Unresectable Pancreatic Ductal Adenocarcinoma Research Articles

Correlation of UGT1A1 Gene Polymorphisms or Prior Irinotecan Treatment and Treatment Outcomes of Nanoliposomal-Irinotecan plus 5-Fluorouracil/Leucovorin for Pancreatic Ductal Adenocarcinoma: A Multicenter, Retrospective Cohort Study (HGCSG2101).

The effects of UGT1A1 gene polymorphisms or prior irinotecan treatment on treatment outcomes of nanoliposomal-irinotecan plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with unresectable pancreatic ductal adenocarcinoma (PDAC) are not established. This multicenter, retrospective cohort study compared treatment outcomes in patients with UGT1A1*1/*1 and those with UGT1A1*1/*6 or *1/*28 genotypes. We also analyzed the impact of prior irinotecan treatment on survival outcomes in 54 patients treated with nal-IRI+5-FU/LV. Comparable effectiveness was found regardless of the UGT1A1 genotypes. While no significant differences were found, grade ≥3 neutropenia and febrile neutropenia were more frequent in patients with UGT1A1*1/*6 or *1/*28 than in those with UGT1A1*1/*1 genotypes (grade ≥3 neutropenia, 50.0% vs. 30.8%, p = 0.24; febrile neutropenia, 9.1% vs. 0.0%, p = 0.20, respectively). No significant difference in progression-free survival (PFS) and overall survival (OS) was observed between irinotecan-naïve-patients and other patients. However, irinotecan-resistant patients showed significantly shorter PFS (hazard ratio (HR) 2.83, p = 0.017) and OS (HR 2.58, p = 0.033) than other patients. Our study indicated that patients with UGT1A1*1/*6 or *1/*28 may be prone to neutropenia, though further study is needed. The survival benefit of nal-IRI+5-FU/LV could be maintained in patients without disease progression after irinotecan therapy.

Prognosis of Pancreatic Cancer Based on Resectability: A Single Center Experience

Although conversion surgery has increasingly been performed for initially unresectable advanced pancreatic ductal adenocarcinoma (PDAC), the rate of conversion, including that for patients who do not undergo resection, remains unclear. Patients with PDAC who were treated between January 2013 and December 2018 were classified into three groups: resectable (R), borderline resectable (BR), and unresectable (UR). We analyzed patient outcomes, including the rate of surgical resection and survival, in each of these groups. In total, 211 patients (R, 118; BR, 22; UR, 81) were selected. Among them, 117 (99%), 18 (82%), and 15 (19%) patients in the R, BR, and UR groups, respectively, underwent surgical resection. R0 resection rates were 88, 78, and 67%, whereas median overall survival (OS) from treatment initiation were 31, 18, and 11 months (p < 0.0001) in the R, BR, and UR groups, respectively. In patients who underwent surgical resection, relapse-free survival (RFS) and OS were similar among the three groups (R vs. BR vs. UR; median RFS (months), 17 vs. 13 vs. 11, p = 0.249; median OS (months), 31 vs. 26 vs. 32, p = 0.742). Lymph node metastases and incomplete adjuvant chemotherapy were identified as independent prognostic factors for OS. Although the surgical resection rate was low, particularly in the BR and UR groups, the prognosis of patients who underwent surgical resection was similar irrespective of the initial resectability status.

A phase I study of CPI-613 (devimistat) in combination with chemoradiation in patients with pancreatic adenocarcinoma.

TPS760 Background: Local tumor progression is a cause of significant mortality and morbidity in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). Effective approaches to achieve durable local control are urgently needed. Metabolic reprogramming and enhanced mitochondrial function, both hallmarks of PDAC, are known contributors to chemo- and radio-resistance. CPI-613, a lipoic acid analog that selectively inhibits components of the Krebs cycle in tumors, showed promising preclinical synergy in combination with gemcitabine and radiation therapy (gem-RT). Methods: We describe a single-arm, single-center, open-label, phase I study designed to determine the maximum tolerated dose of CPI-613 when used concomitantly with gemcitabine and intensity modulated radiation therapy (IMRT) for local control of PDAC. CPI-613 will be administered once weekly by intravenous infusion over approximately 2 hours at a starting dose of 500 mg/m2 and dose-escalated/de-escalated using a Bayesian optimal interval design. Gemcitabine will be given once weekly at 400 mg/m2 dosage and IMRT as 54 Gray (Gy) in 30 fractions (1.8 Gy per fraction) with five fractions given per week. Up to 24 patients will be enrolled for the study after meeting the following main eligibility criteria, which include: pathologically confirmed PDAC; inoperable disease that by institutional pancreatic multidisciplinary tumor board or multidisciplinary review are considered to benefit from definitive local control of the primary tumor; ECOG of 0-2; and adequate organ and marrow function after completion of intended systemic chemotherapy. The secondary objectives are to determine the recommended phase II dose of CPI-613 when used with gem-RT, safety and tolerability of CPI-613-gem-RT, overall survival, local progression-free survival (PFS), overall PFS, patient-reported quality of life after treatment, and late gastrointestinal toxicities following treatment with CPI-613-gem-RT. Clinical trial information: NCT05325281 . Support: Cornerstone Pharmaceuticals. [Table: see text]

The utility of PD-L1 as a prognostic marker in pancreatic ductal adenocarcinoma (PDAC).

