Pembrolizumab Plus Lenvatinib in the Treatment of Unresectable Cutaneous Angiosarcoma: A study protocol of Multicenter, Open-label Phase II Study (NCCH2213, PLAS)

Background: Cutaneous angiosarcoma (cAS) is a rare, aggressive malignancy with poor prognosis. The most common age for cAS is 79–85 years, and the number of cAS patients is increasing owing to the aging population. Standard treatment for cAS includes radical surgery, radiation therapy, chemotherapy, and their combinations. Although paclitaxel is a widely used option, the 5-year overall survival (OS) is 32%. The development of effective treatment is imperative. The immunomodulatory effect of lenvatinib is expected to provide potent efficacy with PD-1/L1 signal inhibitors in preclinical models. In clinical settings, the combination of pembrolizumab and lenvatinib has been approved for uterine corpus cancer and renal cell carcinoma. This study aims to evaluate the efficacy and safety of pembrolizumab and lenvatinib combination therapy in unresectable cAS patients. Methods: PLAS study (NCCH2213) is a multicenter, open-label, phase II, investigator-initiated study comprising two cohorts: cohort A (patients having received chemotherapy) and cohort B (patients having not). Pembrolizumab (200 mg) is administered intravenously on day 1 of each 21-day cycle. Lenvatinib is administered orally at a dose of 20 mg daily from days 1 to 21 of each cycle. Pembrolizumab and lenvatinib are administered for a maximum of 35 cycles, unless the discontinuation criteria are met. The primary endpoint is objective response rate (ORR), as determined by a central review. The secondary endpoints are ORR (determined by the site investigators), progression-free survival, OS, disease control rate, duration of response, time to response, incidence of adverse events (AEs), incidence of adverse drug reactions (ADRs), and incidence of serious AEs/ADRs. An Interim analysis will be performed in accordance with the Southwest Oncology Group two-stage design to assess the primary endpoint. Discussion: This study aims to expand the treatment options for cAS by capitalizing on the synergistic benefits of immune checkpoint and antiangiogenic therapy. The study design reflects feasibility within a rare cancer population and prioritizes patientsafety while aiming for therapeutic innovation. This study has an independent Data and Safety Monitoring Committee and independent external evaluators for the central review of the tumor assessment. Trial registration: ClinicalTrials.gov: NCT06673628; 31-Oct-2024, Japan Registry of Clinical Trials: jRCT2031240448; 31-Oct-2024