Metastatic Pancreatic Carcinoma Research Articles

P133 Anti-synthetase syndrome: an experience from a tertiary referral center

Abstract Background/Aims Anti-synthetase syndrome (ASS) is a subset of Idiopathic inflammatory myositis (IIMs). It is a syndromic diagnosis classified by Connors et al. and Solomon et al. criteria. Raynaud’s phenomenon (RP), fever, arthritis, mechanics hands, ILD and myositis constitute this syndrome along with the classical Anti-aminoacyl tRNA synthetase antibodies (ARS). About 25% of IIMs patients are classified as ASS. This study was planned to evaluate the prevalence of ASS; their phenotype, antibody subtypes, treatment responsiveness and outcomes. Methods All consecutive ASS patients were enrolled in the study fulfilling Connors et al. criteria during January, 2016 to August2023. Their demographic details, clinical features, laboratory and imaging features, treatment were analyzed. ARS were considered positive on a Line Immunoassay with cutoff >6U/ML using BlueDriverQuantrix-ANA25 Screen IgG kit (includes Jo1, Pl-7, Pl-12) from D-tek, Belgium including three ASS antibodies (Jo-1, PL-12, PL-7). Anti EJ, OJ antibodies were not present in the kit. Descriptive analysis were used to describe disease characteristics. Results Among 139 total IIM patients, 21(15%) patients were diagnosed with ASS. All patients fulfilled Connors et al. criteria while 66.6% patients fulfilled stricter criteria by Solomon et al. Mean(±SD) age group was 43(±16.4) years. 71.4% were Females. Anti Jo-1 was the predominant antibody seen in 66.6% while Anti PL-12 and Anti Pl-7 antibodies were present in 19% and 14.3% respectively. 66.6% had ANA positivity and MAA antibodies were seen in 52.3%. Rash was seen in 61.9%, mechanics hands in 38%, RP in 52.3% fever in 38% ,arthritis in 57%, myositis 62% and ILD in 80.9%. NSIP (66.6%) was the predominant type, followed by OP (9.5%) and UIP (4.7%). Median (IQR) CPK level was 736 (210-4556)U/L. Anti Jo-1 patients had higher prevalence of mechanics hands and rash whereas ILD was observed in all cases of Anti PL-7 and Anti PL-12 antibodies. Malignancy was seen in two patients (Malignant fibrous histiocytoma, Metastatic Pancreatic carcinoma). Mean (SD) MMT8 score was 62.8(±22.2) at presentation . Treatment is with steroids in all cases followed by maintenance with azathioprine in 57.1%, Methotrexate in 14.2%. Rituximab was used in 14.2%, cyclophosphamide in 9.5% and mycophenolate mofetil in 23.8%. Mortality was seen in one patient with respiratory failure. Lung involvement was severe in patients with both MSA and MAA positivity. 62% patients were in remission. Conclusion ILD and Arthritis were the main presenting complaints in our cohort. Myositis is relatively less prevalent in ASS. NSIP was the predominant ILD subtype. Non Jo-1 group had high MAA positivity. Jo-1 was associated with mechanic’s hands and rash. Malignancy was less prevalent in ASS. All patients with PL-7 and PL-12 antibodies had lung involvement. Biologics were required in few refractory cases. Disclosure P. Khatri: None. J.R. Yadavalli: None. S. Dhuria: None. N. Negalur: None. K. Shivam: None. R. Gupta: None.

Abstract CT218: Phase II open label trial of Minnelide™ in patients with chemotherapy refractory metastatic pancreatic cancer

