ASCO GU 2022: First-Line Pembrolizumab with or Without Lenvatinib in Patients with Advanced Urothelial Carcinoma (LEAP-011): A Phase 3, Randomized, Double-Blind Study.

( On the second day of the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022, Dr. Yohann Loriot presented in a session highlighting novel therapies in bladder cancer and their toxicities, describing the results of the LEAP-011 trial examining first line pembrolizumab with or without Lenvatinib in patients with advanced urothelial cancer (aUC).

Dr. Loriot began by highlighting that pembrolizumab monotherapy is a standard of care for advanced urothelial carcinoma (UC) among patients who are cisplatin-ineligible. Further, in the phase 1b/2 KEYNOTE-146 study, the combination of pembrolizumab and lenvatinib, a multiple-receptor tyrosine kinase inhibitor with demonstrated anti-tumor activity in several tumor types, showed antitumor activity and acceptable safety.

Thus, the authors designed the phase III LEAP-011 trial (NCT03898180) to compare first-line pembrolizumab and Lenvatinib to pembrolizumab monotherapy as first-line treatment of patients with aUC who are cisplatin-ineligible with PD-L1–positive tumors or are ineligible to receive platinum-based chemotherapy.

The authors enrolled adult patients histologically confirmed, locally advanced/unresectable, or metastatic UC who were either cisplatin-ineligible with tumors expressing PD-L1 (combined positive score ≥10) or were ineligible to receive platinum-based chemotherapy regardless of PD-L1 status. Once enrolled, patients were randomly assigned 1:1 to receive pembrolizumab 200 mg IV Q3W for up to 35 cycles (̃2 years) and either lenvatinib 20 mg orally once daily or placebo.

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The study had dual primary endpoints of progression-free survival per RECIST v1.1 and overall survival, among with key secondary endpoints of ORR per RECIST v1.1, disease control rate (DCR), and duration of response (DOR). The authors planned to enroll 694 patients with an interim analysis planned at 530 PFS events, to occur approximately 2 years after the first patient was randomly assigned. An independent data monitoring committee (DMC) regularly reviewed safety data every 3 months. At the time of present analysis, a total of 487 patients were enrolled with 24 in the combined pembrolizumab and lenvatinib arm and 242 in the pembrolizumab and placebo arm. Based on these data, the DMC recommended stopping enrollment.

Results: Of 487 randomly assigned patients, 254 were assigned to receive pembrolizumab and lenvatinib (of whom 241 were treated) and 242 were assigned to receive pembrolizumab and placebo (of whom 242 were treated).

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As expected based on the randomized design, baseline characteristics were well balanced. The median age was 73-74 years. Approximately 80% of patients were ineligible for any platinum agent and had an ECOG performance status of 2. Approximately three-quarters had visceral disease.

The median duration of treatment was 3.8 months (range, 0.0-20.7) for pembrolizumab and lenvatinib and 3.4 months (range, 0.0-22.0) for pembrolizumab and placebo.

As assessed by blinded independent central review, the median PFS was 4.5 months (95% CI, 4.0-6.0) among those receiving pembrolizumab and lenvatinib and 4.0 months (95% CI, 2.7-5.4) among those receiving pembrolizumab and placebo (HR, 0.90 [95% CI, 0.72-1.16]).

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Similarly, median overall survival did not differ between the two groups: 11.8 months (95% CI, 9.1-15.1) with pembrolizumab and lenvatinib compared to 12.9 months (95% CI, 9.8-17.8) with pembrolizumab and placebo (HR, 1.14 [95% CI, 0.87-1.48].

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The trial further failed to find a difference in confirmed objective response rate (33.1% vs 28.9%) or duration of response (12.8 months versus 19.3 months, with the effect favouring the placebo arm).

In terms of toxicity, any-grade treatment related adverse events occurred in 87.6% of patients in the pembrolizumab and lenvatinib arm and 69.0% of those in the pembrolizumab and placebo arm. Grade 3-5 AEs were similarly more common in the combination arm (51% vs 27%) as was treatment discontinuation due to AEs (19.9% vs 9.1%), serious treatment-related AEs (22.4% vs 9.9%0, and death from treatment-related AEs (2.5% vs 0.4%). In particular, hypothyroidism was much more common in the combination arm (36.9% vs 8.7%).

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In conclusion, while the safety profile of pembrolizumab and lenvatinib was consistent with that of previous studies, there was no additional efficacy compared to pembrolizumab alone in a population of frail patients with aUC who were platinum-ineligible.

Presented by: Yohann Loriot, PhD, MD, Gustave Roussy, Cancer Campus, and University of Paris-Saclay