Lee, Choong‐kun

Abstract Background: Understanding the spatiotemporal dynamics of the tumor microenvironment (TME) during treatment is crucial for improving outcomes in pancreatic ductal adenocarcinoma (PDAC). This study presents a pre-planned spatiotemporal analysis from a phase II trial evaluating neoadjuvant mFOLFIRINOX in resectable PDAC, aimed at elucidating treatment resistance mechanisms and identifying predictive biomarkers. Methods: This multi-institutional, single-arm phase II trial enrolled treatment-naïve patients with histologically confirmed resectable PDAC (NCT05066802) who underwent six cycles of neoadjuvant mFOLFIRINOX followed by surgery. The primary endpoint was the R0 resection rate. Matched pre-treatment tumor biopsies and post-treatment surgical specimens were analyzed from selected responders (R) and non-responders (NR) using high-resolution spatial transcriptomics (10X Genomics Visium). This approach enabled comprehensive mapping of TME evolution and treatment-induced changes. Results: Between May 2020 and February 2022, 27 patients were enrolled. Of these, 24 patients underwent surgery after neoadjuvant treatment (resection rate: 88.9%), and 23 achieved R0 resection (85.2%), meeting the primary endpoint. However, 20 resected patients (83.3%) recurred. Spatiotemporal analysis was performed on matched samples from four R and four NR. In pre-treatment samples from NR group, clusters dominated by fibroblasts (enriched for ECM, EMT, and CAF phenotypes) and B cell subtypes were distinct compared to R group, which exhibited elevated antibody responses and robust T cell and macrophage activity. NR samples showed increased IgM expression but lacked corresponding Fc receptors, suggesting limited immune effector function. Post-treatment NR surgical specimens displayed elevated expression of MUC5AC and CEACAM6 in malignant ductal cells, alongside genes promoting tumor growth. Neoadjuvant mFOLFIRINOX increased fibroblast, while reducing immune cell components. NR tumors formed distinct "resistance niches" after chemotherapy, marked by ECM production, CAF activation, and RTK signaling. Conversely, R tumors showed enhanced epithelial organization with increased type-I hemidesmosome complexes facilitating epithelial adhesion to the basement membrane. Conclusion: Three months of neoadjuvant mFOLFIRINOX was feasible and tolerable for resectable PDAC but associated with high recurrence rate, emphasizing the need for better patient selection. Spatiotemporal analysis revealed critical differences in TME dynamics according to treatment response, including the emergence of resistance niches and distinct pre-treatment spatial signatures. These findings support the integration of spatial biology into future pancreatic cancer trials to improve stratification and therapy. Citation Format: Choong-kun Lee, Changjin Hong, Ho Kyoung Hwang, Min Hwan Kim, Jean Rene Clemenceau, Seock-Jin Chung, Isabel Barnfather, Sumanth Reddy Nakkireddy, Jeong Hwan Park, Ji-Youn Sung, Minji Kim, Yooho Choi, Inyeop Jang, Sunho Park, Sung Hyun Kim, Chang Moo Kang, Hye Jin Choi, Tae Hyun Hwang. Spatiotemporal evolution of the tumor microenvironment predicts treatment response in phase II trial of neoadjuvant chemotherapy for resectable pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 771.

Background and Aims: We compared the safety and efficacy of bintrafusp alfa (BA) in combination with gemcitabine+cisplatin (GemCis), to those of GemCis alone, in patients with biliary tract cancer. Approach and Results: This randomized, double-blind, placebo-controlled, adaptive design phase 2/3 trial (NCT04066491) included adults who are treatment-naive with locally advanced/metastatic biliary tract cancer. Patients (N = 297) were randomized to receive an IV infusion of BA (2400 mg once/3 wk) plus GemCis (gemcitabine 1000 mg/m 2 +cisplatin 25 mg/m 2 on days 1 and 8/3 wk; 8 cycles) (BA group, n = 148) or placebo+GemCis (placebo group, n = 149). The primary end point was overall survival (OS). For adaptation analysis (phase 2-phase 3; data cutoff: May 20, 2021), efficacy was assessed in the first 150 patients who were antibiotic-naive when 80 progression-free survival events had occurred and ≥ 19 weeks of follow-up had been completed (BA, n = 73; placebo, n = 77). Median OS (95% CI) for the BA (11.5 mo [9.3–not estimable]) and placebo (11.5 mo [10.0–not estimable]) groups was comparable (hazard ration 1.23 [95% CI 0.66–2.28]; p = 0.7394); OS data maturity was 27.2% (41 events/151 patients). The most common grade ≥3 treatment-related adverse event was anemia (BA, 26.0%; placebo, 22.8%). Bleeding adverse events were reported more frequently in the BA group (28.8%) versus the placebo group (7.4%). Deaths within 60 days of the first dose were reported in 7.5% and 1.3% of patients in the BA and placebo groups, respectively. Conclusions: BA+GemCis did not provide a clinically meaningful benefit compared with GemCis alone as first-line treatment for biliary tract cancer, and the study was discontinued early (terminated: August 20, 2021).

Background and Aims: Biliary tract cancers are rare, heterogeneous cancers with poor prognoses. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β “trap”) fused to a human IgG1 monoclonal antibody blocking programmed death ligand 1, was evaluated in patients with locally advanced/metastatic chemorefractory biliary tract cancers. Approach and Results: This multicenter, single-arm, open-label, phase 2 study (NCT03833661) enrolled adults with locally advanced or metastatic biliary tract cancer that was intolerant to or had failed first-line systemic platinum-based chemotherapy. Patients received 1200 mg bintrafusp alfa intravenously Q2W. The primary endpoint was confirmed objective response according to Response Evaluation Criteria in Solid Tumors 1.1 assessed by IRC. Secondary endpoints included duration of response, durable response rate, safety, progression-free survival, and overall survival. Between March 2019 and January 2020, 159 patients were enrolled. Median follow-up was 16.1 (range, 0.0–19.3) months; 17 patients (10.7%; 95% CI: 6.4%–16.6%) achieved an objective response. Median duration of response was 10.0 (range, 1.9–15.7) months; 10 patients (6.3%; 95% CI: 3.1%–11.3%) had a durable response (≥6 mo). Median progression-free survival was 1.8 months (95% CI: 1.7–1.8 mo); median overall survival was 7.6 months (95% CI: 5.8–9.7 mo). Overall survival rates were 57.9% (6 mo) and 38.8% (12 mo). Grade ≥3 adverse events occurred in 26.4% of patients, including one treatment-related death (hepatic failure). Frequent grade ≥3 adverse events included anemia (3.8%), pruritus (1.9%), and increased alanine aminotransferase (1.9%). Conclusions: Although this study did not meet its prespecified primary endpoint, bintrafusp alfa demonstrated clinical activity as second-line treatment in this hard-to-treat cancer, with durable responses and a manageable safety profile.