Abstract Background: Triptolide and its water-soluble prodrug, Minnelide™, have shown promising activity against pancreatic ductal adenocarcinoma (PDAC) in both in vitro and in vivo experiments. Triptolide induces apoptosis in pancreatic cancer cells by different pathways, including caspase-dependent apoptotic death and caspase -independent autophagic death. It inhibits the activity of the TFIIH general transcription factor complex and modulates the transcriptional landscape of both the stroma and cancer cell compartments. In the epithelial tumour compartment, triptolide down-regulates key transcription factors such as c-MYC. Preclinical investigations indicate significant activity against super enhancer targets. In the phase I clinical trial of Minnelide™ activity in highly refractory metastatic pancreatic carcinoma was observed. Hence, we undertook this study in patients with chemotherapy refractory metastatic PDAC. Our aims were to determine clinical anticancer effects, and to define effects of the drug on super enhancer expression and downstream effects. Methods: Eligibility criteria included stage IV PDAC progressing on standard chemotherapy, Karnofsky performance status ≥ 70%, and measurable disease by RECIST 1.1. Planned sample size was up to 35 patients with interim analysis after the first 18 evaluable patients, aiming for at least a 20% difference in DCR (10% v 30%). Minnelide™ 0.67 mg/m2 was administered intravenously over 30 minutes on days 1-21, followed by a 7-day rest period in a 28-day cycle. Exploratory objectives included: analyses of paired tumour biopsies for changes in immune cell infiltration, stromal activation, chromatin accessibility, proteomics and metabolism. Results: 17 patients were treated. There were no RECIST responses or stable disease. However, evidence of activity was observed in 4 of 15 evaluable patients. This activity included progression after 117 days treatment in 1 patient and reductions in CT tumour size or FDG-PET uptake and/or significant decreases in circulating CA19.9 levels in 3 others. Minnelide was generally well tolerated. Treatment related toxicities > 3 were: neutropenia 4 patients and cerebellar ataxia 1 patient.Exploratory analyses included ATAC-Seq on paired biopsies where gene ontology analyses showed downregulation of genes negatively regulating cell cycle and upregulation of genes controlling cell cycle checkpoints. Other exploratory analyses will be presented. Conclusions: The study identified a tolerable drug dose and evidence of activity in a highly chemotherapy-refractory population which provides encouraging proof for the principle of targeting TFIIH in human PDAC. Supported by SU2C, Cancer Research UK, Lustgarten Foundation Citation Format: David Propper, Erkut Borazanci, Peter J. O'Dwyer, Daniel Von Hoff, Joseph Hartlebury, Corina E. Antal, Gerard I. Evan, HaiYong Han, Michael Downes, Ronald Evans, Joshua Rabinowitz, Emmanuel Petricoin, Ashok Saluja, Mohana Velagapudi, Hitendra Patel. Phase II open label trial of Minnelide™ in patients with chemotherapy refractory metastatic pancreatic cancer [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 CT218.

A comprehensive analysis of GATA3 expression in carcinomas of various origins with emphasis on lung carcinomas.

GATA3 is a transcription factor involved in embryogenesis of multiple human tissues and in maintaining cell differentiation and tissue homeostasis in the adult organism. GATA3 is also involved in carcinogenesis and regarded as a sensitive marker for urothelial and breast carcinomas, albeit expression in carcinomas of non-breast/urothelial origin has been frequently reported. We sought to examine the extent and intensity of GATA3 expression in various carcinomas, mainly lung, urothelial, and breast and various other primary sites. Patients with breast carcinoma (N=40), carcinoma of the urinary bladder/renal pelvis (N=40), lung carcinoma (N=110) and various other origins (N=45) were included in the study. One hundred and sixty-five patients had a primary tumor diagnosis, and 70 cases had a metastatic tumor diagnosis. Our results showed that GATA3 expression was significantly more common in carcinomas of the breast, urinary bladder and renal pelvis compared to all other origins. All primary and 93% of metastatic urinary bladder carcinomas and 94% of the primary and 80% of metastatic breast carcinomas expressed GATA3. Expression was lower in non-urothelial histology of urinary primaries and in triple negative breast carcinomas. Focal staining, mostly faint, was seen in 5.6% of the primary lung adenocarcinomas and 35% of the primary lung squamous cell carcinomas. More extensive and intense staining was seen in 3.7% of the primary lung adenocarcinomas and 12% of the primary lung squamous cell carcinomas. Expression, mostly focal was also seen in 30% of the metastatic lung carcinomas. Finally, high expression was seen in 12.5% of the other tumors (one metastatic pancreatic carcinoma, one metastatic salivary gland adenocarcinoma NOS, one metastatic squamous cell carcinoma of the skin, one primary uterine cervix serous carcinoma, and one squamous cell carcinoma of the head and neck) and focal expression was present in another 22% of them. No ideal cut-off for positivity for GATA3 staining could be identified. In conclusion our study shows that GATA3 staining has two caveats in its use: the first is that non classical histologies of urothelial carcinomas and TNBC may be negative for the marker and secondly carcinomas of various origins may show (although rarely) intense positivity.

