Phase 2 LEAP-009: Lenvatinib (Lenva) With or Without Pembrolizumab (Pembro) vs. Chemotherapy (Chemo) for Recurrent or Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (HNSCC) That has Progressed on Platinum and Immunotherapy

Purpose/Objective(s) Pembro monotherapy and pembro plus platinum-based chemo are now standard-of-care options for the first-line treatment of R/M HNSCC. However, the optimal second-line regimen for R/M HNSCC that has progressed on or after immunotherapy or platinum-based chemo remains unclear. Pembro given in combination with the multikinase inhibitor lenva showed promising antitumor activity and acceptable safety in patients with metastatic HNSCC in the phase 1b/2 Study 111/KEYNOTE-146 trial. The open-label, randomized, phase 2 LEAP-009 (NCT04428151) study is designed to investigate the efficacy and safety of lenva ± pembro versus SOC chemo in patients with R/M HNSCC that has progressed after platinum-based chemo and a PD-1/PD-L1 inhibitor. Materials/Methods Key eligibility criteria include age ≥18 years; histologically confirmed R/M HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx; disease incurable by local therapy; measurable disease per RECIST v1.1 by BICR; ECOG performance status of 0 or 1; and no major blood vessel invasion/infiltration. Patients must have had disease progression on or after platinum-containing chemo ± cetuximab and have had disease progression on a PD-1/PD-L1 inhibitor (progression within 12 weeks of the last dose; must have received ≥2 doses). Patients will be randomly allocated 3:3:2 to lenva 20 mg PO QD + pembro 200 mg IV Q3W (≤35 pembro cycles), investigator's choice of SOC chemotherapy (docetaxel, paclitaxel, cetuximab, or capecitabine), or lenva monotherapy 24 mg PO QD. Treatment will continue until centrally verified disease progression, unacceptable toxicity, or withdrawal from study. Randomization will be stratified by PD-L1 tumor proportion score (<50% vs ≥50%) and ECOG performance status (0 vs 1). Patients with disease progression in the chemo or lenva monotherapy arms may be eligible to cross over to pembro + lenva. The primary end point is ORR per modified RECIST v1.1 by BICR. Secondary end points are PFS and DOR per RECIST v1.1 by BICR, OS, and safety. Imaging by CT or MRI will be performed every 6 weeks through year 1 and every 9 weeks thereafter. Safety will be monitored throughout the study and for 30 days after treatment end (90 days for serious AEs unless new anticancer treatment is initiated). An interim futility analysis will be conducted for the lenva monotherapy arm. Estimated enrollment is 400 patients. Recruitment is currently underway. Results TBD Conclusion TBD Pembro monotherapy and pembro plus platinum-based chemo are now standard-of-care options for the first-line treatment of R/M HNSCC. However, the optimal second-line regimen for R/M HNSCC that has progressed on or after immunotherapy or platinum-based chemo remains unclear. Pembro given in combination with the multikinase inhibitor lenva showed promising antitumor activity and acceptable safety in patients with metastatic HNSCC in the phase 1b/2 Study 111/KEYNOTE-146 trial. The open-label, randomized, phase 2 LEAP-009 (NCT04428151) study is designed to investigate the efficacy and safety of lenva ± pembro versus SOC chemo in patients with R/M HNSCC that has progressed after platinum-based chemo and a PD-1/PD-L1 inhibitor. Key eligibility criteria include age ≥18 years; histologically confirmed R/M HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx; disease incurable by local therapy; measurable disease per RECIST v1.1 by BICR; ECOG performance status of 0 or 1; and no major blood vessel invasion/infiltration. Patients must have had disease progression on or after platinum-containing chemo ± cetuximab and have had disease progression on a PD-1/PD-L1 inhibitor (progression within 12 weeks of the last dose; must have received ≥2 doses). Patients will be randomly allocated 3:3:2 to lenva 20 mg PO QD + pembro 200 mg IV Q3W (≤35 pembro cycles), investigator's choice of SOC chemotherapy (docetaxel, paclitaxel, cetuximab, or capecitabine), or lenva monotherapy 24 mg PO QD. Treatment will continue until centrally verified disease progression, unacceptable toxicity, or withdrawal from study. Randomization will be stratified by PD-L1 tumor proportion score (<50% vs ≥50%) and ECOG performance status (0 vs 1). Patients with disease progression in the chemo or lenva monotherapy arms may be eligible to cross over to pembro + lenva. The primary end point is ORR per modified RECIST v1.1 by BICR. Secondary end points are PFS and DOR per RECIST v1.1 by BICR, OS, and safety. Imaging by CT or MRI will be performed every 6 weeks through year 1 and every 9 weeks thereafter. Safety will be monitored throughout the study and for 30 days after treatment end (90 days for serious AEs unless new anticancer treatment is initiated). An interim futility analysis will be conducted for the lenva monotherapy arm. Estimated enrollment is 400 patients. Recruitment is currently underway. TBD TBD