Clinical trialPhase 2Kidney cancer

Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial

The Lancet Oncology · 2015153 patients

Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, et al. The Lancet Oncology. 2015. 16:1473-1482

Study type: Clinical trial
Phase: Phase 2
Design: Randomised, open-label, multicentre trial with three arms (1:1:1 ratio), conducted at 37 centres in five countries
Sample size: 153 patients
Source: The Lancet Oncology · 2015
Trial registration: NCT01136733

In plain words

In this study, patients with advanced kidney cancer that had progressed again after a targeted anti-VEGF drug received one of three treatments: lenvatinib alone, everolimus alone, or the two together. The combination of lenvatinib and everolimus, and also lenvatinib alone, kept the disease from progressing for longer than everolimus alone. Serious side effects were more common in the groups taking lenvatinib, including diarrhoea and protein loss in the urine. Treatment decisions should be made with the treating doctor, taking each patient's situation into account.

Key results

14.6 months (95% CI 5.9–20.1) vs 5.5 months (3.5–7.1)

Median progression-free survival: lenvatinib + everolimus vs everolimus

HR 0.40 (95% CI 0.24–0.68); P=0.0005

14.6 months vs 7.4 months (95% CI 5.6–10.2)

Progression-free survival: lenvatinib + everolimus vs lenvatinib alone

HR 0.66 (95% CI 0.30–1.10); P=0.12 (not statistically significant)

HR 0.61 (95% CI 0.38–0.98)

Progression-free survival: lenvatinib alone vs everolimus alone

P=0.048

Everolimus: 50% (25 patients); lenvatinib: 79% (41 patients); lenvatinib + everolimus: 71% (36 patients)

Grade 3 and 4 adverse events

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

Dose and schedule cards

Lenvatinib + everolimus

Advanced RCC after one prior anti-angiogenic therapyCycle length: ContinuousOn the page “Kidney cancer” · Regimens for later lines and immunotherapy-free treatment

Advanced RCC after one prior anti-angiogenic therapy

Drug	Dose	Route	Schedule
Lenvatinib	18 mg once daily	Oral, with or without food	Daily, continuously
Everolimus	5 mg once daily	Oral	Daily, continuously

Cycle length: Continuous
Duration: Until progression or unacceptable toxicity

Per the FDA label and the trial. For overlapping toxicities, interrupt or reduce lenvatinib first, then everolimus; lenvatinib dose reductions in RCC: 14 mg, 10 mg, then 8 mg; for CrCl <30 mL/min or Child-Pugh C, 10 mg. Monitor blood pressure, liver tests, urine protein and thyroid function as for the lenvatinib + pembrolizumab regimen.

On the page “Kidney cancer” · Regimens for later lines and immunotherapy-free treatment

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 everolimus

Lenvatinib 18 mg + everolimus 5 mg, both orally once daily, in continuous 28-day cycles until disease progression or unacceptable toxicity (51 patients). This is the same FDA-approved dose for advanced RCC after one prior anti-angiogenic therapy.

2Lenvatinib monotherapy

Lenvatinib 24 mg orally once daily in continuous 28-day cycles until progression or unacceptable toxicity (52 patients).

3Everolimus monotherapy

Everolimus 10 mg orally once daily in continuous 28-day cycles until progression or unacceptable toxicity (50 patients).

Source of the regimen details: Abstract of the paper, ClinicalTrials.gov NCT01136733 and the FDA label for lenvatinib (approved combination dose)

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 unresectable advanced or metastatic clear-cell-predominant renal cell carcinoma, with radiographic progression on or within 9 months of stopping exactly one prior anti-VEGF targeted therapy (such as sunitinib, sorafenib, pazopanib, bevacizumab or axitinib); measurable disease, ECOG 0 or 1 and controlled blood pressure (150/90 mmHg or less). Randomisation was stratified by haemoglobin and corrected serum calcium.

Endpoints

The primary endpoint was progression-free survival (PFS) in the intention-to-treat (ITT) population.

Safety and side effects

Grade 3 and 4 adverse events were less frequent in the everolimus-alone group (25 patients, 50%) than with lenvatinib alone (41 patients, 79%) and lenvatinib + everolimus (36 patients, 71%). The most common treatment-related grade 3 or 4 adverse event was diarrhoea in the combination group (ten patients, 20%), proteinuria in the lenvatinib-alone group (ten patients, 19%) and anaemia in the everolimus-alone group (six patients, 12%). Two deaths related to study drug were reported: one cerebral haemorrhage in the lenvatinib + everolimus group and one myocardial infarction in the lenvatinib-alone group.

Clinical significance and place in guidelines

This phase 2 trial showed that in patients with metastatic renal cell carcinoma after one anti-VEGF therapy, lenvatinib plus everolimus, and also lenvatinib alone, improve progression-free survival compared with everolimus alone, and the authors considered further study of lenvatinib necessary. The abstract gives no information on drug approval or the place of this regimen in guidelines; these should be checked in current guidelines.

Limitations

An open-label phase 2 study with a relatively small sample (153 patients). The lenvatinib-everolimus combination showed no significant progression-free survival superiority over lenvatinib alone (P=0.12). Grade 3 and 4 adverse events were more frequent in the lenvatinib-containing groups. Further information on overall survival and other endpoints should be checked 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.