Induction toripalimab plus chemotherapy sequential concurrent chemoradiotherapy with nimotuzumab followed by toripalimab maintenance in stage IVB hypopharyngeal squamous cell carcinoma: a single-arm phase 2 study.

内容摘要

Optimal induction chemoimmunotherapy sequential concurrent chemoradiotherapy (cCRT) in locally advanced hypopharyngeal squamous cell carcinoma (HSCC) remains undefined. This study aimed to evaluate toripalimab plus chemotherapy sequential cCRT with nimotuzumab, followed by toripalimab maintenance in unresectable stage IVB HSCC. In this single-arm, open-label, phase 2 study, untreated patients received two 21-day cycles of induction toripalimab 240 mg (d1) plus nab-paclitaxel 230 mg/m2 (d1) and cisplatin/nedaplatin 40 mg/m2 (d1-2) sequential cCRT (helical tomotherapy; nab-paclitaxel 230 mg/m2 (d1, 22, 43)) with nimotuzumab 200 mg weekly for 7 weeks. Subsequently, toripalimab maintenance was administered for eight cycles. Primary endpoint was progression-free survival (PFS). From March 16, 2022 to April 24, 2024, 31 patients completed induction chemoimmunotherapy. With a median follow-up of 31 months, median PFS and overall survival (OS) were not reached; 2-year PFS and OS rates were 67.7% and 86.4%. The 2-year larynx preservation rate was 93.3%. 30 (96.8%) patients achieved the best objective response, with 28 (90.3%) complete responses and 2 (6.5%) partial responses. The most common grade 3-4 treatment-related adverse events (TRAEs) were radiation-induced oropharyngeal mucositis and decreased appetite (each 46.9%). No grade 5 and fatal TRAEs occurred. No difficulties in speech and swallowing functions were reported in 96.8% of patients. There was no significant association between PFS and PD-L1 combined positive score, epidermal growth factor receptor expression, tumor-infiltrating T-lymphocytes, tumor mutational burden, or genetic alterations. High baseline peripheral CD3+ and CD8+CD28+ T-cell levels were associated with favorable PFS. Exploratory biomarker analyses identified that patients without disease progression after maintenance exhibited significantly higher levels of CD8+CD28⁻ T cells with a memory phenotype and lower B-cell levels. This exploratory study demonstrated preliminary efficacy and larynx preservation with manageable toxicity, possibly supporting further evaluation of induction toripalimab plus chemotherapy sequential cCRT with nimotuzumab, followed by toripalimab maintenance in stage IVB HSCC. Peripheral lymphocytes may warrant further investigation as candidate biomarkers in locally advanced disease. NCT05860335; ChiCTR2300074672.