Advanced Pancreatic Ductal Adenocarcinoma Research Articles

Exploring racial disparities and tumor characteristics of CA19-9 producer and non-producer among patients with advanced pancreatic ductal adenocarcinoma (PDAC): Implications for survival and personalized treatment strategies.

e16309 Background: Despite substantial progress in cancer treatment, PDAC remains a highly lethal disease. CA19-9 plays a crucial role in PDAC diagnosis and therapeutic response assessment. We aimed to evaluate racial differences, tumor characteristics, and outcomes between CA19-9 non-producers and producers among advanced PDAC patients (pts) at an academic teaching hospital. Methods: A retrospective analysis was conducted in patients with unresectable or metastatic PDAC treated at Mount Sinai Health System between January 2012 and December 2021. Pts were categorized into two groups based on CA19-9 levels, using a threshold of 37 U/mL: CA19-9 non-producers (≤37 U/mL) and CA19-9 producers ( > 37 U/mL). Demographic and clinical data were compared between the two groups, and the association between CA19-9 levels and overall survival (OS) was assessed using Kaplan-Meier estimates and multivariable Cox proportional hazards regression models. Results: A total of 238 pts were included in the analysis, with a median age of 67 years and a balanced gender distribution (52% male). The cohort comprised locally advanced (29.8%) and metastatic (70.2%) cases, with a diverse ethnic composition including non-Hispanic whites (37%), non-Hispanic blacks (25%), and Hispanics (18%). Among the pts, 23.5% were CA19-9 non-producers, while 76.5% were CA19-9 producers. Significant racial differences were observed, with non-Hispanic blacks more likely to be CA19-9 non-producers compared to non-Hispanic whites ( P< 0.001). However, no statistically significant differences were found in age, smoking status, tumor location, size, or site of metastasis between the two groups. Median overall survival (OS) was 13m for CA19-9 producers and 16m for non-producers, but this difference was not statistically significant in both univariate and multivariate analyses (HR 1.09, 95% CI 0.74-1.58, P = 0.66; HR 1.06, 95% CI 0.72-1.58, P 0.8). Hispanic ethnicity was correlated with improved OS (HR 0.59, 95% CI 0.36-0.95, P = 0.029), while larger tumor size predicted worse OS (HR 1.17, P < 0.001). Conclusions: This study highlights racial disparities in CA19-9 production among locally advanced and metastatic PDAC patients. Despite observed differences, CA19-9 levels alone did not emerge as a statistically significant predictor of OS. Future research should delve deeper into the racial disparities observed in CA19-9 production, exploring underlying biological mechanisms and potential implications for diagnostic and therapeutic approaches as this could refine our understanding of PDAC, facilitating targeted interventions for improved patient outcomes.

The clinical application of circulating tumor cells (CTCs) for immunotherapy in advanced pancreatic cancer.

e14541 Background: Circulating tumor cell (CTCs) has the potential utility for screening, prognostic and predictive assessment, and offers the potential for personalized management. This trial aimed to evaluate the prognostic and predictive impact of programmed cell death ligand 1 (PD-L1) positive CTCs in patients with pancreatic ductal adenocarcinoma (PDAC). Methods: Twenty-three heavily treated advanced PDAC patients were randomized to receive camrelizumab combined with apatinib or capecitabine, or placebo plus capecitabine until disease progression or unacceptable toxicity, and peripheral blood CTCs samples were collected at baseline and after treatment. Forty-nine CTCs samples from 23 recruited advanced PDAC patients were detected by subtraction enrichment and immunostaining-FISH (SE-iFISH). PD-L1 expression level also was evaluated in tumor tissue samples by Immunohistochemistry (IHC). Investigator-assessed 6-month overall survival (OS) rate and 3-month progression-free survival (PFS) rate was evaluated. Results: The positive detection rate of CTCs in 23 PDAC patients was 95.7%. The cell sub-types of sizes of CTC analysis showed that 58.6% CTCs was the small CTCs (Diameter < 5μm). CTCs karyotypes analysis exhibited that triploid small CTCs were the main karyotype (41.2%) in small CTC, and pentaploid large CTCs was the major karyotype (74.7%) in large CTCs. PD-L1+ CTCs were detected in 43.5% of PDAC patients. Tissue PD-L1 positive detection rate was 50% (CPS > 1%) in available tissue samples(n=10). The presence of PD-L1+ CTCs cohort exhibited a significant increase in 6-month OS rate (80% versus 38.5%, P < 0.05) and 3-month PFS rate (70% versus 23.1%, P < 0.05) compared to PD-L1- CTCs cohort. Compared with the PD-L1- CTCs patients, the combination therapy camrelizumab markedly improved the 6-month OS rates (75% versus 50%) and 3-month PFS rate (62.5% versus 25%) in PD-L1+ CTC patients. Conclusions: PD-L1+ CTCs could be considered as a favorable prognostic marker in advanced PDAC. These results suggest that PD-L1+ CTCs might be used as a predictor of the efficacy of cancer immunotherapy in advanced PDAC, and provide a new monitoring method for the precise treatment of advanced PDAC. The expanding sample size test is now ongoing. Clinical trial information: ChiCTR1900024095 .

