Gemcitabine and cisplatin chemotherapy plus penpulimab combined with or without anlotinib as neoadjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: A prospective, phase II clinical trial.

e18038 Background: Patients with locoregionally advanced nasopharyngeal carcinoma (LANPC) still have a risk of disease relapse after receiving the standard treatment of neoadjuvant chemotherapy followed by concurrent chemoradiotherapy (CCRT). Nowadays, PD-1 inhibitors have been widely used in recurrent or metastatic NPC, but the efficacy in LANPC requires further investigation. Besides, the synergistic antitumor effects between immune checkpoint inhibitors and anti-angiogenesis agents have been well established. In this phase II trial, we compared the efficacy and safety of gemcitabine and cisplatin (GP) + penpulimab (PD-1 inhibitor) combined with or without anlotinib (VEGFR-targeted TKI) as neoadjuvant therapy (NAT) for LANPC to establish the optimal regimen. Methods: Patients with LANPC (stage III–IVa, AJCC 8 th Staging System, excluding T3–4N0 and T3N1 with only retropharyngeal lymph node +) were enrolled. In the first stage, patients were randomly assigned 1:1 to receive 3 cycles of GP + penpulimab (200 mg, day 1, Q3W) combined with or without anlotinib (10 mg, days 1 to 14, Q3W) for 3 cycles. All patients were followed by CCRT and penpulimab maintenance treatment. The primary endpoint in the first stage was the clinical complete response (CR) rate after NAT based on endoscopy and imaging examinations. A pick-the-winner statistical design was applied and the regimen with a higher CR rate ( > 2.5%) was the winner. In the second stage, patients were continuingly enrolled and treated with the winner regimen; the primary endpoint was 3-year progression-free survival. Results: In the first stage, 60 patients were enrolled between August 2022 and April 2023 (30 patients in each arm). After NAT, 27 patients (45.0%) had CR, with 11 patients (36.7%; 95% CI, 18.4% to 55.0%) in the GP + penpulimab arm and 18 patients (60.0%; 95% CI, 41.4% to 78.6%) in the GP + penpulimab + anlotinib arm (winner regimen). In the second stage, 45 patients were enrolled between June 2023 and October 2023 and treated with GP + penpulimab + anlotinib. Among all 75 patients receiving the winner regimen, the CR rate was 53.3% (95% CI, 41.8% to 64.9%) after NAT. Acute adverse events (AEs) during NAT and CCRT were analyzed. In the first stage, grade 3-4 acute AEs were reported in 22 (73.3%) patients in the GP + penpulimab arm and 26 (86.7%) patients in the GP + penpulimab + anlotinib arm. The most common grades 3-4 acute AEs in the GP + penpulimab arm and GP + penpulimab + anlotinib arm were neutropenia (40% vs 46.7%), leukopenia (40% vs 30%) and mucositis (33.3% vs 36.7%). Among all 75 patients receiving additional anlotinib, the incidence of grade 3-4 acute toxicities was 85.3%. Conclusions: GP + penpulimab + anlotinib regimen showed encouraging efficacy as NAT for LANPC. This finding requires validation in longer follow-up and larger phase III clinical trials. Clinical trial information: NCT05193617 .