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Lenvatinib fails to improve on pembrolizumab in patients with advanced urothelial carcinoma

LEAP-011 is a randomised, global, phase III trial to test the hypothesis that the addition of lenvatinib to first-line pembrolizumab in advanced urothelial carcinoma may improve outcomes compared to pembrolizumab plus placebo. Unfortunately however, frontline treatment with pembrolizumab in combination with lenvatinib did not improve progression-free survival and overall survival when compared with pembrolizumab alone in patients with advanced urothelial carcinoma who were ineligible for platinum-based chemotherapy.

Pembrolizumab is an approved first-line therapy for cisplatin-ineligible patients who have previously treated advanced urothelial carcinoma. Lenvatinib, a multiple-receptor tyrosine kinase inhibitor, has shown antitumour activity in several advanced solid tumours. In the phase Ib/II Keynote-146 study, pembrolizumab plus lenvatinib showed promising preliminary activity and manageable safety in previously treated patients with advanced urothelial carcinoma, regardless of PD-L1 status. At ASCO GU 2022, data from the phase III LEAP-011 study were presented.

Study design

The phase III LEAP-011 study enrolled adults with histologically confirmed, locally advanced/unresectable or metastatic urothelial carcinoma who were cisplatin-ineligible with tumours expressing PD-L1 (combined positive score =10) or were ineligible for any platinum-based chemotherapy regardless of PD-L1 status. Patients were randomly allocated in a 1:1 ratio to receive pembrolizumab 200 mg IV Q3W for up to 35 cycles (approximately two years) plus either lenvatinib 20 mg orally once daily or placebo. Patients could not have received prior systemic chemotherapy and were required to have an ECOG performance status 0-2. Dual primary endpoints were progression-free survival (PFS) per RECIST v1.1 and overall survival (OS). An independent data monitoring committee (DMC) reviewed safety data every three months. The DMC determined the benefit to risk ratio of pembrolizumab plus lenvatinib (pembro + lenva) by evaluating safety and efficacy endpoints. Based on the data described below, the DMC made the recommendation to stop enrolment.


Of 487 randomly assigned patients, 245 were assigned to receive pembro + lenva and 242 were assigned to receive pembro + placebo. The median age of patients in the lenvatinib arm was 74 years compared with 73 years in the placebo arm. In the lenvatinib and placebo arms, respectively, most patients were male (69.0% vs. 76.0%) and ineligible for any platinum agent with an ECOG performance status of 2 (80.0% vs. 80.2%). Median follow-up was 5.9 months for the lenvatinib arm and 7.0 months for the placebo arm and duration of treatment was 3.9 and 3.8 months, respectively. Median PFS was highly comparable in both arms, with 4.5 months in the lenvatinib group and 4.0 months in the placebo group (HR[95%CI]: 0.90[0.72-1.14]). Furthermore, median OS was also not different (11.8 vs. 12.9 months, respectively, HR[95%CI]: 1.14[0.87-1.48]). The objective response rate was 33.1% with pembro + lenva vs. 28.9% with pembro + placebo, with median duration of response of respectively 12.8 and 19.3 months.

In 483 treated patients, treatment-related adverse events (TRAEs) occurred in 211 of 241 patients (87.6%) in the pembro + lenva group and in 167 of 242 patients (69.0%) in the pembro + placebo group. Grade 3-5 TRAEs occurred in 51.0% and 27.3%, respectively. Furthermore, the discontinuation rate of any drug because of a TRAE was higher for patients treated with pembrolizumab plus lenvatinib, as compared to pembrolizumab alone (19.9% vs. 9.1%). Serious TRAEs were reported in respectively 22.4% and 9.9% of patients. Death from a TRAE occurred in 6 patients (2.5%) in the lenvatinib arm and in 1 patient (0.4%) in the control arm.

The most common TRAEs of any grade in the lenvatinib and placebo arms, respectively, were proteinuria (37.8% vs. 18.6%), hypothyroidism (36.5% vs. 7.0%), hypertension (34.9% vs. 7.0%), diarrhoea (20.7% vs. 10.3%), decreased appetite (14.5% vs. 5.8%) and fatigue (14.5% vs. 12.0%).


First-line pembrolizumab plus lenvatinib treatment showed comparable antitumour activity as pembrolizumab plus placebo in a frail population of platinum-ineligible patients with advanced urothelial carcinoma. Safety was generally consistent with the known profile of pembrolizumab plus lenvatinib and no new safety signals were detected. The benefit-risk ratio for pembrolizumab plus lenvatinib was not considered positive and the study stopped enrolment based on the recommendation of the data monitoring committee. First-line pembrolizumab monotherapy therefore remains a standard of care in Europe for patients who are cisplatin-ineligible and have tumours that express PD-L1 with a CPS ≥10.


Loriot Y, et al. First-line pembrolizumab (pembro) with or without lenvatinib (lenva) in patients with advanced urothelial carcinoma (LEAP-011): A phase 3, randomized, double-blind study. Presented at ASCO GU 2022; Abstract 432.

Speaker Yohann Loriot

Yohann Loriot

Yohann Loriot, MD, PhD, Gustave Roussy, Cancer Campus, and University of Paris-Saclay, Villejuif, France


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