Tislelizumab with anlotinib and chemotherapy for second-line treatment of pancreatic ductal adenocarcinoma: A pilot study early result.

e16316 Background: Advanced pancreatic ductal adenocarcinoma is a malignant tumor with poor prognosis. At present, chemotherapy is still the standard treatment, however the efficacy is unsatisfied. The lack of second-line treatment options for pancreatic cancer results in progression-free survival often lasting less than 3 months. For pancreatic cancer is an immune desert type of tumor, immunotherapy has not brought breakthrough therapeutic regimen compared to the remarkable data in other tumors.There is still insufficient therapeutic evidence treated with PD1 antibody in pancreatic cancer. Anlotinib is a tyrosine kinase inhibitor (TKI) with anti-tumor effects. It has been shown the combination of PD1 and multi-target tyrosine kinase inhibitors can increase immunotherapy efficacy. The purpose of this study is to evaluate the efficacy and tolerability of Tislelizumab combined with Anlotinib, as well as chemotherapy (the choice of the investigator) in second-line treatment of patients with pancreatic ductal adenocarcinoma. Methods: In this single arm, phase II, prospective exploratory study, it was planned to recruit 30 adult patients with treated pancreatic ductal adenocarcinoma who have never received any PD (L) 1 and TKI. Eligible patients received Tislelizumab (iv, 200mg, Q3W), Anlotinib (PO, 10mg, QD), and chemotherapy (determined by the researchers) till disease progression or death. The primary endpoint was median progression-free survival (mPFS), the secondary endpoints were objective response rate (ORR), median overall survival(mOS), disease control rate (DCR), and treatment safety profile. Results: 14 eligible patients were recruited till Jan 2024, 12 patients with PFS records were included. Median follow-up time was 208 days (104 days-504 days). mPFS was 106 days, OS is not reached, BOR (best of response) was stable disease. The 3-months DCR rate was 58.3%, 6-months DCR rate was 25%. One patient was observed to have a 20% tumor shrinkage after two cycles of treatment and is still being followed up. The most common treatment-related adverse events(TRAEs) was neutropenia with level ≤grade 3, observed in 8/14 patients. The immune-related adverse event of concern was hypothyroidism(grade 1/2), which occurred in two patients. Two patients experienced grade 4 obstructive jaundice caused by the progression of the disease. Conclusions: The second-line combination regimen of Tislelizumab with Anlotinib based on chemotherapy demonstrated survival improvement trend and no new safety signals identified in pancreatic cancer. These data suggest Tislelizumab + Anlotinib+Chemo may be a promising novel treatment option for patients with pancreatic cancer. Clinical trial information: NCT05681390 .

357P Single-center analysis of DNA damage repair (DDR) germline mutations (GM) in patients (pts) with advanced pancreatic ductal adenocarcinoma (aPDAC)

357P Single-center analysis of DNA damage repair (DDR) germline mutations (GM) in patients (pts) with advanced pancreatic ductal adenocarcinoma (aPDAC)

Safety and efficacy of IBI389, an anti-CLDN18.2/CD3 bispecific antibody, in patients with advanced pancreatic ductal adenocarcinoma: Preliminary results from a phase 1 study.

4011 Background: CLDN18.2 expression has been observed in various solid tumors. In pancreatic ductal adenocarcinoma (PDAC), positive CLDN18.2 expression was reported in nearly 60% patients (pts), indicating its potential as a novel target for anti-tumor therapy. IBI389 is an anti-CLDN18.2/CD3 bispecific antibody that induces immune synapse formations by linking CD3 molecules in T-cell receptor complexes and CLDN18.2 antigens on the membrane of tumor cells. Herein, we report preliminary result from a phase I study to evaluate safety and efficacy of IBI389 in pts with PDAC. Methods: EligibleCLDN18.2-positivepts with locally advanced, refractory or metastaticPDAC who failed or were intolerant to standard treatments were enrolled. IBI389 monotherapy was intravenously administered at 6 dose levels (5-600 µg/kg, Q3W or Q2W) during the 2-stage dose escalation and the dose expansion. In dose levels ≥ 30 µg/kg, the step-up dosing strategy with priming dose of 3 to 10 µg/kg was applied. The primary objective was safety. Secondary objective was efficacy assessed by investigator per RECIST v1.1 including objective response rate (ORR) and disease control rate (DCR). Results: As of January 9, 2024, a total of 64 CLDN18.2-positive PDAC pts were enrolled (males: 64.1%, females:35.9%, median age: 60.0 years, stage IV: 84.4%). All patients received prior therapy with a median of 2 lines (range: 1 to 5). Treatment-related adverse events (TRAEs) occurred in 62 (96.9%) pts including 35 (54.7%) pts had grade ≥3 TRAEs. The most common grade ≥3 TRAEs (≥5%) were gamma-glutamyl transferase increased (20.3%), lymphocyte count decreased (9.4%) and nausea (7.8%). Cytokine release syndrome (CRS) related adverse events occurred in 33 (51.6%) pts with no grade ≥3 CRS occurred. TEAEs leading to dose interruption and treatment discontinuation occurred in 24 (37.5%) and 3 (4.7%) pts. Preliminary efficacy of IBI389 was observed in pts with CLDN18.2 expression ≥10% (immunohistochemistry 2+/3+) at 600 µg/kg. As of January 31, 2024, there were 23 evaluable pts including 7 pts with PR and 9 pts with SD. The ORR was 30.4% (95%CI: 13.2-52.9) and DCR was 69.6% (95%CI: 47.1-86.8). The median duration of response (DoR) and progression-free survival (PFS) was not reached. More updated data on safety and efficacy will be presented at the meeting. Conclusions: IBI389 showed manageable safety profiles in pts with advanced PDAC. Preliminary efficacy was observed, including in pts with relatively low expression of CLDN18.2. Clinical trial information: NCT05164458 .

Safety and efficacy of IBI343 (anti-claudin18.2 antibody-drug conjugate) in patients with advanced pancreatic ductal adenocarcinoma or biliary tract cancer: Preliminary results from a phase 1 study.

