Phase 3 BURAN Trial Shows Buparlisib-Paclitaxel Combination Fails to Improve Survival in PD-1-Refractory Head and Neck Cancer
核心洞察
The phase 3 BURAN trial demonstrated that buparlisib plus paclitaxel did not improve overall survival compared to paclitaxel alone in patients with PD-1 (搜索)/PD-L1 (搜索)-pretreated recurrent/metastatic head and neck squamous cell carcinoma, with median survival times of 9.6 versus 9.7 months respectively.
Despite showing a numerically higher overall response rate (30.3% vs 20.7%), the combination therapy was associated with significantly more severe adverse events, with 87.5% of patients experiencing grade 3 or higher side effects compared to 59.4% in the paclitaxel-alone group.
The study enrolled 487 patients between April 2021 and November 2023, highlighting the continued unmet medical need in immunotherapy-refractory head and neck cancer patients.
The combination of buparlisib and paclitaxel failed to demonstrate superior overall survival compared to paclitaxel monotherapy in patients with PD-1 (搜索)/PD-L1 (搜索)-pretreated recurrent/metastatic head and neck squamous cell carcinoma (HNSCC (搜索)), according to phase 3 results from the BURAN trial presented at the 2025 ESMO Congress.
The study showed median overall survival of 9.6 months with the buparlisib-paclitaxel combination versus 9.7 months with paclitaxel alone (HR, 1.02; 95% CI, 0.83-1.26; P = .85), missing the primary endpoint in this challenging patient population that has exhausted immunotherapy options.
Study Design and Patient Population
The randomized, controlled phase 3 trial enrolled 487 patients between April 2021 and November 2023, with participants assigned 2:1 to receive either buparlisib at 100 mg once daily plus paclitaxel at 80 mg/m² on days 1, 8, and 15 every three weeks, or paclitaxel alone at the same dosage.
To be eligible, patients required recurrent or metastatic HNSCC (搜索) with prior PD-1 (搜索)/PD-L1 (搜索) inhibitor treatment in the recurrent/metastatic setting, one to two prior lines of therapy, and an ECOG performance status of 0 or 1. The patient population was predominantly male (80.3%) with a median age of 61.5 years, and 29.8% were HPV positive.
"The buparlisib plus paclitaxel combination arm has a numerically higher overall response rate, but there was no increase in progression-free survival compared to the paclitaxel-only arm," said lead study author Denis Souliéres, MD, MSc, FRCPC, full professor of medicine at the Université de Montréal, Canada.
Efficacy Outcomes Show Mixed Results
While the primary endpoint was not met, the combination demonstrated improved response rates. The confirmed overall response rate per independent radiological review committee was 30.3% with buparlisib/paclitaxel compared to 20.7% with paclitaxel alone (P = .024). Unconfirmed response rates were even more pronounced at 44.3% versus 28.0% respectively (P = .0005).
However, progression-free survival remained unchanged, with median PFS of 4.1 months in both arms (HR, 0.97; 95% CI, 0.77-1.22; P = .77). The median duration of response was 5.6 months with the combination versus 9.1 months with paclitaxel alone (HR, 1.48; 95% CI, 0.89-2.44; P = .12).
Safety Profile Raises Concerns
The combination therapy came with a substantial increase in toxicity. Grade 3 or higher adverse events occurred in 87.5% of patients receiving the combination compared to 59.4% of those on paclitaxel alone. Treatment-related severe adverse events were reported in 71.0% versus 33.8% respectively.
Adverse events leading to study drug discontinuation occurred in 45.2% of combination patients compared to 16.9% in the paclitaxel-alone group. Of the discontinuations in the combination arm, 37.7% were buparlisib-related and 35.2% were paclitaxel-related.
Most patients discontinued treatment due to disease progression, affecting 98.5% of combination patients and 98.8% of monotherapy patients. However, adverse events were the second leading cause of discontinuation, affecting 38.1% of combination patients versus 17.7% of monotherapy patients.
Subgroup Analysis Reveals Potential Signals
Despite the overall negative results, subgroup analyses identified potential areas of benefit. Patients with HPV-positive oropharynx cancer showed a potential survival advantage with the combination (HR, 0.73; 95% CI, 0.46-1.17) compared to other HPV status and primary site combinations (HR, 1.09; 95% CI, 0.86-1.37).
Geographic differences were also notable, with North American patients showing significantly higher overall survival advantage with buparlisib/paclitaxel (HR, 0.46; 95% CI, 0.29-0.73) compared to Asian Pacific patients (HR, 1.05; 95% CI, 0.73-1.52) and European patients (HR, 1.39; 95% CI, 1.02-1.89).
"There were more HPV-positive patients that were North American patients compared to what we saw in Asia and Europe, but I will remind you that the HPV positivity did not specifically translate into an OS in the overall analysis," Souliéres noted.
Clinical Context and Future Directions
Buparlisib is an oral pan-PI3K inhibitor targeting all four isoforms of class I PI3K. The rationale for this combination was supported by prior phase 1b data showing clinical activity in taxane-pretreated advanced solid tumors, and phase 2 BERIL-1 trial results demonstrating both progression-free survival improvement (HR, 0.65; P = .65) and overall survival benefit (HR, 0.72; P = .041) in platinum-pretreated recurrent or metastatic HNSCC (搜索).
However, the phase 3 results failed to replicate these earlier promising signals in the immunotherapy-refractory setting. Souliéres emphasized that "translational data will permit to explore if molecular subgroups derive significant benefit," suggesting that biomarker-driven approaches may be necessary to identify patients most likely to benefit from PI3K inhibition.
The investigator concluded that "the immunotherapy-refractory HNSCC (搜索) patient population remains one with significant unmet need," highlighting the continued challenge of treating patients who have progressed on PD-1 (搜索)/PD-L1 (搜索) inhibitors in this aggressive malignancy.