Hanna Glenn J, Oakley L B, Shi R, ONeill A, Shin K Y, Scarfo N, Sehgal K, Dennis M J, Quinn N, Jo V Y, Wong K, Shvyrkova A, Kushnarev V, Shanthappa B U, Tkachuk A, Kryukov K, Sarachakov A, Svekolkin V, Lennerz J, Waters S, Haddad R I
Center for Head and Neck Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
Clin Cancer Res. 2025 Feb 17;31(4):619-627. doi: 10.1158/1078-0432.CCR-24-2262.
Treatments after anti-PD-1 therapy for patients with recurrent, metastatic head and neck squamous cell carcinoma (HNSCC) are limited. Blocking PI3K signaling may lead to tumor immunomodulation and enhanced taxane sensitivity. This phase 2 trial evaluated dual, selective PI3Kδ/γ inhibition with docetaxel in patients with anti-PD-1 refractory recurrent, metastatic HNSCC.
Patients received duvelisib (25 mg orally twice daily) with docetaxel (75 mg/m2 IV) every 21 days. The primary endpoint was overall response rate (RECIST v1.1), using a Simon two-stage design. Secondary endpoints were safety, progression-free survival, and overall survival, and exploratory endpoints were correlating immunologic and genomic parameters with outcomes.
From 11/1/21 to 10/10/23, 26 patients were enrolled (median age: 64, 96% men, 54% with human papillomavirus+ disease; primary site: 12 oropharynx, 11 oral cavity, and 3 larynx/hypopharynx. The best overall response rate was 19% [5/26; 95% confidence interval (CI), 6.8%-40.7%]. All were partial responses [median duration: 5.1 months (0.7-15.5)]; 46% (12/26) exhibited stable disease, and 32% (8/26) exhibited progression (1 unevaluable). Two patients remain on-treatment at data cutoff; 25% (6/24) came off for toxicity. Grade 3+ treatment-related adverse events were observed in 50% (13/26), most often elevated liver function tests (6, 23%). No deaths were treatment-related. At median follow-up of 6.5 months (0.7-26), median progression-free survival was 2.8 months (95% CI, 1.9-7.0); 17/26 patients had died. Median overall survival was 10.2 months (95% CI, 6.7-15.9), favoring human papillomavirus-negative patients. Greater tumor CD3+/CD8+ T-cell infiltration trended with improved outcomes.
We report a favorable response rate when combining a selective PI3K pathway inhibitor and taxane in patients with anti-PD-1 refractory HNSCC.
复发性、转移性头颈部鳞状细胞癌（HNSCC）患者接受抗PD-1治疗后的治疗选择有限。阻断PI3K信号传导可能导致肿瘤免疫调节并增强紫杉烷敏感性。这项2期试验评估了多西他赛联合选择性PI3Kδ/γ抑制剂治疗抗PD-1难治性复发性、转移性HNSCC患者的疗效。
患者每21天接受一次度维利西布（口服，25mg，每日两次）联合多西他赛（静脉注射，75mg/m²）治疗。主要终点为总缓解率（RECIST v1.1），采用Simon两阶段设计。次要终点为安全性、无进展生存期和总生存期，探索性终点为免疫和基因组参数与疗效的相关性。
从2021年11月1日至2023年10月10日，共入组26例患者（中位年龄：64岁，96%为男性，54%为人类乳头瘤病毒阳性疾病；原发部位：12例口咽癌、11例口腔癌和3例喉/下咽癌）。最佳总缓解率为19%[5/26；95%置信区间（CI），6.8%-40.7%]。所有均为部分缓解[中位持续时间：5.1个月（0.7-15.5）]；46%（12/26）疾病稳定，32%（8/26）疾病进展（1例未评估）。在数据截止时，有2例患者仍在接受治疗；25%（6/24）因毒性停药。50%（13/26）的患者发生3级及以上治疗相关不良事件，最常见的是肝功能检查指标升高（6例，23%）。无治疗相关死亡病例。中位随访6.5个月（0.7-26），中位无进展生存期为2.8个月（95%CI，1.9-7.0）；26例患者中有17例死亡。中位总生存期为10.2个月（95%CI，6.7-15.9），人类乳头瘤病毒阴性患者生存期更长较好。肿瘤中CD3+/CD8+T细胞浸润程度越高，疗效越好。
我们报告了在抗PD-1难治性HNSCC患者中联合使用选择性PI3K通路抑制剂和紫杉烷时具有良好的缓解率。