753 Background: The PDAC tumor microenvironment is notoriously immune suppressive, and PD-L1 expression is one mechanism by which tumor cells evade immune surveillance. In PDAC, clinical trials evaluating immunotherapy have not been successful in microsatellite stable tumors, and PD-L1 has not been shown to be predictive of immunotherapy response. Studies suggest that high PD-L1 expression may be associated with worse clinical outcomes and more advanced disease. We aimed to evaluate PD-L1 as a prognostic marker in routine clinical practice using a real-world population of patients with PDAC. Methods: We conducted a retrospective study of patients with PDAC at Mount Sinai Health System from 5/2017 to 12/2021 for whom PD-L1 status by immunohistochemistry (22c3) and combined positive score (CPS) were reported. We assessed the association between PD-L1 expression and overall survival (OS) using Kaplan-Meier estimates and multivariable Cox proportional hazards regression models. Chi-squared tests were used to evaluate the association between PD-L1 expression and mutations detected by routine next generation sequencing (NGS) using a standard panel. Results: 107 patients were evaluable. At diagnosis, median age was 68 years, 43% of patients were male, 83% had ECOG performance status 0-1, 38% had resectable disease, 14% had borderline resectable disease, and 48% had unresectable disease. Ultimately, 45 patients (42%) underwent surgery. 44% patients had gemcitabine-based initial therapy, perioperatively or as first-line, and 56% had 5FU-based initial therapy. 35% of patients had radiation therapy (RT) at any time. In the entire cohort, 44 (41%) patients had PD-L1 CPS &lt; 1, and 63 patients had CPS ≥ 1. 93 patients had NGS, but no associations were found between PD-L1 status and commonly mutated genes, such as KRAS and SMAD4. For patients who underwent surgery, the median OS (mOS) of patients with PD-L1 CPS ≥ 1 was 46.1 months, and mOS of PD-L1 CPS &lt; 1 was 29.8 months ( P = 0.13). For patients who did not receive surgery, mOS was 12.3 months for CPS ≥ 1 and 15.8 months for CPS &lt; 1 ( P = 0.07). When adjusted for age, gender, ECOG score, stage, type of chemotherapy, RT, and baseline CA 19-9 level, patients who received surgery and had a CPS ≥ 1 had better OS than those who had CPS &lt; 1 (HR 0.22, 95% CI 0.06-0.77, P = 0.02). For patients without resection, CPS ≥ 1 was not associated with OS in the adjusted model (HR 1.52, 95% CI 0.73-3.15, P = 0.26). However, patients with PD-L1 CPS ≥ 10 without surgery had worse OS compared to patients with CPS &lt; 1 in the adjusted model (HR 11.02, 95% CI 2.89-41.96, P &lt; 0.001). Chemotherapy type and receipt of RT did not modify OS based on PD-L1 expression. Conclusions: In resected PDAC, PD-L1 CPS ≥ 1 was independently associated with improved OS, whereas in unresectable PDAC, PD-L1 CPS ≥ 10 was independently prognostic of worse OS. PD-L1 expression is a potential prognostic factor in PDAC and may be a useful and context-dependent biomarker.

Updates to NeoOPTIMIZE: An open-label, phase II trial and biomarker discovery platform to assess the efficacy of adaptive switching of modified FOLFIRINOX (mFFX) or gemcitabine/nab-paclitaxel (GA) as a neoadjuvant strategy for patients with resectable/borderline resectable and locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC).

TPS776 Background: Neoadjuvant chemotherapy (NAC) and/or chemo-RT may confer benefit to patients with localized PDAC, by better tolerability, tumor down-staging, and increased R0 resections. mFFX or GA are the current NAC backbones; however, a lack of robust predictive biomarker(s) hampers identification of patients most likely to benefit from mFFX or GA. Further, desmoplastic stroma/poor vascularity compromise NAC efficacy, but angiotensin II receptor inhibitor, losartan, might remodel vascular perfusion to enhance chemotherapy activity. We designed the NeoOPTIMIZE trial for patients with newly diagnosed localized PDAC to provide a flexible clinical platform to: 1) evaluate the feasibility and efficacy of early switching of mFFX to GA, and 2) establish a robust biomarker/imaging discovery platform to optimize the NAC backbone. Methods: NeoOPTIMIZE (NCT04539808) is an open-label, non-randomized, phase II trial assessing the preliminary efficacy of an adaptive treatment strategy that allows for early switching of NAC in patients with localized PDAC. Sixty patients (n = 40 resectable/BRCP; n = 20 locally advanced unresectable [uLAPC]) will be enrolled to receive 2 months of preoperative mFFX (oxaliplatin, 85 mg/m2; folinic acid, 400 mg/m2; irinotecan, 150 mg/m2; 5-FU, 2400 mg/m2), then restaging by a multidisciplinary tumor board (multiD-TB). Absent progression (by panc protocol CT and CA19-9 decline/increase &lt; 30% from baseline), patients continue mFFX (4 cycles). If progression (by panc protocol CT; CA19-9 increase &gt; 30%), patients switch to GA (nab-paclitaxel, 125 mg/m2; gemcitabine, 1000 mg/m2) for 2 months. After 4 months of mFFX or mFFX/GA, another restaging multiD-TB will decide to proceed with: a) RT (if vascular involvement) then resection, b) resection, or c) continued chemo (if unresectable). Losartan (50 mg PO QD) is given throughout NAC and RT regimens. The primary endpoint estimates the proportion of resectable/BRPC patients with R0 resection. Assuming that the proportion of R0 is 60%, a sample size of 32 will provide a 95% CI (0.41, 076). To account for a 20% dropout, 40 patients will be enrolled towards primary endpoint. A separate exploratory cohort of 20 uLAPC patients will be enrolled. Secondary endpoints include DFS, PFS, OS, and AEs. Exploratory objectives include correlating clinical outcomes data with changes in blood-based biomarkers (CA19-9, ctDNA, circulating tumor cells etc.) and research DCE-MRI. To date, the trial has enrolled 19 patients: 8 resectable, 7 BRCP, and 4 uLAPC. Clinical trial information: NCT04539808 .