3037 Background: Prognosis for advanced pancreatic ductal adenocarcinoma (PDAC) and biliary tract cancer (BTC) remains poor, with limited treatment options available. Expression of claudin18.2 (CLDN18.2) has emerged as a potential target for anti-cancer treatment. Herein, we report preliminary safety and efficacy results of IBI343, an antibody-drug conjugate (ADC) consisting of anti-CLDN18.2 monoclonal antibody conjugated to exatecan (topoisomerase I inhibitor), in patients (pts) with advanced PDAC or BTC in a phase 1 study. Methods: Eligible pts who failed or were intolerant to standard treatment were enrolled. IBI343 were intravenously administered at 6 mg/kg or 8 mg/kg Q3W. In dose escalation, pts were enrolled regardless of CLDN18.2 expression. In dose expansion, pts were required to have CLDN18.2 expression ≥40% (1+/2+/3+ staining intensity by immunohistochemistry). Primary endpoint was safety. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and progression free survival (PFS) assessed by investigator per RECIST v1.1. Results: As of December 19, 2023, 35 pts (1 pt in dose escalation and 34 pts in dose expansion) were enrolled from China and Australia (males: 57.1%, median age: 58.0 years, ECOG PS 1: 71.4%, stage IV: 91.4%, median lines of prior treatment: 2) including 28 PDAC pts and 7 BTC pts. Pts received IBI343 at 6 mg/kg (n=17) or 8 mg/kg (n=18). Median duration of treatment was 7.0 weeks (range: 3.0-23.6) with 23 (65.7%) pts still on treatment. In all pts, treatment-related adverse events (TRAEs) occurred in 28 (80.0%) pts including grade ≥3 TRAEs in 9 (25.7%) pts. Common TRAEs (≥20%) were anemia (42.9%), neutrophil count decreased (28.6%), nausea (25.7%), vomiting (25.7%) and white blood cell count decreased (22.9%). Serious TRAEs occurred in 4 (11.4%) pts. TRAEs leading to dose interruption and treatment discontinuation occurred in 7 (20.0%) pts and 1 (2.9%) pt respectively. No TRAE led to death. Safety profiles of IBI343 in PDAC and BTC were comparable with the whole study cohort and no new safety signal was observed. As of January 15, 2024, 25 pts at 6 mg/kg and 8 mg/kg were efficacy evaluable. Partial response (PR) was observed in 7 pts (5 PDAC and 2 BTC). The ORR was 28.0% (95%CI: 12.1-49.4) and DCR was 80.0% (95%CI: 59.3-93.2). In evaluable pts at 6 mg/kg with CLDN18.2 expression ≥60% (1+/2+/3+, n=13), 5 pts had PR with ORR of 38.5% (95%CI: 13.9-68.4) and DCR of 84.6% (95%CI: 54.6-98.1). Among 10 PDAC pts in this subgroup, ORR was 40% (95%CI: 12.2-73.8). DoR and PFS data were immature. More updated data on safety and efficacy will be presented at the meeting. Conclusions: IBI343 was well tolerated with favorable safety profiles and encouraging efficacy in CLDN18.2-positive PDAC and BTC. Clinical trial information: NCT05458219 .

Phase II clinical trial of nab‐paclitaxel plus cisplatin plus gemcitabine (NABPLAGEM) in patients with untreated advanced pancreatic cancer

AbstractBackgroundA previous phase IB/II study of nab‐paclitaxel + cisplatin + gemcitabine (NABPLAGEM) in 25 patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC) demonstrated favorable results. This phase II study was conducted to further evaluate the safety, efficacy, and impact on quality of life (QOL) of NABPLAGEM in a multi‐center setting.MethodsParticipants were ≥18 years; had measurable PDAC; Karnofsky performance status of ≥70%; life expectancy ≥12 weeks; <grade 2 pre‐existing peripheral neuropathy, and adequate hematologic, hepatic, and renal function. Study treatment included nab‐paclitaxel (125 mg/m2), cisplatin (25 mg/m2), and gemcitabine (1000 mg/m2), on Days 1 and 8 of a 21‐day cycle. The primary endpoint was 12‐month overall survival (OS).ResultsA total of 42 patients were enrolled with a median age of 66.8 years, a majority were male (66.7%) and white (76.2%). Treatment‐related adverse events ≥grade 3 were: thrombocytopenia (64.3%), anemia (47.6%), and neutropenia (26.1%). OS at 12 months was 38.1%, with 12% of patients alive as of last contact (20–40+ months). In 37 evaluable participants responses included: partial response (40.5%), stable disease (43.2%), and progressive disease (16.2%), with overall response rate of 40.5% and DCR of 88.6%. Statistically significant improvement in QOL was reported during the first three cycles.ConclusionThe primary objective of achieving a 12‐month survival comparable to the previous phase Ib/II NABPLAGEM PCRT 12‐001 was not achieved in this trial. NABPLAGEM has efficacy in advanced PDAC, demonstrating early disease control noted by improvement in patient symptoms, decrease in tumor volume and tumor markers within the first 9 weeks. The activity and tolerability make this a suitable regimen for further testing in the neoadjuvant setting.

Phase 2 randomized study of rintatolimod following FOLFIRINOX in patients with locally advanced pancreatic adenocarcinoma.

