Lenvatinib falls short as add-on to pembrolizumab in urothelial carcinoma

Findings from the phase 3 LEAP-011 trial showed that the addition of lenvatinib (Lenvima) to frontline pembrolizumab (Keytruda) did not improve overall survival (OS) vs pembrolizumab alone in patients with advanced urothelial carcinoma who were ineligible for platinum-based chemotherapy.1

Results from the placebo-controlled trial presented at the 2022 ASCO Genitourinary Cancers Symposium showed that the median OS in the lenvatinib arm was 11.8 months (95% CI, 9.1-15.1) vs 12.9 months (95% CI, 9.8-17.8) in the pembrolizumab plus placebo group (HR, 1.14; 95% CI, 0.87-1.48). The median PFS was 4.5 (95% CI, 4.0-6.0) versus 4.0 months, respectively (95% CI, 2.7-5.4) (HR, 0.90; 95% CI, 0.72-1.14).

“The antitumor activity observed with pembrolizumab plus placebo was consistent with previous results of pembrolizumab monotherapy in similar populations of patients who are cisplatin ineligible or who are ineligible for any platinum-based chemotherapy,” lead study author Yohann Loriot, MD, PhD, of Gustave Roussy, Cancer Campus, and University of Paris-Saclay in Villejuif, France, said during the presentation. “First-line pembrolizumab monotherapy remains the standard of care in the United States for patients who are ineligible for any platinum-based chemotherapy, regardless of PD-L1 status.”

Pembrolizumab is an approved first-line therapy for patients with advanced urothelial carcinoma who are ineligible for platinum-based chemotherapy. Results from the phase 2 KEYNOTE-052 trial (NCT02335424) demonstrated the ability of pembrolizumab to generate meaningful and durable responses in cisplatin-ineligible patients.2 Findings from KEYNOTE-052 served as the basis for the accelerated approval of the agent in this setting, which was subsequently converted to a full approval in August 2021 in a platinum-ineligible population.3,4

When combined with pembrolizumab, lenvatinib showed promising early activity and manageable safety in previously treated patients with advanced urothelial carcinoma, regardless of PD-L1 status, based on data from the phase 1b/2 KEYNOTE-146 trial (NCT02501096).5

The LEAP-011 trial aimed to examine this combination in the first-line setting for patients with histologically confirmed advanced or metastatic urothelial carcinoma. Patients were required to be ineligible for cisplatin-based chemotherapy and have tumors with a PD-L1 combined positive score (CPS) of 10 or higher, or be ineligible for any platinum-based chemotherapy, regardless of PD-L1 status. Other eligibility criteria included no prior systemic chemotherapy and an ECOG performance status between 0 and 2.

The double-blinded, 1:1 randomized study planned to enroll 694 patients and place 347 patients in both the lenvatinib and placebo cohorts. An interim analysis of OS and PFS was planned to follow 530 PFS events, or approximately 24 months after the first patient was randomized. However, an independent data monitoring committee, which reviewed safety data every 3 months, determined the benefit-to-risk ratio of lenvatinib plus pembrolizumab, based on OS, PFS, and overall response rate (ORR) data, warranted stopping enrollment for the trial.

Ultimately, 487 patients were enrolled, with 245 enrolled to the lenvatinib arm and 242 enrolled in the placebo arm. Patients either received 20 mg of oral lenvatinib once daily or placebo. All patients were administered 200 mg of intravenous pembrolizumab once every 3 weeks for up to 35 cycles.

The dual primary end points of the trial were OS and PFS based on RECIST version 1.1 criteria by blinded independent central review. Key secondary end points included ORR, duration of response (DOR), disease control rate, safety, and tolerability.

The median age of patients in the lenvatinib arm was 74 years (range, 43-93) compared with 73 years (range, 47-92) in the placebo arm. In the lenvatinib and placebo arms, respectively, most patients were male (69.0% vs 76.0%), and most were ineligible for any platinum agent with an ECOG performance status of 2 (80.0% vs 80.2%). The remaining patients were cisplatin ineligible with a CPS of at least 10 (20.0% vs 19.8%). Other baseline characteristics included lymph node–only disease (24.1% vs 21.1%), visceral disease (74.7% vs 76.4%), liver metastases (24.9% vs 26.0%), and hemoglobin of at least 10 g/dL (89.8% vs 87.6%).

The lenvatinib arm achieved an ORR of 33.1% compared with a 28.9% ORR in the placebo arm. Additionally, the lenvatinib group had a median DOR of 12.8 months (range, 1.2+ to 20.8+) compared with 19.3 months (range, 1.4+ to 21.9+) in the placebo group.

Treatment-related adverse effects (TRAEs) of any grade were observed in 87.6% of patients in the lenvatinib group and 69.0% of patients in the placebo group. Grade 3 to 5 TRAEs occurred in 51.0% of patients in the lenvatinib arm and 27.3% of patients in the placebo arm. Notably, 19.9% of patients in the lenvatinib arm discontinued any drug because of a TRAE vs 9.1% of patients in the placebo group. Specifically, 10.0% of patients in the lenvatinib arm and 5.0% of patients in the placebo arm discontinued pembrolizumab, 19.1% discontinued lenvatinib, 8.7% discontinued placebo, and 7.9% in the lenvatinib arm and 3.3% in the placebo arm discontinued both drugs.

The lenvatinib arm reported serious TRAEs in 22.4% of patients, and 6 patients died from a TRAE. The placebo arm reported serious TRAEs in 9.9% of patients, and 1 patient died due to a TRAE. The duration of treatment was 3.9 months (range, 0-23.4) and 3.8 months (range, 0-25.0) in the lenvatinib and placebo groups, respectively.

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%), diarrhea (20.7% vs 10.3%), decreased appetite (14.5% vs 5.8%), fatigue (14.5% vs 12.0%), increased lipase (12.0% vs 7.0%), asthenia (12.0% vs 5.0%), nausea (11.6% vs 8.3%), pruritus (11.2% vs 14.5%), dysphonia (10.8% vs 0.4%), and rash (10.0% vs 5.8%).


1. Loriot Y, Grivas P, de Wit R, et al. First-line pembrolizumab with or without lenvatinib in patients with advanced urothelial carcinoma (LEAP-011): a phase 3, randomized, double-blind study. J Clin Oncol. 2022;40(suppl 6):432. doi:10.1200/JCO.2022.40.6_suppl.432

2. Vuky J, Balar AV, Castellano D, et al. Long-term outcomes in KEYNOTE-052: phase II study investigating first-line pembrolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer. J Clin Oncol. 2020;38(23):2658-2666. doi:10.1200/JCO.19.01213

3. Pembrolizumab (Keytruda): advanced or metastatic urothelial carcinoma. News release. FDA. May 19, 2017. Accessed February 18, 2022. https://bit.ly/3gTUI7f

4. FDA approves updated indication for Merck’s KEYTRUDA (pembrolizumab) for the treatment of certain patients with urothelial carcinoma (bladder cancer). News release. Merck. August 31, 2021. Accessed February 18, 2022. https://bwnews.pr/3zCgh3N

5. Taylor MH, Lee CH, Makker V, et al. Phase Ib/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J Clin Oncol. 2020;38(11):1154-1163. doi:10.1200/JCO.19.01598