Comprehensive immunoprofile analysis of prognostic markers in pancreaticobiliary tract cancers.

Pancreaticobiliary tract cancer has a poor prognosis with unmet needs in a new target treatment. Some studies have reported that an enhancement of T-cell immunity is associated with a good prognosis. The aim of this study is to investigate the immunoprofile as a prognostic marker of pancreaticobiliary tract cancers. Unresectable pancreatic ductal adenocarcinoma (PDAC, n=80) and biliary tract cancer (BTC, n=74) diagnosed between January 2012 and December 2018 in Samsung Medical Center were analyzed. Expression levels of CD8, FOXP3, PD-1, PD-L1, and CXCL13 in PDAC and BTC tissue samples were examined with immunohistochemical staining, which was evaluated with various clinical factors. In PDAC, higher degree of PD-L1 expression was significantly associated with shorter overall survival (OS) (p=0.0095). On the other hand, higher infiltrations of PD-1+ immune cells (p=0.0002) and CD8+ T cells (p=0.0067) were associated with longer OS. In BTC, higher FOXP3+ (p=0.0343) and CD8+ (p=0.0028) cell infiltrations were associated with better survival. Low infiltration of CD8+ (p=0.0148), FOXP3+ (p=0.0208), PD-1+ (p=0.0318) cells in PDAC, and FOXP3+ cells (p=0.005) in BTC were considerably related to metastasis. In a combined evaluation of clinical factors and immunoprofiles, univariate analysis revealed that operation after chemotherapy (p < 0.0001), mass size (p=0.0004), metastasis (p=0.006), PD-L1 (p < 0.0001), PD-1 (p=0.003) and CD8 (p=0.0063) was significantly associated with OS in PDAC, and CD8 (p=0.007) was statistically related to OS in BTC. In multivariate analysis, prognostic factors were operation after chemotherapy (p=0.021) in PDAC and CD8 (p=0.037) in BTC. Therefore, immunoprofile analysis of cells expressing CD8, FOXP3, PD-1, and PD-L1 might have prognostic values in patients with pancreaticobiliary tract cancers.

STNM01, the RNA oligonucleotide targeting carbohydrate sulfotransferase 15, as second-line therapy for chemotherapy-refractory patients with unresectable pancreatic cancer: An open label, phase I/IIa trial.

The impact of stroma-targeting therapy on tumor immune suppression is largely unexplored. An RNA oligonucleotide, STNM01, has been shown to repress carbohydrate sulfotransferase 15 (CHST15) responsible for tumor proteoglycan synthesis and matrix remodeling. This phase I/IIa study aimed to evaluate the safety and efficacy of STNM01 in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). This was an open-label, dose-escalation study of STNM01 as second-line therapy in gemcitabine plus nab-paclitaxel-refractory PDAC. A cycle comprised three 2-weekly endoscopic ultrasound-guided locoregional injections of STNM01 at doses of 250, 1,000, 2,500, or 10,000nM in combination with S-1 (80-120mg twice a day for 14 days every 3 weeks). The primary outcome was the incidence of dose-liming toxicity (DLT). The secondary outcomes included overall survival (OS), tumor response, changes in tumor microenvironment on immunohistopathology, and safety (jRCT2031190055). A total of 22 patients were enrolled, and 3 cycles were repeated at maximum; no DLT was observed. The median OS was 7.8 months. The disease control rate was 77.3%; 1 patient showed complete disappearance of visible lesions in the pancreas and tumor-draining lymph nodes. Higher tumoral CHST15 expression was associated with poor CD3+ and CD8+ T cell infiltration at baseline. STNM01 led to a significant reduction in CHST15, and increased tumor-infiltrating CD3+ and CD8+ T cells in combination with S-1 at the end of cycle 1. Higher fold increase in CD3+ T cells correlated with longer OS. There were 8 grade 3 adverse events. Locoregional injection of STNM01 was well tolerated in patients with unresectable PDAC as combined second-line therapy. It prolonged survival by enhancing T cell infiltration in tumor microenvironment. The present study was supported by the Japan Agency for Medical Research and Development (AMED).

HPB P30 What is the Impact of Neoadjuvant Chemotherapy on Survival after Palliative Procedures for Pancreatic Ductal Adenocarcinoma?