TPS4214 Background: The immunosuppressive microenvironment of pancreatic ductal adenocarcinoma (PDAC) is a driver of its lethality and resistance to immunotherapy. Strategies which modulate the immunosuppressive milieu have the potential to improve the anti-tumor response and improve outcomes in patients with PDAC. Rintatolimod is a synthetic double-stranded RNA molecule that activates the toll-like receptor 3 (TLR3) present on dendritic cells, B-cells, natural killer cells and pancreatic epithelial cells. TLR3 stimulation may increase cytotoxic T-cell activity in PDAC through dendritic cell maturation, antigen priming and downstream proliferation of cytotoxic T-cells. Twenty-seven patients were treated with rintatolimod in a single center Named Patient Program at Erasmus University Medical Center in Rotterdam between January 2017 and February 2019. All had locally advanced or metastatic PDAC which had not progressed on FOLFIRINOX (median 8 cycles). Maintenance rintatolimod, administered intravenously twice weekly for up to 18 weeks, was generally well tolerated. The most common toxicities were grade 1-2 myalgia (30%), chills (52%) and fatigue (30%); no toxicities ≥ grade 3 were observed. Progression-free and overall survival (from cycle 1 FOLFIRINOX) were 13 and 19 months. Methods: This is a phase 2 randomized, open-label, multicenter clinical trial. The primary objective is to assess the efficacy of rintatolimod compared to observation in subjects with locally advanced PDAC which has not progressed after FOLFIRINOX. Eligible patients have completed at least 4 months of FOLFIRINOX, have no evidence of progressive disease, have measurable disease by RECIST v1.1, Karnofsky Performance Status ≥80 and have adequate organ function. Subjects with resected PDAC or metastatic disease are not eligible. Subjects are randomized 2:1 to rintatolimod vs. observation. Rintatolimod is administered intravenously twice weekly until disease progression in the experimental arm. Cross-sectional imaging is performed every 8 weeks in both arms. The primary endpoint is progression-free survival, as assessed by the investigator. Secondary endpoints include overall survival, objective response rate, duration of response and safety, as assessed by CTCAE v5.0. Exploratory endpoints include quality of life and changes in immune cell composition and T-cell response in the peripheral blood to characterize the immunomodulatory effects of rintatolimod. The planned sample size is 90 subjects. The final analysis will be performed after 64 events (disease progression or death) have been observed. The study is powered to detect a hazard ratio of 0.47 for median PFS with 80% power and significance level of 5%. Clinical trial information: NCT05494697 .

Chemotherapy with or without surgery for locally advanced or borderline resectable pancreatic ductal adenocarcinoma: A retrospective multicenter international study.

e16352 Background: Current clinical guidelines recommend surgery for patients with locally advanced (LA)/borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) who achieve disease control after induction therapy. However, the additional survival benefit of surgery in these patients is unknown. Methods: In this multicenter international retrospective cohort study, consecutive patients with BR/LA PDAC who achieved disease control after three to six months of induction therapy (combination chemotherapy or chemoradiotherapy) between January 2014 and July 2021 were retrospectively identified at 8 centers in Germany and Italy. Resectability status was determined by consensus in a multidisciplinary tumor board based on imaging findings, serum CA19-9, performance status and clinical response. Patient characteristics, progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Cox regression analysis was used to compare survival data. Results: A total of 138 patients who achieved disease control with induction therapy were analyzed. The median age at diagnosis was 66 years (range 45-82) and 43% of patients were female. 73 patients underwent surgery and 65 patients did not (median age 64 and 69 years, respectively, p = 0.02). Median OS was 20.0 months (95%CI 16.1-23.8) in the surgery group and 18.0 months (95%CI 13.6-22.4) in the nonsurgery group (hazard ratio for death, 0.90; 95%CI, 0.63 to 1.29, p = 0.57). Median PFS was 14.0 months (95%CI 8.9-19.1) in the surgery group and 15.0 months (95%CI 11.7-18.3) in the nonsurgery group (hazard ratio for disease progression, 1.04; 95%CI, 73 to 1,47, p = 0.83). The 2-year survival rates in the surgery and nonsurgery groups were 32.9% and 40.0%, respectively, with an overall odds ratio of 0.74 (95% CI: 0.37-1.47). Conclusions: In our multicenter international retrospective analysis, additional surgery did not confer a survival advantage to patients with BR/LA PDAC who achieved disease control with induction therapy.

Phase 1 study to evaluate safety and preliminary efficacy of padeliporfin vascular targeted photodynamic therapy (VTP) in patients with locally advanced (LA) unresectable pancreatic ductal adenocarcinoma (PDAC).

TPS4204 Background: Pancreatic cancer is the third most common cause of cancer death. Surgery offers the best survival rates however only a minority of patients are eligible. Approximately 15-20% of patients are deemed unresectable due to vascular involvement LA. Conversion of unresectable tumors, due to vascular involvement to resectable, is an unmet clinical need. Methods: A novel approach was developed to destroy the tumor encasing the artery combining padeliporfin, a photosensitive drug, locally activated by laser light illumination. The effectiveness of the strategy was confirmed in an orthotopic mouse model. A proof-of-concept study using 12 non-tumor pigs demonstrated an acceptable safety profile. A phase I dose escalation trial (NCT5918783) will be performed to evaluate the safety and maximal tolerated dose (MTD) of laser light dose of padeliporfin VTP. VTP will be delivered through an endovascular fiber integrated in a standard angioplasty balloon. The balloon will be advanced under fluoroscopy to the encased vascular segment of the superior mesenteric artery (SMA) and inflated. Following IV administration of padeliporfin, it will be activated by the laser light. Part A will be a classic 3+3 dose-escalation design to determine the MTD of laser light. The identified MTD will be applied in the Part B for preliminary efficacy evaluation. The primary objectives are to determine safety and MTD and/or recommended phase 2 laser light dose of VTP treatment. Secondary objectives are: rate of surgical conversion; evaluation of the pattern of disease progression (local regional and/or metastatic disease) after VTP based on CT. Standard of care surgery can be performed after 14 days post VTP. Key inclusion criteria: patients with histologically/cytologically confirmed stage III unresectable LA-PDAC in the head/uncinate process of the pancreas, with SMA solid tumor contact ˃180° with measurable disease per RECIST 1.1 and ECOG 0-1. Key exclusion criteria: metastatic disease, other malignancy, photosensitive skin diseases or porphyria, concurrent investigational therapy within past 30 days, medically uncontrolled moderate or severe ascites, previous radiation to pancreas, SMA variants. Recruitment begins in April 2024. Conversion of unresectable locally advanced pancreatic cancer to surgery is a critical unmet need. This phase I trial explores a novel approach to treat the tumor encasement enabling surgery. Clinical trial information: NCT5918783 .

