PD-1 blockade plus chemotherapy followed by concurrent SBRT with SIB as preoperative therapy for patients with borderline resectable and locally advanced pancreatic cancer: A biomolecular exploratory, single-arm phase II clinical trial

4159 Background: Pancreatic cancer is fatal malignant tumor with low resection rate and poor prognosis. We aimed to assess the safety and efficacy of a new mode of preoperative therapy for patients with locally advanced (LAPC) or borderline resectable pancreatic cancer (BRPC). Methods: This is a single arm, exploratory phase II clinical trial (ChiCTR2000032955). Gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2; AG) were administered to patients with LAPC or BRPC on days 1 and 8, along with tislelizumab (200 mg) on day 1 intravenously (IV) every three weeks. Concurrently, the patients underwent stereotactic body radiotherapy (SBRT) with simultaneous integrated boost (SIB) during the third cycle of treatment. Surgical intervention was reassessed after four cycles of treatment. Objective response rate (ORR), R0 resection rate, median overall survival (mOS), median progression-free survival (mPFS) and safety were analyzed. Multiomics potential predictive biomarkers were investigated as exploratory objectives. Results: Between May 2020 and October 2021, 29 patients were enrolled in the study, 25 of them included in the intention-to-treat analysis. At the end of the last follow-up (November 30, 2022), 15 patients had a best response of partial response, the ORR was 60%. Ten patients underwent resection, and the R0 resection rate was 90% (9/10). The disease control rate (DCR) was 100%. Two of the ten resected patients achieved pathologic complete response and one patient achieved major pathological response. The mPFS, 12-months PFS rate, and 12-months OS rate were 13.7 months (95% CI: 11.7–NR), 64% (95% CI: 47.6%–85.8%), and 72% (95% CI: 56.3%–91.9%), respectively. Grade 3 or higher adverse events are anemia (8%), thrombocytopenia (8%) and jaundice (8%). Biomarker analysis indicated that patients with continuous carbohydrate antigen 19-9 decline and elevated peripheral blood eosinophil counts during treatment exhibited better survival outcomes. Furthermore, circulating tumor DNA analysis reveals that patients with a >50% decline in maximal somatic variant allelic frequency (maxVAF) between the first clinical evaluation and baseline have a longer survival outcome and higher response rate than those who are not (PFS: 20.03 vs. 10.32 months, p = 0.024; OS: not reached vs. 13.47 months, p = 0.024; ORR: 90% vs. 35.7%, p = 0.013). Moreover, maxVAF decline (> 50%) is significantly associated with the surgical rate after preoperative therapy (70.0% vs. 21.4%; p = 0.035). Conclusions: Anti-PD-1 inhibitor tislelizumab plus AG chemotherapy followed by concurrent SBRT with SIB displayed promising antitumor activity and acceptable safety profile for patients with LAPC or BRPC. Multiomics potential predictive biomarkers are identified and warrant further verification. Clinical trial information: ChiCTR2000032955 .