# CLEAR: lenvatinib plus pembrolizumab versus sunitinib as first treatment for advanced kidney cancer

Source: https://onco.cc/key-papers/paper-clear-nejm-2021/  
OnCo record `paper-clear-nejm-2021` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Combining the multi-kinase inhibitor lenvatinib with pembrolizumab more than doubled the time to progression compared with sunitinib in advanced clear-cell kidney cancer and improved survival, with 71% of patients responding.

## Summary

Open-label phase 3 trial of 1,069 patients with untreated advanced clear-cell renal cell carcinoma randomised to lenvatinib plus pembrolizumab, lenvatinib plus everolimus, or sunitinib. Primary endpoint was PFS by independent review.

Median PFS was 23.9 vs 9.2 months (HR 0.39) for lenvatinib plus pembrolizumab, with OS HR 0.66 and an objective response rate of 71.0% vs 36.1%. Alongside KEYNOTE-426 (axitinib plus pembrolizumab), CheckMate 9ER (cabozantinib plus nivolumab) and CheckMate 214 (nivolumab plus ipilimumab), it established immunotherapy-based combinations as universal first-line therapy for advanced kidney cancer.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: New England Journal of Medicine
- Year: 2021
- DOI: 10.1056/NEJMoa2035716
- Authors: Motzer R, Alekseev B, Rha SY, et al.
- Findings: Median PFS 23.9 vs 9.2 months; HR 0.39 (95% CI 0.32-0.49).; Overall survival HR 0.66 (95% CI 0.49-0.88) at the primary analysis; subsequent follow-up showed median OS about 53.7 vs 54.3 months with HR 0.79, as sunitinib patients received later immunotherapy.; Objective response 71.0% vs 36.1%; complete response 16.1% vs 4.2%.; Benefit across all IMDC risk groups, including favourable risk.; Grade 3 or higher adverse events 82.4% vs 71.8%; hypertension, diarrhoea and proteinuria led to frequent lenvatinib dose reductions.
- What it means: Patients with newly diagnosed advanced clear-cell kidney cancer should receive an immunotherapy-based combination; lenvatinib plus pembrolizumab gives the highest response rate and longest PFS of the available options, at the cost of more side effects requiring dose adjustment. Sunitinib alone is no longer an appropriate standard. Choosing among the combinations depends on risk group, symptoms, comorbidity and the value placed on treatment-free survival, which favours nivolumab plus ipilimumab in intermediate and poor risk.
- Caveats: Open-label; no head-to-head comparison among the immunotherapy combinations.; The OS advantage narrowed with longer follow-up because of subsequent immunotherapy in the sunitinib arm.; High rates of dose reduction and discontinuation of lenvatinib; the 20 mg starting dose is debated.; Non-clear-cell histologies were excluded.

## Sources

- NEJM 2021: https://doi.org/10.1056/NEJMoa2035716
- ClinicalTrials.gov NCT02811861: https://clinicaltrials.gov/study/NCT02811861

## Connected records

- cancers: [Clear cell renal cell carcinoma](https://onco.cc/cancers/clear-cell-rcc/), [Renal cell carcinoma](https://onco.cc/cancers/rcc/)
- technologies: [Anti-angiogenic therapy](https://onco.cc/technologies/antiangiogenic/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [PD-1](https://onco.cc/targets/pd1/), [VEGF / VEGFR](https://onco.cc/targets/vegf/)
- drugs: [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- companies: [Eli Lilly (incl. Loxo)](https://onco.cc/companies/eli-lilly/), [Merck & Co. (MSD)](https://onco.cc/companies/merck/)
- terms: [Lines of therapy](https://onco.cc/terms/first-line/), [Objective response rate (ORR)](https://onco.cc/terms/orr/), [Overall survival (OS)](https://onco.cc/terms/os/), [Progression-free survival (PFS)](https://onco.cc/terms/pfs/)
- people: [Robert J. Motzer](https://onco.cc/people/robert-motzer/), [Sun Young Rha](https://onco.cc/people/rha-sun-young/), [Toni K. Choueiri](https://onco.cc/people/toni-choueiri/)
- bottlenecks: [Too many combinations to test](https://onco.cc/bottlenecks/b-combination-space/), [Toxicity and quality of life are undervalued](https://onco.cc/bottlenecks/b-toxicity-qol/), [Wrong doses](https://onco.cc/bottlenecks/b-dose-optimisation/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)

---
JSON: https://onco.cc/api/v1/entities/paper-clear-nejm-2021.json