Bortezomib plus gemcitabine-cisplatin versus gemcitabine-cisplatin as first-line treatment for advanced biliary tract cancers: A randomized phase II clinical trial with exploratory analysis of PTEN status.

4112 Background: Biliary tract cancers (BTCs) are aggressive malignancies with limited treatment and poor prognosis, including intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (perihilar and distal), gallbladder cancer and ampullary cancer. Our previous research indicated that bortezomib is a promising treatment option as proteasome inhibitor in PTEN-loss iCCA patients (Clin Transl Med. 2024 May;14(5): e1675). In this randomized phase II clinical trial, we expanded the indication to BTCs and explored clinical benefit and safety of bortezomib plus gemcitabine-cisplatin (GPB) compared with gemcitabine-cisplatin (G based) as first line treatment for advanced BTCs and further evaluated the potential predictive value of PTEN status. Methods: Between September 1, 2020, and December 31,2023, a total of 105 patients were screened. 59 patients were enrolled. The 59 patients were randomly assigned to either GPB group (n = 32) or G based group (n=27). PTEN status was not known at the time of randomization. PTEN immunohistochemical staining was subsequently performed in all patients identifying 18 patients (30.5%) with PTEN loss (PTEN=0) and 41 patients (69.5%) with PTEN expression (PTEN=1). The GPB regimen consisted of gemcitabine 1000 mg/m 2 day 1,8, cisplatin 75 mg/m 2 day 1, 8, plus bortezomib 1.3 mg/m 2 day 1, 4, 8, and 11 of a 21-day cycle. The G based group received gemcitabine based regimens including G-cisplatin (GP), G-Oxaliplatin (GMOX) or G-S-1 (GS). The primary endpoint was mediate progress-free survive (mPFS) according to RECIST v 1.1. Statistical analyses were performed using SPSS. The last follow-up date was July 25, 2025. Results: With a median follow-up of 31.8 months (95% CI, 21.3–42.3), the mPFS was 5.49 months in the GPB group and in 5.95 months in the G-based group, with no significant statistically significant difference (HR, 0.86; 95% CI, 0.50–1.47; P = 0.59). The median overall survival (OS) was 16.23 months with GPB and 15.01 months with G-based group (HR, 0.88;95% CI, 0.47–1.67; P = 0.70). Biomarker analyses showed that within the GPB group, patients with PTEN loss had significantly longer PFS than those with PTEN expression (9.26 vs. 3.35 months; HR, 0.64; 95% CI, 0.42–0.96; P = 0.03). Among PTEN=0 patients, GPB was associated with improved mPFS compared with G-based (9.26 vs. 3.59 months; HR, 0.25; 95% CI, 0.08–0.78; P = 0.01). Grade ≥3 CTCAE AEs were mainly hematologic, with thrombocytopenia most common (50.0% vs 14.8%). Conclusions: Although no significant survival benefit was observed in the overall GPB group, a clinically meaningful improvement in mPFS was identified in the PTEN-loss subgroup. PTEN status may serve as a promising biomarker for identifying patients more likely to benefit from GPB therapy, warranting further prospective validation. Clinical trial information: ChiCTR2000035916.