BURAN: A Phase 3 Randomized Trial of Paclitaxel With or Without Buparlisib in Recurrent/Metastatic Head and Neck Squamous Cell Cancer After PD-1/PD-L1 Inhibitor Failure

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Abstract
Background: Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) progressing after PD-1/PD-L1 inhibitors have poor outcomes and limited treatment options. In the phase 2 BERIL-1 study, the pan-class I PI3K inhibitor buparlisib combined with paclitaxel improved objective response rates (ORR) and progression-free survival (PFS), supporting further evaluation in the post-immunotherapy setting. Methods: BURAN was an international, open-label, randomized phase 3 trial conducted at 142 centers in 18 countries. Eligible patients with R/M HNSCC and disease progression following PD-1 or PD-L1 inhibitor therapy were randomly assigned (2:1) to receive buparlisib plus paclitaxel or paclitaxel alone. The primary endpoint was overall survival (OS). Secondary endpoints included PFS, ORR, duration of response (DoR), safety and health-related quality of life. Findings: Between April 2021 and November 2023, 487 patients were randomly assigned to receive buparlisib plus paclitaxel (n=323) or paclitaxel alone (n=164). Median OS was 9·6 months with buparlisib plus paclitaxel and 9·7 months with paclitaxel alone (HR 1·02, 95% CI 0·83-1·26; p=0·85). PFS was similar between groups. ORR was numerically higher with buparlisib plus paclitaxel (30·3% vs 20·7%; difference 9·6%, 95% CI 1·3-17·3; nominal p=0·024), although responses were not more durable. Grade ≥3 adverse events occurred more frequently with buparlisib plus paclitaxel than with paclitaxel alone (87·5% vs 59·4%), leading to higher rates of treatment discontinuation. Interpretation: In patients with R/M HNSCC progressing after PD-1/PD-L1 inhibitors, the addition of buparlisib to paclitaxel did not improve survival outcomes despite increasing response rates. The lack of durable clinical benefit and increased toxicity do not support the use of buparlisib plus paclitaxel in an unselected population in this setting.