Abstract Background Neoadjuvant chemotherapy (NAT) is increasingly offered to patients before attempting resection of pancreatic ductal adenocarcinoma (PDAC), most often to downstage locally advanced tumours but may also potentially control existing micrometastases. Unfortunately, curative resection may still not be possible in these patients. Therefore, the aim of this study was to evaluate the impact of neoadjuvant therapy on outcomes after palliative procedures for unresectable PDAC. Methods All patients who underwent a palliative procedure for PDAC between 2014–2020 were identified from our prospectively collected and maintained institutional database. Relationships between demographics, perioperative variables, chemotherapy and postoperative survival were explored. Results 131 patients were suitable for inclusion, of which 15 patients received neoadjuvant chemotherapy (12%). The most common reason for palliative procedure was local invasion (50%) and the most common palliative procedure was combined gastrojejunostomy and hepaticojejunostomy (55%). The NAT group were significantly younger (63 years vs. 70 years; p=0.012) but other demographic information was similar. There was no significant difference in overall survival between the NAT and no NAT groups (p=0.216). Significant independent predictors of 6-month survival were palliative chemotherapy (PC) (p&amp;lt;0.001) and locally advanced disease being the reason for unresectability (p=0.037), compared to liver or peritoneal metastases. PC was the only independent predictor of 12-month survival (p&amp;lt;0.001). Conclusions NAT does not appear to significantly influence survival after palliative procedure for PDAC; PC remains the main factor determining survival. Low patient numbers in the NAT group reduce the statistical power of the present study, so multicentre collaborative studies are required to further investigate this important question.

Survival impact of occult liver metastasis and peritoneal dissemination compared with radiologically defined distant organ metastasis in pancreatic ductal adenocarcinoma

BackgroundCharacteristics and prognoses of patients with occult metastases (OM) of pancreatic ductal adenocarcinoma (PDAC) compared with radiologically defined metastases (RM) have been rarely reported. ObjectiveWe aimed to clarify the prognosis of OM compared with RM and to establish a treatment strategy for PDAC patients with OM. MethodsThis single-institution, retrospective study evaluated patients with unresectable PDAC between 2008 and 2018. OM was defined as abdominal metastasis that was detected by staging laparoscopy or open laparotomy but not in the initial assessment of radiological images. ResultsOM and RM were identified in 135 and 112 patients, respectively. Eastern Cooperative Oncology Group Performance Status (ECOG PS), neutrophil to lymphocyte ratio (NLR), tumor diameter, and rate of local unresectability were significantly lower in the OM group. Median overall survival (OS) of OM was significantly better than that of RM (13.0 vs 8.9 months, p < 0.001). In multivariate analysis of OS, ECOG PS ≥ 1 (HR 1.64, p = 0.009), NLR ≥5 (HR 1.97, p = 0.004), carbohydrate antigen (CA) 19–9 ≥1000 (HR 1.68, p = 0.001), tumor diameter ≥40 mm (HR 1.40, p = 0.027), conversion surgery (HR 0.12, p < 0.001), and multiple lines of chemotherapy (HR 0.38, p < 0.001) were independent predictors. However, type of metastasis (OM vs RM) not an independent predictor (HR 1.10, p = 0.590). ConclusionThe prognosis of PDAC with OM was relatively better than that with RM, but general and nutritional statuses, primary tumor size and CA19-9, conversion surgery and multiple lines of chemotherapy were independent predictors but not tumor burden.

Routine Molecular Profiling in Both Resectable and Unresectable Pancreatic Adenocarcinoma: Relevance of Cytologic Samples

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease, for which it is crucial to promptly detect actionable and prognostic alterations to drive specific therapeutic decisions, regardless of tumor resectability status. Endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) is of key importance for PDAC diagnosis and can contribute significantly to tumor molecular profiling. Comprehensive genomic profile by targeted next-generation sequencing (NGS) was performed on 2 independent PDAC patient cohorts. Cohort 1 consisted of 77 patients with resectable PDAC for whom the histologic sample at the time of resection was available; for 56 patients cytologic specimens at the time of diagnosis also were obtained by EUS-FNA. Cohort 2 consisted of 20 patients with unresectable PDAC, for whom only the EUS-FNA cytologic sample was available. In cohort 1, a complete concordant mutational profile between the cytologic sample at diagnosis and the corresponding histologic specimen after surgery was observed in 88% of the cases, proving the ability to detect potential clinically relevant alterations in cytologic samples by NGS analysis. Notably, clinically actionable mutations were identified in 20% of patients. In cohort 2, comprehensive mutational profiling was obtained successfully for all samples. Consistent with the findings of cohort 1, KRAS, TP53, CDKN2A, and SMAD4 were the most altered genes. Most importantly, 15% of the patients harbored actionable mutations. Our findings show the feasibility of an NGS approach using both surgical specimens and cytologic samples. The model proposed in this study can be included successfully in the clinical setting for comprehensive molecular profiling of all PDAC patients irrespective of their surgical eligibility.