P-53 Prognostic factors in metastatic pancreatic carcinoma: A multivariate analysis and predictive score of survival

P-53 Prognostic factors in metastatic pancreatic carcinoma: A multivariate analysis and predictive score of survival

Metastatic pancreatic carcinoma – the diagnosis was on the skin

A 82-year-old woman was admitted to the emergency room with dyspnea. On examination she had SaTO2 of 93% with FiO2 of 28%, crackles in the base of both lungs

Abstract 4165: A systemically administered killed bacteria-based multiple immune receptor agonist for pulsed anti-tumor immunotherapy

Abstract Systemic activation of multiple immune receptors, such as Toll-like (TLR), NOD-like (NLR) and Stimulator of Interferon Genes (STING) is essential for efficient innate and adaptive immune responses. Attempts to use single receptor agonists for advanced cancers have not produced approved products. Limitations include insufficient immune activation and dose-limiting toxicities associated with continuous exposure. Gram-negative bacteria (G-NB) contain multiple TLR, NOD and STING agonists. Potential utility of G-NB for cancer immunotherapy is supported by observation of tumor regression in the setting of infection and Coley’s Toxins. Coley reported that i.v. administration was likely most effective but produced toxicity. The discovery of TLRs, particularly the broad/potent activities of the TLR4 agonist lipopolysaccharide (LPS) suggest that it may be both a critical active ingredient and a dose-limiting feature of i.v. G-NB. Non-pathogenic E. coli were treated with polymyxin to achieve ~90% reduction of LPS activity without lysis and were then killed and stabilized with glutaraldehyde. The resulting product, Decoy10, was shown to contain multiple TLR, NOD and STING agonists and exhibited reduced i.v. toxicity (mice, rabbits) relative to unprocessed cells. Surprisingly, despite reduction in LPS activity and toxicity, Decoy10 induced secretion of similar or higher levels of most cytokines/chemokines by peripheral blood mononuclear cells, compared to unprocessed bacteria. Higher cytokine/chemokine induction was also observed compared to monospecific TLR agonists. Administration of 4 to 8 weekly or twice a week i.v. doses of Decoy10 to mice with established s.c., orthotopic or metastatic syngeneic breast, colorectal, hepatocellular, pancreatic carcinomas or syngeneic or human non-Hodgkin’s lymphoma was well-tolerated and produced single agent anti-tumor activity and/or combination-mediated durable tumor regressions, with induction of immunological memory. Regressions were observed, without significantly increased toxicity, when Decoy10 was combined with chemotherapy, a non-steroidal anti-inflammatory drug, anti-PD-1 therapy or rituximab. Tumor regressions were associated with activation of innate and adaptive immune pathways in tumors after one dose of Decoy10 and were mediated by NK, CD4+ and CD8+ T cells. Published studies have demonstrated that systemic bacteria are engulfed by and activate immune cells in the liver and spleen, with rapid clearance in mice, rabbits, and humans. Systemic bacteria have also been shown to accumulate in or around tumors. We have taken advantage of these phenomena to produce a detoxified but potent multiple immune agonist that induces systemic innate and adaptive anti-tumor immune activation without requirement for continuous systemic exposure. A Decoy product has been cleared by the US FDA for a Phase 1 oncology trial. Citation Format: Michael J. Newman. A systemically administered killed bacteria-based multiple immune receptor agonist for pulsed anti-tumor immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4165.

Impact of Sarcopenia on Survival in Patients Treated with FOLFIRINOX in a First-Line Setting for Metastatic Pancreatic Carcinoma.

