What are the first-line treatment options for a patient with advanced clear cell renal cell carcinoma, considering the availability of pembrolizumab (Pembro) and other therapies?

First-Line Treatment Options for Advanced Clear Cell Renal Cell Carcinoma

Pembrolizumab is NOT available as monotherapy in the first-line setting for advanced clear cell RCC—only combination regimens with pembrolizumab (plus axitinib or lenvatinib) are approved and recommended for first-line treatment. 1, 2, 3

Clarifying the Confusion: Adjuvant vs. Advanced Disease Settings

You may be confusing two different clinical scenarios:

• Adjuvant setting (post-nephrectomy): Pembrolizumab monotherapy is FDA-approved for adjuvant treatment after surgery in patients at high risk of recurrence 1
• Advanced/metastatic setting (first-line): Pembrolizumab is ONLY used in combination with VEGFR TKIs, never as monotherapy 1, 2, 3

First-Line Treatment Combinations for Advanced Clear Cell RCC

The current standard of care consists of immune checkpoint inhibitor (ICI) combinations with VEGFR tyrosine kinase inhibitors (TKIs), not single-agent pembrolizumab. 1

Preferred First-Line Combination Regimens (All IMDC Risk Groups)

The following ICI-based combinations are recommended with Level I, A evidence across all risk groups 1:

• Pembrolizumab + axitinib: OS HR 0.68 (95% CI 0.55-0.85), PFS HR 0.71 (0.60-0.84), with estimated OS gain of 16.8 months 1, 2
• Lenvatinib + pembrolizumab: OS HR 0.66 (0.49-0.88), PFS HR 0.39 (0.32-0.49), with PFS gain of 14.7 months and OS gain of 8.8% at 2 years 1, 3
• Cabozantinib + nivolumab: OS HR 0.60 (0.40-0.89), PFS HR 0.51 (0.41-0.64), with PFS gain of 8.3 months and OS gain of 10.1% at 1 year 1, 4
• Nivolumab + ipilimumab (for intermediate/poor-risk): OS HR 0.65 (0.54-0.78), with OS gain of 21.5 months in intermediate/poor-risk patients 1, 4

No single PD-1 inhibitor/VEGFR TKI combination is preferred over others; indirect cross-trial comparisons are not recommended. 1, 4

Alternative Single-Agent TKI Options (When ICI Contraindicated)

When immunotherapy cannot be given, single-agent VEGFR TKIs are alternatives 1, 5:

• Sunitinib: Category 2A across all risk groups, with superior PFS and OS versus interferon-alpha 5, 4
• Pazopanib: Category 2A across all risk groups, comparable efficacy to sunitinib but superior quality of life profile 5, 4
• Cabozantinib: Preferred for intermediate/poor-risk patients when ICI cannot be given 1, 5, 4

For favorable-risk disease specifically, single-agent TKIs (sunitinib, pazopanib) may be preferred due to lack of clear OS superiority for ICI combinations in this subgroup. 1, 4

Critical Treatment Selection Algorithm

Step 1: Determine IMDC Risk Group

Classify patient as favorable, intermediate, or poor risk 5, 4

Step 2: Assess ICI Eligibility

Evaluate for contraindications to immunotherapy (active autoimmune disease, need for immunosuppression) 3

Step 3: Select Regimen Based on Risk and ICI Eligibility

If ICI-eligible:

• Intermediate/poor-risk: Strongly consider nivolumab + ipilimumab (21.5-month OS gain) or any of the three VEGFR TKI + PD-1 inhibitor combinations 1, 4
• Favorable-risk: Consider single-agent TKI (sunitinib, pazopanib) OR ICI combination based on individual patient factors 1, 4

If ICI-contraindicated:

• Intermediate/poor-risk: Cabozantinib monotherapy 1, 5
• Favorable-risk: Sunitinib or pazopanib 5, 4

Important Safety Considerations

Lenvatinib + pembrolizumab probably increases the risk of serious adverse events (SAEs) to 61% compared to 40% with sunitinib (RR 1.52,95% CI 1.06-2.19). 6

Nivolumab + ipilimumab probably increases SAE risk to 57% (RR 1.40,95% CI 1.00-1.97), with 35% requiring high-dose steroids and 22% experiencing treatment discontinuation. 4, 6

Pembrolizumab + axitinib probably increases SAE risk slightly to 52% (RR 1.29,95% CI 0.90-1.85). 6

Pazopanib requires monitoring for hepatotoxicity with 30% grade 3 ALT elevation rates 4

Common Pitfalls to Avoid

• Do NOT use pembrolizumab monotherapy in the first-line advanced setting—it is not approved and has no supporting evidence 1, 2
• Do NOT use avelumab + axitinib—it failed to demonstrate OS benefit despite PFS improvement (ESMO-MCBS score of only 3) 1, 4
• Do NOT continue ICI therapy after progression on first-line ICI-based therapy—randomized data are lacking and this is not recommended 1
• Do NOT use lenvatinib + everolimus as first-line treatment—it should only be used as subsequent therapy 1