A phase 2 multicohort study (LEAP-005) of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors: Pancreatic cancer cohort

Abstract

Background:Over the past few decades, the global incidence and mortality ratesassociated with pancreatic cancer have continued to increase. Pancreatic cancer has aparticularly poor prognosis, with a 5-year survival rate of only approximately 5%. Patientswith pancreatic cancer generally respond poorly to chemotherapy, and their treatmentoptions in the second-line or later setting are limited. In two multicohort, open-labeltrials, including the phase 1b/2 KEYNOTE-146 (NCT02501096) and phase 2 LEAP-005(NCT03797326) studies, the combination of theantiangiogenic multikinase inhibitorlenvatinib and the anti‒PD-1 monoclonal antibody pembrolizumab demonstratedpromising antitumor activity with a manageable safety profile in patients with previouslytreated (both studies) and untreated (KEYNOTE-146) histologically or cytologicallyconfirmed metastatic (both studies) and/or unresectable (LEAP-005) solid tumors. In theLEAP-005 trial, benefit was seen in cohorts with glioblastoma multiforme and biliary tractcancer (second-line treatment), triple-negative breast cancer (second- and third-linetreatment), gastric and colorectal cancer (third-line treatment), and ovarian cancer(fourth-line treatment). Based on these encouraging results and the unmet need forpatients with pancreatic cancer, the LEAP-005 protocol was amended to include apancreatic cancer cohort. Here we describe the LEAP-005 trial design for this cohort.Trial design:Eligible patients are aged 18 years with histologically or cytologicallyconfirmed metastatic pancreatic ductal adenocarcinoma and have received 1 or 2prior lines of therapy (including 1 platinum- or gemcitabine-containing regimen),have measurable disease per RECIST version 1.1, have ECOG performance status of0 or 1, and provide a tissue sample for evaluation of PD-L1 expression. Patientsreceive lenvatinib 20 mg once daily plus pembrolizumab 200 mg Q3W for up to 35cycles of pembrolizumab (approximately 2 years) or until confirmed disease pro-gression, unacceptable toxicity, or withdrawal of consent. Treatment with lenvatinibcan continue beyond 2 years in patients experiencing clinical benefit. The primaryendpoints are ORR (per RECIST version 1.1 by blinded independent central review)and safety. The primary safety endpoints are treatment-emergent AEs, serious AEs,and discontinuations due to AEs, with AEs graded using National Cancer InstituteCommon Terminology Criteria for Adverse Events version 4.0. Secondary endpointsinclude disease control rate (comprising CR, PR, and SD), duration of response, PFS,and OS. Health-related quality of life is assessed using validated patient-reportedoutcome instruments including the European Organisation for the Research andTreatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30). Tumorimaging is performed Q9W from treatment initiation for 54 weeks, then Q12W toweek 102, and Q24W thereafter. PD-L1 expression is assessed by a central laboratoryusing PD-L1 IHC 22C3 (Agilent Technologies, Carpinteria, CA). The pancreatic cancercohort began enrollment in March 2021. An interim analysis is planned when thefirst30 patients enrolled have been followed up for approximately 6 months.