Prognostic value of circulating proteins in patients undergoing surgery for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death. Less than 20% of patients are diagnosed with resectable disease. Identifying truly resectable disease is challenging because 20%-40% of the patients subjected to resection are found to have advanced disease during surgery. The aim of our study was to identify panels of circulating proteins that could be used to distinguish patients with unresectable PDAC from patients with resectable PDAC and to identify prognostic signatures for both groups. We measured 92 circulating immuno-oncology-related proteins using the proximity extension assay from Olink Proteomics in 273 patients eligible for surgery for PDAC. Two bioinformaticians worked independently of one another on the same data. LASSO and Ridge regression were used in the statistical analyses. One protein index for determining resectability had an AUC value of 0.66. Several indices for prognosis had AUC values between 0.50 and 0.75 and were therefore not better than existing prognostic markers. Our study did not reveal any new high-performing protein panels that could be used to identify patients with inoperable PDAC before surgery. The panel of 92 proteins investigated has previously been found to be applicable for diagnostic use in patients with PDAC, but it does not seem to warrant further investigation regarding resectability in the subgroup of patients with PDAC referred to surgery.

Fine-needle biopsy with 19G needle is effective in combination with endoscopic ultrasound-guided tissue acquisition for genomic profiling of unresectable pancreatic cancer.

Comprehensive genomic profiling (CGP) has been approved in Japan since June 2019, enabling mutation-specific therapy. Although tissue sampling via endoscopic ultrasound-guided tissue acquisition (EUS-TA) is standard in pancreatic cancer, reports on obtaining appropriate samples for CGP, especially for the OncoGuide NCC Oncopanel System (NOP) and FoundationOne CDx (FOne), are lacking. Therefore, we investigated the success rate and factors related to appropriate EUS-TA sampling for CGP analysis suitability in unresectable pancreatic ductal adenocarcinoma (UR-PDAC). Participants comprised 150 UR-PDAC patients who underwent EUS-TA and tumor sample evaluation for CGP analysis suitability between June 2019 and December 2021. The proportion of patients meeting the criteria was evaluated considering tumor size, puncture lesion, presence of metastasis, type and size of puncture needle, suction method, number of punctures, and puncture route. In total, 39.2% (60/153) of samples met NOP analysis suitability criteria and 0% met FOne analysis suitability criteria. The suitability rate was significantly higher with 19G fine-needle biopsy (FNB) (56.0%; 42/75) than with 22G FNB (32.6%; 14/43) and 22G fine-needle aspiration (11.4%; 4/35). Nineteen-gauge needle (odds ratio [OR] 2.53; 95% confidence interval [CI] 1.15-5.57; P = 0.021) and FNB (OR 3.57; 95% CI 1.05-12.20; P = 0.041) were independent factors contributing to NOP analysis suitability. Among 30 patients who underwent actual NOP analysis, the analysis success rate was 100% (30/30). In sample collection via EUS-TA, 19G and FNB needles contribute to NOP analysis suitability.

Changes in intestinal bacteria and imbalances of metabolites induced in the intestines of pancreatic ductal adenocarcinoma patients in a Japanese population: a preliminary result

Background The relationship between pancreatic ductal adenocarcinoma (PDAC) and the intestinal environment is not fully understood. The purpose of this study was to elucidate the characteristics of the intestinal environment in PDAC. Methods We performed a case-control study of 5 Japanese patients with unresectable PDAC located in the body or tail (PDAC-bt). The number of patients analyzed was limited for this preliminary study. We included 68 healthy subjects, herein control, of pre-printed study in the preliminary study. 16S rRNA amplicon sequencing and metabolomic analysis were performed using fecal samples from the subjects. Results There was no difference in the Shannon index and Principal Coordinate Analysis between PDAC-bt and the control. However, a significant increase in oral-associated bacteria (Actinomyces, Streptococcus, Veillonella, Lactobacillus) was observed. A significant decrease of Anaerostipes was demonstrated in the feces of PDAC-bt compared with the control. The intestinal propionic acid and deoxycholic acid were significantly lower in PDAC-bt compared with the control. Conclusions We showed that the intestinal environment of PDAC-bt is characterized by an increase in oral-associated bacteria and an imbalance of metabolites but without changes in alpha and beta diversity of the gut microbiota profiles. Clinical Trial Registration: www.umin.ac.jp, UMIN 000041974, 000023675, 000023970.

Prognostic value of disseminated tumor cells in unresectable pancreatic ductal adenocarcinoma: a prospective observational study

BackgroundAlthough pancreatic ductal adenocarcinoma (PDAC) rarely metastasizes to the skeleton, disseminated tumor cells have been detected in bone marrow samples from patients with this disease. The prognostic value of such findings is currently unclear. Thus, the current study aimed to clarify the prognostic information associated with disseminated tumor cell detection in samples from patients with PDAC.MethodsBone marrow aspirates were obtained from 48 patients with locally advanced (n = 11) or metastatic (n = 37) PDAC, before and after 2 months of chemotherapy. Disseminated tumor cells were detected with an mRNA panel and quantitative reverse transcription PCR. We used the highest levels measured in healthy bone marrow (n = 30) as a threshold to define the positive detection of disseminated tumor cells. Progression-free and overall survival were analyzed with Kaplan–Meier and Cox proportional hazards regression analyses.ResultsDisseminated tumor cells were detected in 15/48 (31%) bone marrow samples obtained before starting chemotherapy and in 8/25 (32%) samples obtained during chemotherapy. Patients with disseminated tumor cells detected before therapy had significantly shorter progression-free (p = 0.03; HR = 2.0) and overall survival (p = 0.03; HR = 2.0), compared to those without disseminated tumor cells in the bone marrow. When restricting disseminated tumor cell detection to keratins KRT7 and KRT8, the prognostic information was substantially stronger (p = 1 × 10–6; HR = 22, and p = 2 × 10–5; HR = 7.7, respectively). The multivariable Cox regression analysis demonstrated that disseminated tumor cell detection prior to treatment had independent prognostic value. In contrast, disseminated tumor cells detected during treatment did not have prognostic value.ConclusionsDisseminated tumor cells detected before commencing chemotherapy had prognostic value in patients with inoperable PDAC.

