A; ESMO-MCBS score: 1] 1

There is no preferred combination among these three options, and indirect cross-trial comparisons should not be used to select between them. 1

Alternative for Intermediate and Poor-Risk Disease:

• Ipilimumab-nivolumab (dual checkpoint inhibitor therapy) [Level I, A; ESMO-MCBS score: 4] is recommended for intermediate and poor-risk patients, though it remains an option for favorable-risk disease [Level I, C]. 1

When Immunotherapy is Contraindicated or Unavailable:

If PD-1-targeted therapy cannot be administered:

• Sunitinib [Level I, A] 1
• Pazopanib [Level I, A] 1
• Tivozanib [Level II, B] 1
• Cabozantinib (for intermediate/poor-risk only) [Level II, A] 1

Role of Cytoreductive Nephrectomy

Cytoreductive nephrectomy should generally be avoided in this patient with metastatic disease. 1 The CARMENA trial demonstrated that sunitinib alone provided superior median overall survival (18.4 vs 13.9 months) compared to immediate cytoreductive nephrectomy followed by sunitinib in patients with intermediate or poor-risk disease. 1

Cytoreductive nephrectomy should only be considered after multidisciplinary team review in highly selected patients with:

• Favorable or intermediate-risk disease
• Good performance status
• Large symptomatic primary tumor
• Limited volume of metastatic disease 1

Deferred cytoreductive nephrectomy may be considered for patients achieving durable near-complete response at metastatic sites following systemic therapy. 1

Management of Pleural Effusion

The pleural effusion requires diagnostic thoracentesis to confirm malignant involvement (PAX8-positive cells would support metastatic RCC origin). 4, 5, 6

For symptomatic pleural effusion management:

• Therapeutic thoracentesis for immediate symptom relief
• Consider pleurodesis if recurrent and symptomatic
• Systemic therapy remains the primary treatment approach 4, 7

Treatment Duration and Monitoring

• Checkpoint inhibitors should be considered for cessation after 2 years of treatment [Level IV, B] 1
• Treatment breaks from VEGFR TKI therapy do not appear detrimental to efficacy [Level I, C] 1
• Tumor assessments should occur at baseline, Week 12, then every 6 weeks until Week 54, then every 12 weeks thereafter 3

Critical Pitfalls to Avoid

1. Do not perform immediate cytoreductive nephrectomy in patients with high metastatic burden or poor/intermediate-risk features without first establishing disease control with systemic therapy 1

2. Do not use single-agent VEGFR TKI monotherapy when combination therapy is feasible—the 2024 guidelines clearly establish combination regimens as superior across all risk groups 1

3. Do not use axitinib-avelumab—this combination lacks overall survival benefit compared to sunitinib [Level I, D] 1

4. Do not delay risk stratification—IMDC classification must be completed before therapy selection to optimize outcomes 2

5. Do not use single-agent nivolumab as first-line therapy—this is only appropriate in the second-line setting after prior VEGFR-targeted therapy 2

Special Consideration for Pleural Metastases

Given the pleural-based mass and effusion, cabozantinib-containing regimens may offer additional benefit as cabozantinib demonstrates activity across multiple metastatic sites and has shown particular efficacy in patients with bone and soft tissue metastases. 8 However, any of the three recommended PD-1 plus VEGFR TKI combinations remain appropriate first-line choices. 1