Lenvatinib ± Pembrolizumab Versus Chemotherapy for Recurrent/Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (HNSCC) That Progressed after Platinum and Immunotherapy: The Phase 2 LEAP-009 Study

Purpose/Objective(s) Pembrolizumab monotherapy and pembrolizumab plus platinum-based chemotherapy are the standard of care for first-line treatment of R/M HNSCC. However, there is a growing unmet need for safe and efficacious treatment options for patients with R/M HNSCC whose disease progressed on or after platinum-based chemotherapy and immunotherapy. The randomized, open-label, phase 2 LEAP-009 (NCT04428151) study is being conducted to evaluate the safety and efficacy of lenvatinib plus pembrolizumab or lenvatinib monotherapy versus chemotherapy in patients with R/M HNSCC whose disease progressed after treatment with platinum-based therapy and a PD-1/L1 inhibitor. Materials/Methods Eligible patients have pathologically confirmed, locally incurable, histologically confirmed R/M HNSCC of the oral cavity, oropharynx, hypopharynx, and/or larynx, ECOG PS of 0/1, no ulceration and/or fungation of disease on skin, and disease progression on or after platinum-based therapy (with/without cetuximab) and PD-1/L1 inhibitor (progression must be <12 weeks from last dose, and patients must have received ≥2 doses). Patients will be randomly assigned 3:3:2 to receive oral lenvatinib 20 mg once daily plus pembrolizumab 200 mg IV every 3 weeks (≤35 pembrolizumab cycles), standard-of-care chemotherapy (investigator's choice of docetaxel, paclitaxel, cetuximab, or capecitabine), or oral lenvatinib monotherapy 24 mg once daily until centrally verified disease progression, unacceptable toxicity, or withdrawal. Patients with centrally confirmed disease progression in chemotherapy or lenvatinib monotherapy arms may transition to lenvatinib plus pembrolizumab at time of disease progression following consultation with the sponsor. Stratification factors are PD-L1 tumor proportion score (<50% vs ≥50%) and ECOG PS (0 vs 1). Imaging will be performed every 6 weeks through year 1 and every 9 weeks thereafter. Response will be assessed per RECIST v1.1 by blinded independent central review. Safety will be monitored throughout the study and for 30 days following treatment end (90 days for serious adverse events) and graded per NCI CTCAE v5.0. The primary end point is objective response rate; and secondary end points are progression-free survival, duration of response, overall survival, and safety. Results Approximately 400 patients will be enrolled, and recruitment is ongoing in Asia, Australia, Europe, and North America. Conclusion Results of LEAP-009 will offer insights into the efficacy and safety of lenvatinib with/without pembrolizumab versus chemotherapy for patients with R/M HNSCC whose disease progressed after platinum and immunotherapy.