CLEAR

Biomarker / PD-L1

PD-L1 was not an eligibility or treatment-selection requirement. A subsequent prespecified biomarker analysis assessed PD-L1 by immunohistochemistry and reported combined positive score (CPS) as a continuous biomarker; PD-L1 levels were not associated with response or PFS within either treatment arm, and the PFS benefit of lenvatinib+pembrolizumab was consistent across PD-L1-defined subgroups. Other exploratory biomarkers included T-cell-inflamed gene-expression signatures, RCC driver mutations and molecular subtypes.

Absolute Effect

Overall survival: final OS HR 0.79 (95% CI 0.63–0.99); median OS 53.7 vs 54.3 months. The 36-month survival difference provides the fixed-time absolute effect.

PFS: HR 0.47 (95% CI 0.38–0.57). Response was 71.3% vs 36.7% (RR 1.94, 95% CI 1.67–2.26).

Safety: Treatment-emergent AEs occurred in >90% in both groups; grade ≥3 events were 82.4% versus 71.8%. The combination has substantial hypertension, proteinuria, renal and other TKI-related burden.

Interpretation & limitations

The OS medians converged despite the PFS advantage; the 36-month OS rate is therefore more informative for absolute benefit than the median OS. Open-label treatment and subsequent therapy can influence OS.

Primary source

Motzer R, et al. N Engl J Med. 2021;384:1289–1300; final OS analysis.

Read the final analysis →

Current-practice context · reviewed 14 October 2026

Lenvatinib/pembrolizumab remains an established first-line IO–TKI option in advanced clear-cell RCC. Interpret its long-term PFS/response advantage alongside final OS results, treatment burden and toxicity. The pivotal comparator was sunitinib; the trial does not support direct ranking against other current combinations. In IMDC favorable-risk disease, PFS/response benefit has not translated into a clear OS advantage versus sunitinib.

EAU RCC disease-management guidance ↗

Targeted freshness note added 14 October 2026; exhaustive guideline reconciliation remains pending.