PURPOSE: 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 AND METHODS: 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. RESULTS: 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. CONCLUSIONS: We report a favorable response rate when combining a selective PI3K pathway inhibitor and taxane in patients with anti-PD-1 refractory HNSCC.