Two cycles of neoadjuvant therapy with low-dose radiotherapy, PD-1 inhibitor tislelizumab, albumin-bound paclitaxel, and cisplatin for resectable locally advanced head and neck squamous cell carcinoma (NeoRTPC02): A phase II, open-label, single-arm t

6039 Background: Despite standard treatments, mortality rates remain high in locally advanced head and neck squamous cell carcinoma (LA HNSCC). Neoadjuvant immunotherapy combined with chemotherapy has improved response rates, but further enhancement is needed. Recent studies suggest that low-dose radiotherapy (LDR) can reprogram the tumor microenvironment, reversing immune suppression and improving the efficacy of PD-1 inhibitors. This study aims to evaluate the safety and efficacy of neoadjuvant LDR combined with tislelizumab and chemotherapy in LA HNSCC. Methods: This was an open-label, single-arm, phase II clinical trial for patients with untreated, histologically confirmed stage III-IVB HNSCC. Patients received neoadjuvant low-dose radiotherapy (1 Gy/1F, days 1, 2, 8, and 15, Q3W) combined with tislelizumab (200 mg, day 1, Q3W), albumin-bound paclitaxel (100 mg/m², days 1, 8, and 15, Q3W), and cisplatin (25 mg/m², days 1, 8, and 15, Q3W) for two cycles. Afterward, patients underwent radical surgery approximately 4 weeks later. The primary endpoint was the pathological complete response (pCR) rate, while secondary endpoints included major pathological response (MPR) rate, ORR, R0 resection rate, safety, and treatment-related surgical delay rate. The exploratory endpoints were the 3-year progression-free survival and 3-year overall survival. To further investigate the underlying mechanisms of treatment effects, we used single-cell RNA sequencing (scRNA-seq) to explore how this combination modulates the tumor microenvironment(TME) in HNSCC. Results: A total of 37 patients were assessed for eligibility, of which 28 patients were enrolled and received the assigned neoadjuvant treatment. A total of 23 patients proceeded to surgery, and pathological response evaluation was conducted in these patients. Among the 23 patients, 14 (60.9%) achieved pCR, and the MPR and pCR/MPR rates were 21.7% and 82.6%, respectively. The ORR was 64.3% (18/28), including 2 (7.1%) complete response and 16 (57.1%) partial response. The R0 resection rate was 100%. Treatment-related adverse events (TRAEs) were manageable, with grade 3 or 4 TRAEs occurring in 12 (42.9%) patients. The main side effects included neutropenia and decreased white blood cell count. No surgical delays were observed. ScRNA-seq results suggested that this neoadjuvant regimen may reshape the HNSCC TME by enhancing adaptive immunity and potentially increasing FOLR2 + macrophage infiltration. Conclusions: Neoadjuvant LDR combined with tislelizumab, albumin-bound paclitaxel, and cisplatin resulted in an impressive pCR rate and demonstrated promising efficacy with manageable toxicity in patients with resectable LA HNSCC. Long-term survival data are still follow-up. Clinical trial information: NCT05343325 .