First-Line Systemic Therapy for Metastatic Clear Cell RCC with IMDC Intermediate Risk (Score 1)
For this 70-year-old gentleman with metastatic clear cell renal cell carcinoma involving L2 vertebra and liver with IMDC intermediate risk (score 1), the recommended first-line systemic therapy is an immune checkpoint inhibitor (ICI) combined with a VEGFR tyrosine kinase inhibitor (TKI), specifically one of the following: pembrolizumab plus axitinib, nivolumab plus cabozantinib, or pembrolizumab plus lenvatinib. 1
Standard of Care Options for IMDC Intermediate Risk
The current guidelines from the European Association of Urology (2022) and ESMO (2024) establish three ICI-based combination regimens as standard of care with Level 1b evidence for intermediate-risk disease: 1
Primary Recommended Combinations:
Pembrolizumab plus axitinib: Demonstrated OS HR 0.73 and PFS HR 0.68, with 60% overall response rate and 10% complete response rate at 42.8 months median follow-up 1, 2
Nivolumab plus cabozantinib: Showed OS HR 0.70 and PFS HR 0.56, with 56% overall response rate and 12% complete response rate at 32.9 months median follow-up 1
Pembrolizumab plus lenvatinib: Achieved OS HR 0.72 and PFS HR 0.42, with 69% overall response rate and 17% complete response rate, though dose reductions were required in 68.8% of patients 1, 3
Alternative ICI Combination:
- Nivolumab plus ipilimumab: Remains an option for IMDC intermediate and poor-risk disease with Level 1b evidence, showing OS HR 0.63 in the intermediate/poor-risk population, though it is specifically designed for this risk category rather than favorable risk 1, 4
Treatment Selection Algorithm
Step 1: Assess ICI eligibility - Exclude active autoimmune disease requiring systemic immunosuppression, uncontrolled brain metastases, or absolute contraindications to immunotherapy 1, 2
Step 2: If ICI-eligible (which applies to this patient), select from the three VEGFR TKI plus PD-1 inhibitor combinations based on: 1, 2
Toxicity profile considerations: Pembrolizumab plus lenvatinib requires dose reductions in 68.8% of patients; nivolumab plus cabozantinib in 56.3%; pembrolizumab plus axitinib has more manageable toxicity 1
Bone metastases presence: Given this patient has L2 vertebral involvement, nivolumab plus cabozantinib may be particularly appropriate as cabozantinib has specific activity in bone metastases 5
Hepatic involvement: All three regimens are appropriate for liver metastases, though hepatic function monitoring is essential 1
Step 3: If ICI-contraindicated, use cabozantinib monotherapy as the preferred single-agent TKI for intermediate-risk disease with Level 2a evidence 1, 5
Why Not Other Options
Sunitinib or pazopanib monotherapy: These are relegated to alternative options when immunotherapy is contraindicated or unavailable, as ICI combinations have demonstrated superior overall survival 1, 2
Nivolumab plus ipilimumab: While approved for intermediate/poor-risk disease, the three VEGFR TKI plus PD-1 combinations offer more consistent efficacy across all intermediate-risk patients 1
Pembrolizumab monotherapy: Not recommended in the metastatic setting; only approved for adjuvant therapy post-nephrectomy in high-risk patients 2, 3
Critical Practical Considerations
No PD-L1 testing required: All ICI-based combinations are recommended irrespective of PD-L1 expression status, and treatment should not be delayed for biomarker testing 1, 3, 4
Treatment duration: PD-1 inhibitors in combination regimens are typically continued for 2 years or until progression, while VEGFR TKIs continue until progression or unacceptable toxicity 1
Dose modifications: Anticipate need for VEGFR TKI dose reductions (56-69% of patients across trials), which does not compromise efficacy 1
Monitoring requirements: Hepatic function monitoring is essential with all VEGFR TKIs, particularly pazopanib which has 30% grade 3 ALT elevation rates 2, 5
Common Pitfalls to Avoid
Do not use single-agent TKI therapy when ICI combinations are feasible, as this represents outdated standard of care with inferior overall survival outcomes 1
Do not delay treatment for cytoreductive nephrectomy in intermediate-risk disease with multiple metastatic sites; systemic therapy should be initiated first with consideration for deferred nephrectomy in responding patients 6, 7
Do not attempt indirect comparisons between the three ICI plus VEGFR TKI combinations to select "the best" option, as head-to-head data do not exist and guidelines explicitly state no preferred combination 1, 3