What is the best approach for a patient with metastatic clear cell renal carcinoma and multiple metastases who can only access Keytruda (pembrolizumab) due to financial constraints preventing the purchase of Lenvatinib (lenvatinib)?

Pembrolizumab Monotherapy is Not Recommended for Metastatic Clear Cell RCC

Do not use pembrolizumab (Keytruda) as monotherapy for this patient with metastatic clear cell renal carcinoma—instead, prescribe a single-agent VEGFR tyrosine kinase inhibitor such as sunitinib, pazopanib, or cabozantinib, as pembrolizumab monotherapy has no established efficacy data in the metastatic setting and will likely result in inferior outcomes. 1

Why Pembrolizumab Alone Will Not Work

The evidence is unequivocal that pembrolizumab should never be used as monotherapy in metastatic clear cell RCC:

• ASCO guidelines explicitly state that pembrolizumab must be combined with axitinib or lenvatinib—there is no role for pembrolizumab monotherapy in first-line treatment of advanced clear cell RCC. 1

• No clinical trial data exists for pembrolizumab monotherapy in the advanced/metastatic setting. All pivotal trials (KEYNOTE-426 with axitinib, KEYNOTE-581/CLEAR with lenvatinib) evaluated pembrolizumab only in combination regimens. 1, 2

• The synergy between pembrolizumab and VEGFR inhibitors is fundamental to efficacy. The combination of lenvatinib plus pembrolizumab achieved median PFS of 23.9 months versus 9.2 months with sunitinib alone (HR 0.39), with objective response rate of 71% versus 36%. 2 This dramatic benefit is lost without the VEGFR TKI component. 1

• ESMO guidelines clarify that pembrolizumab monotherapy has FDA approval only for adjuvant treatment after surgery in high-risk patients, not for advanced/metastatic disease where it is exclusively used in combination. 1

Recommended Alternative: Single-Agent VEGFR TKI Therapy

Since lenvatinib is financially inaccessible, you should prescribe a single-agent VEGFR TKI, which has established efficacy and is recommended by ASCO when immunotherapy cannot be given:

First-Line Options (in order of preference):

1. Sunitinib: The most extensively studied option with proven efficacy

   • Median PFS of 9.2 months and 2-year OS of 70.4% in the CLEAR trial control arm 1
   • Standard dosing: 50 mg orally once daily for 4 weeks, then 2 weeks off treatment 2
   • Well-established safety profile with predictable toxicities 1

2. Pazopanib: Comparable efficacy to sunitinib with superior quality of life profile

   • Demonstrated non-inferior efficacy to sunitinib in phase III trials 1, 3
   • Category 2A recommendation across all IMDC risk groups when immunotherapy is contraindicated 4
   • Better tolerability profile but requires hepatic monitoring (30% grade 3 ALT elevation rates) 4
   • Standard dosing: 800 mg orally once daily continuously 3

3. Cabozantinib: Particularly useful if patient has bone metastases

   • May be preferred for patients with bone metastases based on guideline recommendations 3
   • Proven efficacy in both first-line and subsequent-line settings 3

Critical Clinical Reasoning

The patient's financial constraint preventing lenvatinib access means the pembrolizumab-lenvatinib combination cannot be used. Since pembrolizumab monotherapy has no efficacy data and would likely perform poorly (potentially worse than historical sunitinib controls), using the available pembrolizumab alone would be inappropriate and potentially harmful. 1

Single-agent VEGFR TKI therapy represents the evidence-based standard of care when combination immunotherapy regimens are not feasible. These agents have Level 1 evidence supporting their use and have been the backbone of RCC treatment for over a decade. 5, 3

Risk Stratification Considerations

Before selecting the specific VEGFR TKI, stratify the patient using IMDC criteria (performance status, time from diagnosis to treatment, hemoglobin, calcium, neutrophils, platelets) into favorable, intermediate, or poor risk categories. 5, 3

• For favorable-risk disease: Sunitinib or pazopanib are both appropriate first-line options 3
• For intermediate or poor-risk disease: All three VEGFR TKIs (sunitinib, pazopanib, cabozantinib) remain viable options, though combination therapy would be preferred if financially accessible 5, 3
• For patients with sarcomatoid features: This represents a critical limitation, as these patients specifically benefit from ICI-based combinations and have inferior outcomes with VEGFR TKI monotherapy 5

Common Pitfalls to Avoid

• Do not use pembrolizumab monotherapy based on its approval in the adjuvant setting—the biology and treatment goals are fundamentally different in metastatic disease. 1

• Do not assume pembrolizumab will provide benefit without the VEGFR TKI partner—the dramatic efficacy seen in trials is dependent on the synergistic combination. 1

• Do not delay treatment while attempting to secure lenvatinib—starting effective single-agent VEGFR TKI therapy promptly is superior to using ineffective pembrolizumab monotherapy or delaying treatment. 1

Alternative Financial Solutions to Explore

While initiating single-agent VEGFR TKI therapy, simultaneously explore:

• Patient assistance programs from pharmaceutical manufacturers for lenvatinib or alternative combination partners (axitinib) 5
• Alternative ICI combinations such as nivolumab plus cabozantinib, which may have different cost structures 1, 3
• Clinical trial enrollment, which remains the preferred option for many patients and may provide access to combination regimens 5