Duvelisib with docetaxel for patients with anti-PD-1 refractory, recurrent, or metastatic head and neck squamous cell carcinoma.

6031 Background: Anti-PD-1 therapy alone or in combination with chemotherapy has improved outcomes as first line treatment for patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC), but therapy options are limited in the second line and beyond. The phosphatidylinositol 3-kinase (PI3K) signaling cascade is frequently dysregulated in HNSCC, and blocking this pathway may lead to modifications in the tumor immune microenvironment and enhanced taxane microtubule inhibitor sensitivity. BERIL-1 investigated buparlisib with paclitaxel in platinum-pretreated R/M HNSCC, but here we conducted a phase 2 trial (NCT05057247) evaluating the dual PI3K (δ/γ isoforms) inhibitor duvelisib in combination with docetaxel in patients with R/M HNSCC who previously received anti-PD-1 therapy. Methods: Patients (pts) with R/M HNSCC who had received anti-PD-1 blockade as part of 1-2 prior lines of R/M therapy were eligible regardless of HPV or PI3K tumor mutational status. Pts received duvelisib (25 mg orally twice daily) with docetaxel (75 mg/m 2 IV) every 21-days until progression. The primary endpoint was overall response rate (ORR) (RECIST v1.1), employing a Simon two-stage design (stage 1: enroll 13, <2 in response yields futility; stage 2: enroll 13, >4/26 in response rules out 10% ORR [89% power, α=0.09] warranting further investigation). Secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), and correlating pre-treatment PD-L1 status and genomics with outcomes. Results: Twenty-six pts enrolled from 11/1/21 to 10/10/23. Median age of the cohort was 64 (34-74), comprised of 96% (25/26) men, 69% (18/26) former/current smokers, and 50% (13/26) 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 5 were partial responses (median duration: 6.9 months [0.7-15.5]); with 46% (12/26) exhibiting stable disease and 32% (8/26) progression (1 unevaluable). Two pts remain on-treatment at data cutoff; 25% (6/24) came off for toxicity. Grade 3+ treatment-related adverse events were observed in 13/26 (50%), most often elevated liver function tests (6, 23%). No deaths were treatment related. At median follow-up of 7.1 months (0.7-22+), median PFS was 2.8 months (95%CI: 1.9-7.0); 10/26 pts had died. Median OS was 10.2 months (95%CI: 6.7-NA) and 1-year OS was 48%. Median baseline tumor PD-L1 score was 18 (0-100), which did not differ statistically by response (p=1.00; Wilcoxon rank-sum test). Disease in response was observed in 3/8 pts with somatic alterations in PIK3CA. Conclusions: We report a favorable response rate when combining a PI3K pathway inhibitor with taxane chemotherapy in patients with anti-PD-1 refractory HNSCC. Further evaluation of this strategy is ongoing in the phase 3 BURAN trial which is investigating buparlisib with paclitaxel. Clinical trial information: NCT05057247 .