Efficacy and safety of sitagliptin, in combination with gemcitabine plus nab-paclitaxel (GnP) in patients with previously untreated advanced pancreatic ductal adenocarcinoma (PDAC).

e16329 Background: Chemoresistance is the main reason for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Thus, there is an urgent need to identify new targets and compounds to overcome chemotherapeutic resistance. Methods: The high-throughput virtual drug screening, molecular docking analysis and organoid biobank-based drug screening were performed to identify the candidates to efficiently overcome chemotherapy resistance. In vitro and in vivo PDOs, PDXs and KPC GEMM models were used to evaluate the effects of the compounds. Spatial single cell RNA-sequence, spatial metabolomics and proteomics were employed to elucidate the mechanism. Additionally, an ongoing open-label, randomized, single-arm, single-center phase 2 investigator-initiated clinical trial (NCT05947825) is investigating the efficacy and safety of the candidate in sensitizing gemcitabine plus nab-paclitaxel (GnP) in previously untreated advanced PDAC patients. Objective tumor responses were assessed according to RECIST1.1 criteria and any adverse events were graded using CTCAE 5.0. The primary endpoint was progression-free survival (PFS), and secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and treatment-emergent adverse events (TEAEs). Results: High-throughput drug screening of chemotherapy-resistant PDOs identified Sitagliptin that could significantly induce the degradation of RRM1/RRM2 in a ubiquitin proteasome-dependent manner and further result in unrestrained pyrimidine biosynthesis and alleviation of replication stress. In vitro and in vivo assays confirmed that Sitagliptin could synergistically enhance the ability of GnP regimen to suppress PDAC progression. In the phase 2 study (NCT05947825), previously untreated advanced PDAC received Sitagliptin, 100mg/qd and gemcitabine (G, 1000mg/m2 )plus nab-paclitaxel (nP, 125 mg/m2 )on Days 1 and 8 in a 21-day cycle. Till February 1, 2024, 12 patients with ECOG 0 to 2 have been enrolled in the study. The primary endpoint has not been reached. Among the 8 evaluable patients, 3 showed partial responses and 5 had stable diseases. The objective response rate (ORR) and disease control rate (DCR) were 37.5% and 100% respectively. There were no instances of treatment-related death in this study. The most common treatment-emergent adverse events (TEAEs) were decreased white blood cells and fatigue. One patient experience skin rash. Conclusions: Sitagliptin could effectively improve efficacy of GnP regimen by suppressing RRM1/RRM2-mediated pyrimidine metabolism. Sitagliptin plus GnP regimen is a feasible regimen with a manageable safety profile. Sitagliptin in combination with GnP regimen shows encouraging antitumor activity in PDAC, meriting continued development. Clinical trial information: NCT05947825 .

Multidisciplinary Standards and Evolving Therapies for Patients With Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDA) is a challenging disease that presents at an advanced stage and results in many symptoms that negatively influence patients' quality of life and reduce their ability to receive effective treatment. Early implementation of expert multidisciplinary care with nutritional support, exercise, and palliative care for both early-stage and advanced disease promises to maintain or improve the patients' physical, social, and psychological well-being, decrease aggressive interventions at the end of life, and ultimately improve survival. Moreover, advances in treatment strategies in the neoadjuvant and metastatic setting combined with novel therapeutic agents targeting the key drivers of the disease are leading to improvements in the care of patients with pancreatic cancer. Here, we emphasize the multidisciplinary supportive and therapeutic care of patients with PDA, review current guidelines and new developments of neoadjuvant and perioperative treatments for localized disease, as well as the treatment standards and the evolving field of precision oncology and immunotherapies for advanced PDA.

TRIANGLE operation, combined with adequate adjuvant chemotherapy, can improve the prognosis of pancreatic head cancer: A retrospective study.

