LEAP-014: first-line lenvatinib + pembrolizumab + chemotherapy in advanced/metastatic esophageal squamous cell carcinoma

Treatment options for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) are improving. Current guidelines recommend first-line pembrolizumab plus chemotherapy for patients with unresectable or metastatic ESCC, which has led to improvements in survival outcomes. Antiangiogenic therapy combined with immune checkpoint inhibitors can act synergistically to convert the immunosuppressive tumor microenvironment to an immune supportive microenvironment, thus enhancing antitumor immune responses. In preclinical models, the antiangiogenic agent lenvatinib combined with an anti-PD-1 agent showed synergistic antitumor activity. We describe the design and rationale for the randomized, open-label, phase III LEAP-014 study of lenvatinib in combination with pembrolizumab plus chemotherapy in patients with advanced or metastatic ESCC. Overall survival and progression-free survival are the dual primary end points. <b>Clinical Trial Registration:</b>NCT04949256 (ClinicalTrials.gov) For the approximately 50% of patients with esophageal cancer who are diagnosed with unresectable or metastatic disease, current guidelines recommend first-line pembrolizumab in combination with a platinum-based chemotherapy or a fluoropyrimidine. Given the limited survival benefit observed with the currently recommended first-line therapy of pembrolizumab plus chemotherapy, there is a considerable need for alternative strategies for patients with advanced, metastatic esophageal cancer. PD-L1 and PD-L2 are expressed by tumor cells in approximately 20–40% of esophageal cancers and are associated with an unfavorable prognosis. Pembrolizumab has shown antitumor activity in patients with advanced esophageal cancer, and the addition of pembrolizumab to standard-of-care chemotherapy may translate to increased effectiveness and improved patient outcomes. Preclinical data demonstrated the immune-modulating effects of lenvatinib and synergistic antitumor activity of lenvatinib when combined with an anti-PD-1 agent. Lenvatinib plus pembrolizumab was recently approved for first-line treatment of adult patients with advanced renal cell carcinoma. In the phase II EPOC1706 trial, lenvatinib plus pembrolizumab showed promising antitumor activity and an acceptable safety profile in patients with advanced gastric cancer in both the first- and second-line setting. LEAP-014 is a randomized, active-controlled, parallel-group, multisite, open-label, two-part, phase III study designed to evaluate the safety and efficacy of lenvatinib in combination with pembrolizumab plus chemotherapy compared with pembrolizumab plus chemotherapy in patients with esophageal squamous cell carcinoma. The primary end point is safety and tolerability for part 1 (safety run-in). The dual primary end points are overall survival and progression-free survival for part 2 (main study). Adults with histologically or cytologically confirmed diagnosis of previously untreated metastatic squamous cell carcinoma of the esophagus. LEAP-014 study will further define the role of combination therapy with lenvatinib, pembrolizumab and chemotherapy in the first-line setting for patients with metastatic esophageal cancer, for whom there remains an unmet medical need for better treatment options that are tolerable.