Abstract

Abstract Background: Treatments after anti-PD-1 therapy for patients with recurrent, metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are limited. Blocking phosphatidylinositol 3-kinase (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 R/M HNSCC. Design: Patients received duvelisib (25 mg orally twice daily) with docetaxel (75 mg/m2 IV) every 21-days. The primary endpoint was overall response rate (ORR) (RECISTv1.1), employing a Simon two-stage design. Secondary endpoints: safety, progression-free survival (PFS), overall survival (OS); exploratory endpoints: correlating immunologic and genomic parameters with outcomes. Results: From 11/1/21 to 10/10/23, 26 patients enrolled (median age: 64, 96% men, 54% with HPV+ disease; primary site: 12 oropharynx, 11 oral cavity, 3 larynx/hypopharynx. Best ORR was 19% (5/26) (95%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) 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 PFS: 2.8 months (95%CI: 1.9-7.0); 17/26 patients had died. Median OS: 10.2 months (95%CI: 6.7-15.9), favoring HPV-negative patients. Greater tumor CD3+/CD8+ T cell infiltration trended with improved outcomes. Conclusion(s): We report a favorable response rate when combining a selective PI3K pathway inhibitor and taxane in patients with anti-PD-1 refractory HNSCC. ClinicalTrials.gov: NCT05057247