The TRIANGLE operation involves the removal of all tissues within the triangle bounded by the portal vein-superior mesenteric vein, celiac axis-common hepatic artery, and superior mesenteric artery to improve patient prognosis. Although previously promising in patients with locally advanced pancreatic ductal adenocarcinoma (PDAC), data are limited regarding the long-term oncological outcomes of the TRIANGLE operation among resectable PDAC patients undergoing pancreaticoduodenectomy (PD). To evaluate the safety of the TRIANGLE operation during PD and the prognosis in patients with resectable PDAC. This retrospective cohort study included patients who underwent PD for pancreatic head cancer between January 2017 and April 2023, with or without the TRIANGLE operation. Patients were divided into the PDTRIANGLE and PDnon-TRIANGLE groups. Surgical and survival outcomes were compared between the two groups. Adequate adjuvant chemotherapy was defined as adjuvant chemotherapy ≥ 6 months. The PDTRIANGLE and PDnon-TRIANGLE groups included 52 and 55 patients, respectively. There were no significant differences in the baseline characteristics or perioperative indexes between the two groups. Furthermore, the recurrence rate was lower in the PDTRIANGLE group than in the PDnon-TRIANGLE group (48.1% vs 81.8%, P < 0.001), and the local recurrence rate of PDAC decreased from 37.8% to 16.0%. Multivariate Cox regression analysis revealed that PDTRIANGLE (HR = 0.424; 95%CI: 0.256-0.702; P = 0.001), adequate adjuvant chemotherapy ≥ 6 months (HR = 0.370; 95%CI: 0.222-0.618; P < 0.001) and margin status (HR = 2.255; 95%CI: 1.252-4.064; P = 0.007) were found to be independent factors for the recurrence rate. The TRIANGLE operation is safe for PDAC patients undergoing PD. Moreover, it reduces the local recurrence rate of PDAC and may improve survival in patients who receive adequate adjuvant chemotherapy.

Morbidity and mortality in patients with stage IV pancreatic adenocarcinoma and acute cholangitis: Outcomes and risk prognostication

BackgroundAcute cholangitis (AC) is a common complication of pancreatic ductal adenocarcinoma (PDAC). Herein, we evaluated outcomes after the first AC episode and predictors of mortality and AC recurrence in patients with stage IV PDAC. MethodsWe conducted a single-center, retrospective observational study using institutional databases. Clinical data and outcomes for patients with stage IV PDAC and at least one documented episode of AC, were assessed. Overall survival (OS) was estimated using the Kaplan-Meier method, and Cox regression model was employed to identify predictors of AC recurrence and mortality. ResultsOne hundred and twenty-four patients with stage IV PDAC and AC identified between January 01, 2014 and October 31, 2020 were included. Median OS after first episode of AC was 4.1 months (95 % CI, 4.0–5.5), and 30-day, 6, and 12-month survival was 86.2 % (95 % CI, 80.3–92.5), 37 % (95 % CI, 29.3–46.6 %) and 18.9 % (95 % CI, 13.1–27.3 %), respectively. Primary tumor in pancreatic body/tail (HR 2.29, 95 % CI: 1.26 to 4.18, p = 0.011), concomitant metastases to liver and other sites (HR 1.96, 95 % CI: 1.16 to 3.31, p = 0.003) and grade 3 AC (HR 2.26, 95 % CI: 1.45 to 3.52, p < 0.001), predicted worse outcomes. Intensive care unit admission, sepsis, systemic therapy, treatment regimen, and time to intervention did not predict survival or risk of recurrence of AC. ConclusionsAC confers significant morbidity and mortality in advanced PDAC. Worse outcomes are associated with higher grade AC, primary tumor location in pancreatic body/tail, and metastases to liver and other sites.

The Role of Pretreatment Serum Interleukin 6 in Predicting Short-Term Mortality in Patients with Advanced Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is notorious for its aggressive progression and dismal survival rates, with this study highlighting elevated interleukin 6 (IL-6) levels in patients as a key marker of increased disease severity and a potential prognostic indicator. Analyzing pre-treatment serum from 77 advanced PDAC patients via ELISA, the research determined optimal cutoff values for IL-6 and the IL-6:sIL-6Rα ratio using receiver operating characteristic curve analysis, which then facilitated the division of patients into low and high IL-6 groups, showing significantly different survival outcomes. Notably, high IL-6 levels correlated with adverse features such as poorly differentiated histology, higher tumor burden, and low albumin levels, indicating a stronger likelihood of poorer prognosis. With a median follow-up of 9.28 months, patients with lower IL-6 levels experienced markedly better median overall survival and progression-free survival than those with higher levels, underscoring IL-6's role in predicting disease prognosis. Multivariate analysis further confirmed IL-6 levels, alongside older age, and elevated neutrophil-to-lymphocyte ratio, as predictors of worse outcomes, suggesting that IL-6 could be a critical biomarker for tailoring treatment strategies in advanced PDAC, warranting further investigation into its role in systemic inflammation and the tumor microenvironment.

Rintatolimod in Advanced Pancreatic Cancer Enhances Antitumor Immunity through Dendritic Cell-Mediated T-Cell Responses.

Amid the need for new approaches to improve survival in pancreatic ductal adenocarcinoma (PDAC), immune-based therapies have garnered interest. Rintatolimod, a Toll-like receptor 3 (TLR-3) agonist, is a potential candidate due to its dual impact on restraining PDAC cell functions and boosting the antitumor immune response. This study investigates the effect of TLR-3 activation through rintatolimod on the peripheral immune landscape of patients with advanced PDAC. Paired blood samples of 30 patients with advanced PDAC, collected at baseline and after 12 rintatolimod intravenous infusions, underwent comprehensive transcriptomic NanoString and proteomic flow cytometry profiling. The impact of rintatolimod and immunologic factors on survival outcomes was assessed through univariate Cox proportional hazards models. Rintatolimod treatment enhances peripheral immune activity at the transcriptomic and proteomic levels, particularly involving type 1 conventional dendritic cells (cDC1) and T cells. Post-rintatolimod, the increased peripheral abundance of BTLA+ XCR1+ cDC1s and CD4+SELL+ T cells correlated with improved clinical outcomes. Patients with stable disease exhibited pronouncedDCand T-cell activation gene overexpression. Notably, the expression of immune checkpoints PD-L1 and PD-L2 decreased post-rintatolimod across all patients. However, those with progressive disease showed increased expression of genes encoding IDO1 and PD-1. This study presents compelling evidence of the immune-stimulatory properties linked to TLR-3 activation through rintatolimod. Rintatolimod may break immunologic tolerance by enhancing antitumor immunity through DC-mediated Th-cell responses. Furthermore, our findings lay the groundwork for investigating the potential synergy between TLR-3 activation and immune checkpoint inhibitor therapy to improve therapeutic outcomes. See related commentary by Martínez-Riaño et al., p. 3355.

