Clinical trialPhase 3Kidney cancer

Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma

N Engl J Med · 20211069 patients (355 lenvatinib + pembrolizumab, 357 lenvatinib + everolimus, 357 sunitinib)

Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, et al. N Engl J Med. 2021. 384:1289-1300

A newer report of this study has been published: Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study (2024)

Study type: Clinical trial
Study name: CLEAR
Phase: Phase 3
Design: Randomised, open-label, three-arm trial (1:1:1 ratio)
Sample size: 1069 patients (355 lenvatinib + pembrolizumab, 357 lenvatinib + everolimus, 357 sunitinib)
Source: N Engl J Med · 2021
Trial registration: NCT02811861

In plain words

In this study, a combination of the tablet lenvatinib and the immunotherapy drug pembrolizumab was compared with the tablet sunitinib in advanced kidney cancer. With this combination, the disease stayed under control for a median of about 24 months versus about 9 months with sunitinib, and the tumour shrank in about 7 in 10 patients. Side effects such as high blood pressure and diarrhoea were common and need regular follow-up.

Key results

23.9 vs 9.2 months

Median progression-free survival (lenvatinib + pembrolizumab)

HR 0.39; 95% CI 0.32–0.49; P<0.001

HR 0.66

Overall survival (lenvatinib + pembrolizumab, first analysis)

95% CI 0.49–0.88; P=0.005

HR 0.79

Overall survival (prespecified final analysis, 2024)

95% CI 0.63–0.99; median 53.7 vs 54.3 months; 36-month survival 66.4% vs 60.2% (Motzer et al., J Clin Oncol 2024)

71.3% vs 36.7%

Objective response (final analysis)

Relative risk 1.94 (Motzer et al., J Clin Oncol 2024)

HR 1.15

Overall survival (lenvatinib + everolimus)

95% CI 0.88–1.50; P=0.30 (no advantage over sunitinib)

82.4% vs 71.8%

Grade 3 or higher adverse events

Lenvatinib + pembrolizumab vs sunitinib; 83.1% with lenvatinib + everolimus

Drugs in this study:Everolimus (Afinitor)Lenvatinib (Lenvima)Pembrolizumab (Keytruda)

Dose and schedule cards

Lenvatinib + pembrolizumab (CLEAR)

Advanced RCC, first line, all IMDC risk groups; also an EAU-recommended option for non-clear-cell subtypesEach drug’s schedule in the tableOn the page “Kidney cancer” · First-line regimens for advanced RCC

Advanced RCC, first line, all IMDC risk groups; also an EAU-recommended option for non-clear-cell subtypes

Drug	Dose	Route	Schedule
Lenvatinib	20 mg once daily	Oral, with or without food	Daily, continuously
Pembrolizumab	200 mg (or 400 mg)	IV, 30-minute infusion	Day 1 every 3 weeks (400 mg dose: every 6 weeks)

Cycle schedule: Pembrolizumab every 3 weeks (or every 6 weeks with the 400 mg dose); lenvatinib daily and continuously
Duration: Pembrolizumab up to 24 months; lenvatinib until progression or unacceptable toxicity (after 2 years of combination therapy it may be continued alone)

Per the FDA labels and the trial. Lenvatinib dose reductions in RCC: 14 mg, then 10 mg, then 8 mg; in severe renal impairment (CrCl <30 mL/min) or severe hepatic impairment (Child-Pugh C), 10 mg. Control blood pressure before starting, and monitor it after 1 week, then every 2 weeks for 2 months, then at least monthly; liver tests every 2 weeks for 2 months, then monthly; thyroid function and calcium at least monthly; urine protein (if dipstick ≥‎2+‎, obtain a 24-hour urine collection; withhold for ≥2 g/24 h). Withhold lenvatinib at least 1 week before elective surgery and do not start it until 2 weeks after major surgery.

On the page “Kidney cancer” · First-line regimens for advanced RCC

Lenvatinib + pembrolizumab

Advanced kidney cancer, first lineEach drug’s schedule in the tableOn the page “Lenvatinib with pembrolizumab in kidney cancer (CLEAR)”

Advanced kidney cancer, first line

Drug	Dose	Route	Schedule
Lenvatinib	20 mg once a day	Oral	Daily
Pembrolizumab	200 mg	IV	Every 3 weeks

Cycle schedule: Lenvatinib daily; pembrolizumab every 3 weeks
Duration: Until progression; pembrolizumab up to 2 years

As in CLEAR; dose source:.

On the page “Lenvatinib with pembrolizumab in kidney cancer (CLEAR)”

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Lenvatinib + pembrolizumab

Lenvatinib 20 mg orally once daily (21-day cycles) + pembrolizumab 200 mg IV on day 1 of each 21-day cycle; pembrolizumab for up to 35 cycles (about 2 years), then lenvatinib alone until progression or unacceptable toxicity.

2Lenvatinib + everolimus

Lenvatinib 18 mg orally once daily + everolimus 5 mg orally once daily (21-day cycles), until progression or unacceptable toxicity.

3Sunitinib

Sunitinib 50 mg orally once daily, 4 weeks on and 2 weeks off, until progression or unacceptable toxicity.

Source of the regimen details: Abstract of the paper, ClinicalTrials.gov NCT02811861 and full text of the final analysis (J Clin Oncol 2024; PMC11095851)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with advanced renal cell carcinoma with a clear-cell component, without previous systemic therapy, with at least one measurable lesion per RECIST 1.1, Karnofsky performance status 70 or more, controlled blood pressure (150/90 mmHg or less) and adequate kidney function (creatinine 1.5 times the upper limit of normal or less, or CrCl at least 30 mL/min); all risk groups (ClinicalTrials.gov).

Endpoints

Primary endpoint: progression-free survival by independent review committee per RECIST 1.1. Overall survival and safety were also assessed.

Safety and side effects

Grade 3 or higher adverse events (emerging or worsening during treatment) occurred in 82.4% of patients with lenvatinib + pembrolizumab, 83.1% with lenvatinib + everolimus and 71.8% with sunitinib. Grade 3 or higher adverse events with a frequency of at least 10% in any group included hypertension, diarrhoea and elevated lipase.

Clinical significance and place in guidelines

Based on this trial, the FDA approved lenvatinib with pembrolizumab in August 2021 for first-line treatment of advanced renal cell carcinoma. NCCN (version 3.2022) considers it a preferred option with category 1 evidence in all risk groups, but did not include lenvatinib + everolimus in the first line. The EAU 2022 guideline also lists lenvatinib + pembrolizumab among the standard first-line treatments in all IMDC risk groups (level of evidence 1b).

Limitations

Open-label design; in the final overall survival analysis, the overall survival gap between the two groups narrowed over time (HR 0.79) and median overall survival was similar; many patients in the sunitinib group received immunotherapy in later lines; high rate of grade 3 or higher adverse events and need for lenvatinib dose reduction (details in the full text of the paper).

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.