PD-L1 Testing is NOT Required for Pembrolizumab + Lenvatinib in Metastatic Clear Cell RCC
No, PD-L1 testing is not necessary before starting pembrolizumab plus lenvatinib for this patient with metastatic clear cell renal carcinoma. This combination is approved and recommended regardless of PD-L1 expression status.
Evidence from Guidelines and FDA Approval
The CLEAR trial enrolled patients "regardless of PD-L1 tumor expression status," establishing that PD-L1 testing is not required for treatment eligibility 1, 2.
Both the 2025 EAU and 2024 ESMO guidelines recommend pembrolizumab plus lenvatinib as first-line therapy for metastatic clear cell RCC across all IMDC risk groups without any mention of PD-L1 testing requirements 3.
The FDA label for both pembrolizumab and lenvatinib in this indication contains no requirement for PD-L1 testing, in stark contrast to other indications where PD-L1 companion diagnostics are mandated 1, 2.
Why PD-L1 Testing is Not Needed
The mechanism of action differs from PD-L1-dependent regimens: The synergy between pembrolizumab (anti-PD-1) and lenvatinib (VEGFR TKI) does not depend on baseline PD-L1 expression for efficacy 4.
Clinical trial data showed consistent benefit regardless of PD-L1 status: The CLEAR trial demonstrated superior outcomes with pembrolizumab plus lenvatinib versus sunitinib across all patient subgroups, with no stratification by PD-L1 expression 1, 2.
The combination achieved a 71% objective response rate and median PFS of 23.9 months versus 9.2 months with sunitinib (HR 0.39), with overall survival HR of 0.66, demonstrating robust efficacy independent of biomarker selection 1, 2.
Contrast with Other Malignancies
This differs fundamentally from other cancer types where PD-L1 testing is mandatory:
In non-small cell lung cancer, pembrolizumab monotherapy requires PD-L1 expression ≥50% for first-line use, with companion diagnostic testing mandated by FDA 3.
In triple-negative breast cancer, atezolizumab requires ≥1% PD-L1 on immune cells (SP142 assay) and pembrolizumab requires CPS ≥10 (22C3 assay) for treatment eligibility 5.
In metastatic clear cell RCC, no such restriction exists because the VEGFR TKI component (lenvatinib) provides independent anti-tumor activity that complements immunotherapy regardless of PD-L1 status 4, 1.
Clinical Implications for This Patient
For your patient with widespread metastases to bone, lung, and liver:
Proceed directly with pembrolizumab 200 mg IV every 3 weeks plus lenvatinib 20 mg PO daily without waiting for PD-L1 testing results 3, 1, 2.
This regimen showed particular efficacy in patients with bone metastases (HR 0.33 for PFS) and multiple metastatic sites, making it especially appropriate for this clinical scenario 6, 7.
The combination demonstrated consistent benefit across all IMDC risk categories (favorable, intermediate, and poor risk), so risk stratification does not alter the recommendation 3, 8.
Common Pitfall to Avoid
Do not delay treatment initiation to obtain PD-L1 testing, as this would unnecessarily postpone effective therapy without providing actionable information. PD-L1 expression does not predict response to pembrolizumab plus lenvatinib in renal cell carcinoma, unlike in lung or breast cancer where it serves as a validated predictive biomarker 1, 2.