Abstract CT016: Immunomodulation of the tumor microenvironment of pancreatic ductal adenocarcinoma with histone deacetylase inhibition: Results of a phase 2 clinical trial of entinostat in combination with nivolumab

Abstract Background The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDA) is characterized by a paucity of cytotoxic tumor-infiltrating lymphocytes, an abundance of immune-suppressive cell populations, and a general resistance to immune checkpoint inhibitor (ICI) therapy. In preclinical models of PDA, the HDAC inhibitor entinostat modulated the transcriptional programming of myeloid cells, reducing their capacity for immunosuppression and sensitizing tumors to ICI therapy. Methods We conducted a single-center, open-label, Simon two-stage, phase II study of entinostat in combination with the PD1 inhibitor nivolumab in patients with advanced PDA. Patients received oral entinostat 5 mg once a week. After a 14-day lead-in with entinostat monotherapy, patients concurrently receive entinostat 5 mg orally once a week plus nivolumab 240 mg intravenously every 2 weeks. After 4 months, therapy was continued with entinostat 5 mg weekly plus nivolumab at a dose of 480 mg fixed dose every 4 weeks until the time of progression or unacceptable toxicities. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Peripheral immune profiles at baseline and on treatment were assessed by high-dimensional mass cytometry by time of flight (CyTOF) and by Luminex of chemokines in the plasma, and changes in the TME were performed on paired baseline and on treatment biopsies by multiplexed immunohistochemistry (mIHC), image cytometry-based quantification, and bulk RNA-seq analysis. Results From November 2017 to November 2020, 27 evaluable patients were enrolled. Three patients had a partial response (PR) by RECIST v1.1 criteria (objective response rate (ORR)) of 11%, 95% CI, 0.024-0.292), with a median duration of response of 10.2 months. Grade ≥3 treatment-related adverse events (TRAEs) were observed in 19 (63%) patients. The most common grade ≥3 TRAEs were decreased lymphocyte count, anemia hypoalbuminemia, and hyponatremia. Dendritic cell (DC) activation, maturation, migration, antigen processing, and presentation were increased in the periphery after entinostat treatment, consistent with HDAC inhibitor mediated myeloid reprogramming. Gene expression analysis of paired baseline and on treatment tumors demonstrated an enrichment in inflammatory response signaling pathways with combination treatment. Conclusions Entinostat and nivolumab demonstrated durable radiological responses in a subset of patients with PDA. Paired tissue and peripheral analysis showed immunomodulation of myeloid cell populations, consistent with the preclinical hypothesis supporting the trial. This study creates a roadmap for this strategy with future combinatorial therapeutic approaches to enhance the clinical benefit in PDA patients further. Citation Format: Marina Baretti, Ludmila Danilova, Jennifer N. Durham, Courtney B. Betts, Leslie Cope, Dimitrios N. Sidiropoulos, Joseph A. Tandurella, Soren Charmsaz, Nicole Gross, Alexei Hernandez, Won J. HO, Chris Thoburn, Rosalind Walker, James Leatherman Leatherman, Sarah Mitchell, Brian Christmas, Daria A. Gaykalova, Srinivasan Yegnasubramanian, Elana J. Fertig, Lisa M. Coussens, Mark Yarchoan, Elizabeth Jaffee, Nilofer S. Azad. Immunomodulation of the tumor microenvironment of pancreatic ductal adenocarcinoma with histone deacetylase inhibition: Results of a phase 2 clinical trial of entinostat in combination with nivolumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT016.

Abstract CT134: Safety and immunologic impact of neoadjuvant/adjuvant GM-CSF-secreting allogenic pancreatic tumor cell vaccine (GVAX) combined with cyclophosphamide, pembrolizumab, and macrophage-targeting CSF1R inhibitor IMC-CS4 in pancreatic adenocarcinoma

