Clinical trialPhase 3Kidney cancer

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

JCO · 2024712 patients in this comparison (355 lenvatinib + pembrolizumab, 357 sunitinib) of the 1069 patients in the three-arm trial

Motzer RJ, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, et al. JCO. 2024. 42:1222-1228

Study type: Clinical trial
Study name: CLEAR
Phase: Phase 3
Design: Randomised, open-label, multicentre trial; prespecified final overall survival analysis
Sample size: 712 patients in this comparison (355 lenvatinib + pembrolizumab, 357 sunitinib) of the 1069 patients in the three-arm trial
Source: JCO · 2024
Trial registration: NCT02811861

In plain words

In this study, patients with advanced kidney cancer who had not yet had any treatment received either a combination of two drugs, lenvatinib and pembrolizumab, or the drug sunitinib. After longer follow-up, the lenvatinib and pembrolizumab combination lowered the risk of death, gave a longer time before the disease got worse and shrank the tumour in a larger share of patients. Side effects were seen in more than 90% of patients in both groups, but the authors considered them manageable. The choice of treatment should be made with your treating doctor.

Key results

0.79 (95% CI 0.63–0.99)

Overall survival (OS) — hazard ratio

Data cut-off: 31 July 2022; 23 months of additional follow-up compared with the primary analysis

53.7 months vs 54.3 months

Median overall survival

95% CI 48.7 to not estimable vs 40.9 to not estimable

66.4% vs 60.2%

36-month overall survival rate

95% CI 61.1–71.2 vs 54.6–65.2

23.9 months vs 9.2 months

Median progression-free survival (PFS)

Hazard ratio 0.47 (95% CI 0.38–0.57); CIs of the medians: 20.8–27.7 vs 6.0–11.0

71.3% vs 36.7%

Objective response rate (ORR)

Relative risk 1.94 (95% CI 1.67–2.26)

Drugs in this study: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 plus pembrolizumab

Lenvatinib at a starting dose of 20 mg orally once daily in 21-day cycles + pembrolizumab 200 mg IV on day 1 of each 21-day cycle. Pembrolizumab was given for up to 35 cycles (about 2 years), after which lenvatinib alone was continued until progression or unacceptable toxicity (about 34% of patients completed all 35 cycles).

2Sunitinib

Sunitinib at a starting dose of 50 mg orally once daily, 4 weeks on and 2 weeks off.

Source of the regimen details: Full text of the paper (PMC11095851) and ClinicalTrials.gov NCT02811861

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 (most patients MSKCC/IMDC intermediate risk).

Endpoints

This report presents the prespecified final analysis of overall survival (OS). Progression-free survival (PFS), objective response rate (ORR) and treatment-emergent adverse events are also reported.

Safety and side effects

Treatment-emergent adverse events occurred in more than 90% of patients in both groups. Grade 3 or higher adverse events occurred in 84.9% of patients with lenvatinib + pembrolizumab and 74.7% of patients with sunitinib; diarrhoea was the most common adverse event and hypertension the most common grade 3 or higher adverse event. Fatal treatment-related adverse events occurred in 4 patients (1.1%) versus 1 patient (0.3%).

Clinical significance and place in guidelines

This final overall survival analysis shows that the advantage of lenvatinib plus pembrolizumab over sunitinib in first-line treatment of advanced renal cell carcinoma is maintained with longer follow-up (OS HR 0.79; PFS and ORR also favoured the combination). The abstract gives no information on the place of this regimen in guidelines or on drug approvals; the status in current guidelines should be checked separately.

Limitations

The study is open-label. Median overall survival was reported to be almost the same in the two groups (53.7 versus 54.3 months), with wide confidence intervals whose upper limits are not estimable. The upper limit of the confidence interval for the OS HR is 0.99. The number of patients, post-progression treatments and the rate of severe adverse events are not given in the abstract, and the full text of the paper should be consulted for a complete assessment.

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.