A clinical study following phase I/IIa trial of STNM01 to investigate the overall survival and tumor microenvironment in patients with unresectable pancreatic cancer.

4144 Background: Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan biosynthetic enzyme and responsible for tumor matrix remodeling. We reported last year the top-line clinical results of Phase I/IIa (PI/IIa) trial of STNM01, a synthetic RNA oligonucleotide to CHST15, as a second-line (2L) therapy in patients with progressive, unresectable pancreatic ductal adenocarcinoma (PDAC). Here we report the final PI/IIa results and follow-up clinical results investigating the changes of tumor microenvironmental parameters and the correlation with overall survival (OS). Methods: An additional clinical study was followed by PI/IIa trial (jRCT2031190055), which was a multicenter, open-label study of locoregional injections with STNM01 three times at 2 week-interval in 4 weeks as one cycle. A total of 3 cycles were repeated at maximum in combination with systemic 2L chemotherapy, oral fluoropyrimidine S-1 in the PI/IIa trial. The primary objective of this additional clinical study was OS. The secondary objectives were relations of tumor microenvironmental parameters evaluated by immunohistochemistry with OS. For comparison analyses, two-tailed unpaired t-test was performed. For correlation analyses, the Pearson coefficient analyses were performed. Results: A total of 22 patients were enrolled in the study. The average number of tumor-infiltrating CD3+ (13.8/mm2) and CD8+ T cells (8.0/mm2) at baseline in the evaluable population (n = 20) was at most one tenth or less, compared to historical data, indicating 2L population contained more T cell-immune suppressive patients. Baseline CD3+ and CD8+ T cells negatively correlated with tumoral CHST15 expression (p = 0.0051, p = 0.0478, respectively). As the final PI/IIa results, the median OS was 7.8 months with 6 and 12 months-survival rates of 68.2% and 31.8%, respectively. Disease control rate was 76.2% including 1 complete response. STNM01 led to a significant reduction in CHST15 at the end of cycle 1 compared to baseline (p = 0.0095, n = 19), and this was associated with increased CD3+ (p = 0.0331) and CD8+ T cells (p = 0.0146) and reduced CD33+ myeloid-derived suppressor cells (MDSCs) (p = 0.0281) in the tumor. Patient subpopulation who survived over 1 year (n = 5) showed a significant fold increase of CD3+ (p = 0.0033) and CD8+ T cells (p = 0.0147) and decrease of CD33+ MDSCs (p = 0.0403) at the end of cycle 1 compared to another subpopulation who survived less than 1 year (n = 13-14). Higher fold increase of CD3+ T cells (p = 0.0035, n = 19) or fold decrease of CD33+ MDSCs (p = 0.0212, n = 15) at the end of cycle 1 significantly correlated with longer OS. Conclusions: Locoregional injection of STNM01 was able to reactivate and augment tumor-infiltrating T cells while repress MDSCs. These changes in tumor immune cell profiles correlate with prolong prognosis in patients with first-line refractory, unresectable PDAC. Clinical trial information: jRCT2031190055.

Homologous recombination deficiency (HRD) alterations as a predictor of responsiveness to combination pancreatic cancer in advanced pancreatic ductal adenocarcinoma (PDAC).

e16259 Background: Advanced PDAC is associated with a poor prognosis and median survivals of less than one year. FOLFIRINOX and Gemcitabine/Nab-Paclitaxel are both considered standard of care in the first line setting, though there is considerable variability among oncologists regarding sequencing of these regimens. Pre-clinical and clinical data support the use of platinum therapy in HRD+ PDAC, but little is known about how this translates into best practices regarding sequencing of treatment or clinical benefit relevant to Gemcitabine based therapies in this population. Methods: Using the cancer registry and Inova molecular tumor board database, we retrospectively reviewed all patients from January 2015 until November 2021 with unresectable PDAC who had NGS performed and stratified by the presence or absence of HRD mutation. HRD mutations included by BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, ARID1A, FANCA, FANCL. We analyzed for RR to Folfirinox/Folfox and Gemcitabine based therapies, adjusted time to progression on Folfirinox/Folfox (time from first dose of oxaliplatin based combination to first dose of gemcitabine to account for those who stopped oxaliplatin early for neuropathy or received maintenance therapy), and time on gemcitabine based therapy. Results: 142 consecutive patients with advanced PDAC were examined, including 20 with HRD variants. When excluding those who eventually received surgery and those who never received platinum therapy, we were left with 87 (74 in Control and 13 in HRD) for analysis. RR to Folfirinox/Folfox was 60% in HRD+ and 31.25% in control (p = 0.71) (Table). Mean adjusted time to progression on Folfirinox/Folfox was 320.0 days in HRD+ group and 252.9 in the control group (p = 0.57) (Table 2). The time on treatment for gemcitabine based combination therapy was 260.7 in HRD+ and 165.1 in control group. Conclusions: HRD+ patients had longer durations of treatment on both 5-FU based therapy and Gemcitabine based combinations. These data challenges the importance of first line platinum therapy in HRD+ patients, and further exploration should be considered.[Table: see text]

Phase 2 study of azacitidine (AZA) plus pembrolizumab (pembro) as second-line treatment in patients with advanced pancreatic ductal adenocarcinoma.

