Buparlisib/Chemo Combo Misses OS Mark in PD-1–Treated Recurrent HNC

The combination of buparlisib and paclitaxel did not show an improvement in overall survival (OS) compared with paclitaxel alone in patients with PD-1/PD-L1–pretreated recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), according to phase 3 results of the BURAN trial (NCT04338399) that were presented during the 2025 ESMO Congress.¹

Findings showed that the median OS with buparlisib plus paclitaxel was 9.6 months compared with 9.7 months with paclitaxel alone in this patient population (HR, 1.02; 95% CI, 0.83-1.26; P = .85).

“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,” lead study author Denis Souliéres, MD, MSc, FRCPC, full professor of medicine at the Université de Montréal, Canada, said in an oral presentation during the meeting. “Translational data will permit to explore if molecular subgroups derive significant benefit.”

Buparlisib is an oral pan-PI3K inhibitor that targets all 4 isoforms of class I PI3K. Prior phase 1b data showed that buparlisib and paclitaxel showed clinical activity in patients with taxane-pretreated advanced solid tumors.² Additionally, data from the phase 2 BERIL-1 trial showed a progression-free survival (PFS) improvement with buparlisib and paclitaxel vs placebo and paclitaxel (HR, 0.65; P = .65), as well as an OS improvement (HR, 0.72; P = .041) in patients with recurrent or metastatic squamous cell carcinoma of head and neck who experienced failure of 1 prior platinum-based therapy.³

To be eligible for enrollment, patients had to have recurrent or metastatic HNSCC and have received a prior PD-1/PD-L1 inhibitor in the recurrent/metastatic setting, 1 to 2 prior lines of therapy, and an ECOG performance status of 0 or 1.

A total 487 patients were randomly assigned 2:1 between April 2021 and November 2023 to receive buparlisib at 100 mg once daily plus paclitaxel at 80 mg/m² on days 1, 8, and 15 every 3 weeks or paclitaxel alone at the same dosage.

Stratification factors included HPV status (yes vs no). The primary end point was OS. Secondary end points were PFS, objective response rate (ORR), and duration of response (DOR) by independent radiological review committee and via investigator as per RECIST v1.1 criteria; OS, PFS, ORR, and DOR in subgroups by HPV status; safety, and patient-reported outcomes.

Most patients who discontinued the combination (98.5% for both agents) did so because of disease progression (buparlisib, 38.7%; paclitaxel, 39.9%) followed by adverse events (AEs; 38.1%; 35.6%). In the paclitaxel-alone arm, 98.8% of patients discontinued paclitaxel due to disease progression (54.9%) and AEs (17.7%).

Regarding baseline characteristics across both arms, 29.8% of patients were HPV positive, approximately half were from Europe (50.1%), and the majority were male (80.3%). The median age was 61.5 years (IQR, 56-68), and 63.4% were White; most were not Hispanic or Latino (85.6%). HPV positivity only of the oropharynx was in 19.8% of patients who received the buparlisib combination and 17.7% of those who received chemotherapy alone.

A total 42.4% and 39.0% of patients, respectively, previously received a PD-1/PD-L1 inhibitor alone or in combination with non–platinum-based therapy, while 39.3% and 45.1% of patients received the immunotherapy concurrently with platinum-based chemotherapy. A total 16.7% and 15.9% of patients received them in sequence with platinum-based chemotherapy. Furthermore, 70.0% and 68.3% of patients on buparlisib and paclitaxel alone, respectively, had metastatic disease at study entry.

Additional efficacy data showed that the confirmed ORR per IRRC was 30.3% with buparlisib/paclitaxel compared with 20.7% with paclitaxel alone (P = .024); the unconfirmed ORRs by IRRC were 44.3% and 28.0%, respectively (P = .0005). When assessed via investigator, the confirmed ORRs were 29.7% vs 24.4% (P = .22) and unconfirmed ORRs were 44.6% and 28.0% (P = .0004).

The median DOR per IRRC was 5.6 months with buparlisib vs 9.1 months with paclitaxel alone (HR, 1.48; 95% CI, 0.89-2.44; P = .12); per investigator assessment, the median DOR was 7.0 months vs 6.7 months, respectively (HR, 0.97; 95% CI, 0.63-1.49; P = .88).

The median PFS per IRRC was 4.1 months in each arm (HR, 0.97; 95% CI, 0.77-1.22; P = .77); by investigator assessment, the median PFS was 4.3 months compared with 4.2 months, respectively (HR, 0.92; 95% CI, 0.74-1.14; P = .43).

Regarding safety, grade 3 or higher AEs occurred in 87.5% and 59.4% of patients of the combination vs paclitaxel alone arms; treatment-related grade 3 or higher AEs were reported in 71.0% and 33.8%, respectively. A total 60.1% of these AEs were related to buparlisib; 60.4% were paclitaxel related in the combination arm vs 33.8% in the monotherapy arm.

AEs that led to study drug discontinuation occurred in 45.2% and 16.9% of patients in the buparlisib combination and paclitaxel alone groups, respectively. A total 37.7% of those in the combination group were buparlisib related; on the combination arm, 35.2% were related to paclitaxel, and 16.9% were related to paclitaxel on the monotherapy arm. AEs of special interest occurred in 88.2% and 75.0% of patients, respectively.

Souliéres noted that there were no characteristics that were a factor in OS improvement with the combination vs paclitaxel alone, except for a potential survival advantage in patients with HPV-positive oropharynx cancer (HR, 0.73; 95% CI, 0.46-1.17) vs other HPV status and primary site of cancer (HR, 1.09; 95% CI, 0.86-1.37). North American patients also had a significantly higher OS advantage with buparlisib/paclitaxel (HR, 0.46; 95% CI, 0.29-0.73) compared with 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 commented.

Souliéres concluded that the immunotherapy-refractory HNSCC patient population remains one with significant unmet need.

References

1. SouliéresD, et al. BURAN: A phase III study of buparlisib (BUP) plus paclitaxel (PAC) in patients with PD-1(PD-L1)-pretreated recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA48.
2. Zambrano Cruz C, Schuler MH, Machiels J-PH, et al. Phase lb study of buparlisib (BKM120) plus either paclitaxel (PTX) in advanced solid tumors (aST) or PTX plus trastuzumab (TZ) in HER2+ breast cancer (BC).J Clin Oncol. 2014;32(15 suppl):627. doi:10.1200/jco.2014.32.15_suppl.627
3. SouliéresD, Faivre S, Mesía R, et al. Buparlisib and paclitaxel in patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Oncol. 2017;18(3):323-335. doi:10.1016/S1470-2045(17)30064-5