Abstract Background: Strategies are needed to improve effectiveness of immunotherapy in pancreatic ductal adenocarcinoma (PDA). Our recently published study (NCT02648282) showed that increased M1/M2 ratio and decreased PDL1+ M2-like tumor associated macrophages (TAM) in locally advanced PDA is associated with longer overall survival (OS) following combination of stereotactic body radiotherapy, GVAX and anti-PD1 antibody pembrolizumab (Pem). We hypothesized targeting M2-like macrophages, regulated by the colony stimulating factor-1 (CSF1) pathway, would improve outcomes. In this pilot study we investigated the safety and intratumoral immune response of neoadjuvant/adjuvant triplet immunotherapy: GVAX/cyclophosphamide (CY), Pem, and CSF1 receptor blockade (IMC-CS4) in patients with resectable or borderline resectable PDA. Methods: After completing chemotherapy and radiation patients received two 3-week cycles of neoadjuvant triplet immunotherapy. Following surgery, patients received 4 additional cycles followed by booster Pem every 3 weeks and GVAX/CY every 6 months, for one year. Co-primary endpoints were safety, assessed by NCI Common Terminology Criteria for Adverse Events (AEs), and immune response (increased CD8+ T-cell density in surgical specimen as compared to pre-treatment core). Secondary endpoints included disease free survival (DFS), OS, surgical resectability, and pathologic response (PR). Results: Nine patients were enrolled. Two immune related grade 3/4 AEs (diarrhea and rash) were reported. Median DFS was 12.6 months (95% CI: 7.3, NR) and median OS was 20.4 months (95% CI: 17.5, NR). All patients underwent surgery with major PR rate of 78% (defined as &amp;lt;10% residual viable tumor), including one complete PR. Comparing paired biopsies, the study met its primary immunologic endpoint showing 6/8 patients (75%) had a &amp;gt;80% increase of CD8+ T cells; the increase was at least 1.8 times the baseline median absolute deviation following triple therapy (p=0.012). There was a significant increase of Granzyme B+ CD8+ T cells among all patients (p=0.045). No significant change in myeloid cell density, including TAM, was observed, suggesting IMC-CS4 did not deplete macrophages, but potentially reprogrammed them. The 4 patients with greatest drop in CD66b+ granulocyte levels had major PR (grade 0 or 1). Conclusion: The triplet was safe and significantly increased activated CD8+ T cells suggesting the combination can induce an effector T cell response. Decreased granulocyte levels correlated with PR. Citation Format: Arielle Urman, Yingjun Ding, Hao Wang, Richard A. Burkhart, Jin He, Elizabeth M. Jaffee, Amol K. Narang, Dung Le, Daniel A. Laheru, Lei Zheng, Ana De Jesus-Acosta. Safety and immunologic impact of neoadjuvant/adjuvant GM-CSF-secreting allogenic pancreatic tumor cell vaccine (GVAX) combined with cyclophosphamide, pembrolizumab, and macrophage-targeting CSF1R inhibitor IMC-CS4 in pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT134.

Portal-Mesenteric Vein Resection for Borderline / Locally Advanced Pancreatic Cancer: Over 2.5 year survival in patients with good performance status

Background: Pancreatectomy associated with resection of the involved portal-superior mesenteric vein, preceded by neoadjuvant chemotherapy, for locally advanced (LA) and borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) is being performed in major pancreas referral centers globally, but its universal adoption faces challenges, notably in Greece. This study explores our center’s experience with this particular group of patients. Materials and Methods: Data from 43 consecutive patients undergoing pancreatectomy with superior mesenteric (SMV) and/or portal vein (PV) resection (January 2014 – January 2022) were analysed. Clinicopathologic information, perioperative details, complications, and follow-up through December 2023 were recorded. Statistical analyses employed Stata BE version 18.0. Results: Forty-three patients (28 BR, 15 LA) underwent pancreatectomy with superior mesenteric and/or portal vein resection. Neoadjuvant therapy (NAT) was administered to 60.4%, correlating significantly with smaller tumour size (median: 3 cm vs. 5 cm, p = 0.009), but not with overall survival (24 months vs. 26 months, p = 0.95). Venous wall infiltration was present in 55.8%, with a significant correlation with NAT administration (40% vs. 82.3%, p = 0.006). The extent of resection was substantial, with a median of 27 lymph nodes retrieved, 86% R0 resection rate, and a median length of resected vein segments measuring 3 cm, necessitating interposition grafts in 41.8% of cases. Postoperative mortality was 2.3%, with a median overall survival of 25 months. The two-, three-, and five-year overall survival rates were 51.1%, 31%, and 24.1%, respectively, surpassing established benchmark outcomes. Lower Eastern Cooperative Oncology Group (ECOG) status was significantly associated with longer survival (ECOG-0: 32 months, ECOG-1: 24 months, ECOG-2: 12 months, p = 0.018), emphasising its prognostic importance in this context. Conclusions: This series of portomesenteric resection in BR or LA PDAC demonstrated a median survival of two years, extending to 31 months in patients with good performance status, which meet and often exceed established outcome benchmarks.

Albumin-myosteatosis gauge as a prognostic factor in patients with advanced pancreatic cancer undergoing first-line chemotherapy.

Sarcopenia and myosteatosis have been associated with a poor prognosis for several cancers. The albumin-myosteatosis gauge (AMG) is a novel integrated measure proposed to assess myosteatosis along with serum albumin level as a surrogate of systemic inflammation and malnutrition. The aim of this study was to investigate the prognostic value of AMG in patients with advanced pancreatic ductal adenocarcinoma (PDAC). Patients with advanced PDAC treated with chemotherapy between 2013 and 2022 were evaluated. Skeletal muscle radiodensity (SMD) and skeletal muscle index (SMI) were calculated using computed tomography at the level of the L3 vertebra. The AMG was defined as albumin x SMD and expressed as an arbitrary unit (AU). Patients were first categorized by sex-specific quartiles and then dichotomized at the sex-specific median value of the AMG. A total of 196 patients were included. The median age (interquartile range) was 62 (54-67), and 128 (65.3%) were male. With regard to AMG, 142.86 and 114.15 AU were identified as cutoff values for males and females, respectively. In multivariable analyses, lower AMG values (G1-G2 vs. G3-G4) (HR: 1.61, 95% CI 1.17-2.21, p = 0.003), higher ECOG performance score (> 0 vs. 0) (HR: 1.51, 95% CI 1.10-2.06, p = 0.009) and metastatic disease (vs. locally advanced) (HR: 1.88, 95% CI 1.27-2.79, p = 0.001) were associated with OS. The study findings suggest the prognostic value of AMG in patients with advanced PDAC undergoing first-line chemotherapy. Further studies are warranted to validate these findings and assess potential predictive role of AMG in guiding treatment selection.