4158 Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death with a 5-year survival rate of 10%. Novel strategies for advanced PDAC are a critical need. A DNA hypomethylating agent (HMA) increased tumor-infiltrating effector T cells and significantly prolonged survival in combination with immune checkpoint blockade (ICB) in a PDAC mouse model (Gonda et al 2020). We hypothesized that combining HMA with ICB will lead to therapeutic benefit in pts with advanced PDAC. Methods: This is an open-label, single-arm, single-center, Phase 2 trial of AZA plus pembro in pts with unresectable or metastatic PDAC. Pts were treated with AZA 50 mg/m2 subcutaneous daily for 5 days Q4W beginning week 1 day 1 followed by pembro 200 mg IV Q3W starting week 3 day 1. Key eligibility criteria included documented progression on or following first-line systemic treatment, ECOG PS 0-1, and adequate organ function. The primary objective was progression-free survival (PFS). Thirty-one evaluable pts were required to detect an improvement in PFS from 2 mo to 4 mo with a one-sided p-value of 0.05 and 80% power. Secondary endpoints included safety and tolerability, overall response rate (ORR), disease control rate (DCR), and overall survival (OS). Data cutoff was February 10, 2022. Results: Between Oct 2017 and Sept 2021, 36 pts were enrolled (median age 62.5, 75% white, 72% male). At data cutoff, 34 and 31 pts received at least 1 dose of AZA and pembro, respectively. Median PFS for ≥1 dose of AZA was 1.48 mo (95% CI: 1.35, 1.74) and for ≥1 dose of pembro was 1.51 mo (95% CI, 1.38, 3.42). The median OS was 4.67 months. Among the 34 pts, 3 (8.8%) experienced a partial response (PR) by RECIST with a DCR of 32.4%. Of the 3 pts with PR, 2 received 35 doses of pembro and continued beyond 2 years with an ongoing PR. One pt remains on pembro 20 months after study completion. None of the pts with a PR were microsatellite instability-high or tumor mutation burden high, and next-generation sequencing of the 3 cancers identified a BRCA1 variant and POLE variant. Treatment-related AEs (TRAEs) occurred in 20/34 pts (59%), the most common of which were diarrhea and fatigue. Grade ≥3 occurred in 7/34 (21%) including 1 immune-related grade 5 event (encephalitis). Conclusions: AZA plus pembro demonstrated a tolerable safety profile but no PFS benefit compared to historical controls. Our data suggests combined epigenetic therapy and ICB may expand therapeutic options in a subset of pts with PDAC. Further investigation is needed to identify biomarkers to predict response and elucidate effective timing, sequencing, and combination of epigenetic agents. Follow-up for OS is ongoing. Correlative analysis of epigenetic effects and characterization of the tumor immune microenvironment will be reported. Clinical trial information: NCT03264404.

A phase I/II study of LOAd703, a TMZ-CD40L/4-1BBL-armed oncolytic adenovirus, combined with nab-paclitaxel and gemcitabine in advanced pancreatic cancer.

4138 Background: Due to its low tumor immunogenicity and immunosuppressive microenvironment, pancreatic ductal adenocarcinoma (PDAC) remains an immunotherapeutic challenge. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, has been shown to lyse tumor cells selectively, induce anti-tumor cytotoxic T-cell responses, reduce myeloid-derived suppressor cell (MDSC) infiltration, and induce tumor regression in preclinical studies. Methods: In this phase I/II trial, patients with unresectable or metastatic PDAC were treated with intratumoral injections of LOAd703 and standard intravenous nab-paclitaxel/gemcitabine (nPG) chemotherapy. Starting on cycle 1 day 15 of nPG, LOAd703 was injected with image guidance into the primary pancreatic tumor or a metastasis every 2 weeks for 6 injections. In the event of sustained tumor control, subjects were eligible to receive up to 6 more injections. Three dose levels of LOAd703 were investigated using a BOIN dose escalation design. Primary endpoints were safety and feasibility. Results: Of the 22 subjects enrolled, 21 received at least 1 LOAd703 injection, and 18 received at least 3 LOAd703 injections (the a priori definitions of evaluability for dose limiting toxicity [DLT] and efficacy, respectively). Of the 21 subjects injected, median age was 61, 81% had stage IV disease, and 57% had already received chemotherapy for advanced disease. Median CA 19-9 was 1494. Of the 18 response evaluable subjects, 3 were treated at dose level 1 (5x10e10 VP), 4 at dose level 2 (1x10e11 VP), and 11 at dose level 3 (5x10e11 VP). The most common adverse events (AEs) attributable to LOAd703 were fever, chills, nausea, and increased liver enzymes. AEs were short-lived and grade 1/2, except for a grade 3 transaminase elevation in one subject receiving dose level 3 (the only DLT). Objective response rate (ORR) among those treated at the highest dose level was 55% (5/11 subjects), thus meeting the predefined criterion for efficacy. Among all response evaluable patients, overall response rate (ORR) was 44%, and disease control rate (DCR) was 94%. CA 19-9 decreased by ≥50% in 61% of evaluable patients. Median overall survival (OS) among the 21 subjects receiving at least 1 LOAd703 injection was 8.7 months. The proportion of T effector memory cells increased after initiation of on-protocol treatment (p = 0.0232) while the proportion of T regulatory cells and myeloid-derived suppressor cells decreased (p = 0.0410, p = 0.0256, respectively). Conclusions: Combining intratumoral injections of LOAd703 with standard nPG chemotherapy was safe and feasible. The target response rate at the highest dose level was met, and treatment-emergent immune responses were observed. A follow-up clinical trial combining LOAd703, nPG, and the anti-PDL-1 inhibitor atezolizumab is underway. Clinical trial information: NCT02705196.

SO-30 Impact of single-heterozygous UGT1A1 on the clinical outcomes of nano-liposomal irinotecan plus 5-fluorouracil/leucovorin for patients with pancreatic ductal adenocarcinoma

Nanoliposomal irinotecan plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) is one of the standard treatments for patients with gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (PDAC). We have previously reported the real-world clinical data of nal-IRI+5-FU/LV in Japanese patients with PDAC (HGCSG2101). Herein we compared the efficacy and safety of nal-IRI+5-FU/LV by UGT1A1 status, wild type (WT) versus single heterozygous (SH), among the patients enrolled in the HGCSG2101. We retrospectively analyzed patients who received nal-IRI+5-FU/LV for unresectable PDAC at 10 institutions between June and December 2020. Data cutoff for this analysis was 30 June 2021. The median overall survival (OS), progression free survival (PFS) with each 95% confidence interval (CI) were estimated by the Kaplan-Meier method. Differences in the efficacy between each group were tested by means of the Log-rank test. The Cox regression analysis was used to estimate hazard ratios (HRs) of SH compared with WT with 95 % CIs. Tumor response was assessed by RECIST ver. 1.1. Adverse events were evaluated according to CTCAE ver. 5.0. Qualitative and quantitative variables were compared using the chi-square test or Fisher’s test and using a nonparametric (Wilcoxon) test, respectively. A total of 48 patients were evaluated (26 and 22 patients with UGT1A1 WT and SH, respectively). The number of patients who had their initial dose of nal-IRI reduced for any reason was 6 (23.1%) in the WT group and 10 (45.5%) in the SH group, respectively (p=0.20). The median relative dose intensity of nal-IRI was 0.79 (range, 0.43-0.99) in WT group and 0.69 (range, 0.55-0.96) in SH group, respectively (p=0.18). The median PFS was 2.8 months (95%CI: 1.9-6.9) in WT group and 2.4 months (95%CI: 1.9-6.0) in SH group, respectively (HR: 1.2, 95%CI: 0.6–2.1, p=0.63). The median OS was 6.6 months (95%CI: 4.7-11.3) in WT group and 6.8 months (95%CI: 4.3-9.4) in SH group (HR: 1.1, 95% CI: 0.5–2.1, p=0.90), respectively. The response rate was 8.0％ (95%CI: 1.7-26.1) in WT group and 16.7％ (95%CI: 5.0-40.1) in SH group (p= 0.63), respectively. Though there were no significant differences in safety between WT and SH groups, ≥grade3 neutropenia and febrile neutropenia were observed more frequently in SH group (≥grade3 neutropenia: 30.8% vs 50.0%, p=0.24, febrile neutropenia: 0.0% vs 9.1%, p=0.20, respectively). No treatment-related death was observed in each group. There was no significant difference in the treatment outcome of nal-IRI+5-FU/LV between UGT1A1 WT and SH groups. However, ≥grade3 neutropenia and febrile neutropenia tended to be more frequent in SH group despite the fact that more patients had reduced the initial dose of nal-IRI in SH group. Further analysis is needed to investigate the impact of the UGT1A1 status on the treatment outcome of nal-IRI+5-FU/LV for patients with PDAC.

Class III β-Tubulin Expression Is of Value in Selecting nab -Paclitaxel and Gemcitabine as First-Line Therapy in Unresectable Pancreatic Cancer.

Nab -paclitaxel and gemcitabine (GnP) or FOLFIRINOX (a combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin [FFX]) is currently recognized as the standard first-line regimen for unresectable pancreatic ductal adenocarcinoma (PDAC). Class III β-tubulin (TUBB3) has the potential to predict resistance to taxane in various tumors; therefore, this study aimed to clarify whether TUBB3 is a predictive marker for GnP response. We retrospectively reviewed 113 patients with PDAC who received GnP or FFX as first-line chemotherapy and examined immunohistochemically the TUBB3 expression in specimens obtained by endoscopic ultrasound-guided fine-needle aspiration. High TUBB3 expression was associated with a significantly lower disease control rate ( P = 0.017) and shorter progression-free survival (PFS) ( P = 0.019), and multivariate analysis revealed that TUBB3 expression was an independent variable for PFS in the GnP first-line group ( P = 0.045). In addition, in the FFX first-line group, TUBB3 expression was not correlated with PFS or overall survival (OS). In all 113 patients, TUBB3 expression was not also associated with OS. Class III β-tubulin might be a predictive factor for the response of GnP, but not a prognostic factor for OS, helping the selection of an optimized first-line chemotherapy regimen for unresectable PDAC.