Sarcopenia, defined as decreased muscle mass and strength, can be evaluated by a computed tomography (CT) examination and might be associated with reduced survival in patients with carcinoma. The prognosis of patients with metastatic pancreatic carcinoma is poor. The FOLFIRINOX (a combination of 5-fluorouracil, irinotecan, and oxaliplatin) chemotherapy regimen is a validated first-line treatment option. We investigated the impact of sarcopenia on overall survival (OS) and progression-free survival (PFS) in patients with metastatic pancreatic carcinoma. Clinical data and CT examinations of patients treated with FOLFIRINOX were retrospectively reviewed. Sarcopenia was estimated using baseline CT examinations. Seventy-five patients were included. Forty-three (57.3%) were classified as sarcopenic. The median OS of non-sarcopenic and sarcopenic patients were 15.6 and 14.1 months, respectively (p = 0.36). The median PFS was 10.3 in non-sarcopenic patients and 9.3 in sarcopenic patients (p = 0.83). No differences in toxicity of FOLFIRINOX were observed. There was a trend towards a higher probability of short-term death (within 4 months of diagnosis) in sarcopenic patients. In this study, the detection of sarcopenia failed to predict a longer OS or PFS in selected patients deemed eligible by a physician for triplet chemotherapy and receiving the FOLFIRINOX regimen in a first-line setting, confirming the major importance of a comprehensive patient assessment by physicians in selecting the best treatment option.

CNSC-03. NEURONAL INTERMEDIATE FILAMENT (NIF) ANTIBODY POSITIVE PARANEOPLASTIC SYNDROME IN A PATIENT WITH METASTATIC NEUROENDOCRINE PANCREATIC CARCINOMA AND TREATMENT WITH IPILIMUMAB/NIVOLUMAB

Abstract Immune checkpoint inhibitors, such as ipilimumab (CTL-4) and nivolumab (PD-1) have shown effectiveness in many types of neoplasia. This combination has been used as salvage immunotherapy for high grade metastatic pancreatic carcinoma. Nevertheless, severe neurologic immune-mediated adverse effects can result from the use of this treatment. We present a case of a 64-year-old woman with metastatic neuroendocrine pancreatic carcinoma with abrupt left facial and oculomotor cranial nerve palsy as well spastic tetraplegia after one dose of ipilimumab/nivolumab. She had a history of sudden onset diplopia, fever and ground-level fall a few hours after her initial dose of immunotherapy. Initial laboratory assessment showed pronounced lymphocyte predominant leukocytosis and mild chronic hyponatremia. In the following hours, she developed right mydriasis, right sided fast phase nystagmus and right central facial paralysis along with weakness and spasticity in four extremities. Neuroimaging of brain, orbits and CTL spine showed enhancement of intra-orbital and intracranial optic nerves as well chiasm, linear enhancement from C4-C7 and cauda equina, as well as abnormal signal along thoracic spinal cord and conus medullaris. Routine EEG demonstrated non-etiology specific encephalopathy. Lumbar puncture had normal opening pressure, mild pleocytosis, hyper-proteinorrhachia and normal glucose. Viral panel and cytology in the CSF were negative, and myeline basic protein was elevated. She was treated with high dose steroids which improved overall strength and CN palsies. Twenty days after initial presentation, she suddenly developed hypotension, tachypnea, and altered cognition. The patient and family opted for comfort measures only. She passed away that same day. Late report of CSF antibody panels showed positive cell-based assay for heavy and light chain NIF with a titer of 1:512. This case emphasizes the importance of recognition of anti-body mediated paraneoplastic syndromes in patients treated with immunotherapy, their appropriate treatment and prognosis.

Effects of 6-Aminonicotinic Acid Esters on the Reprogrammed Epigenetic State of Distant Metastatic Pancreatic Carcinoma.

In the search for alternatives to 6-aminonicotinamide (6AN), a series of 6-aminonicotinic acid esters were designed and synthesized as precursors of 6-amino-NADP+, a potent inhibitor of 6-phosphogluconate dehydrogenase (6PGD). Like 6AN, some of these esters were found to reverse the loss of histone 3 lysine 9 trimethylation (H3K9me3) in patient-derived pancreatic ductal adenocarcinoma (PDAC) distant metastasis (A38-5). Among them, 1-(((cyclohexyloxy)carbonyl)oxy)ethyl 6-aminonicotinate (5i) showed more potent antiproliferative activity than 6AN. Metabolite analysis revealed that compound 5i produced a marked increase in metabolites upstream of 6PGD, indicating intracellular inhibition of 6PGD by 6-amino-NADP+ derived from compound 5i through 6-aminonicotinic acid (6ANA) via the Preiss-Handler pathway. Despite the more potent pharmacological effects shown by compound 5i in A38-5, compound 5i was found to be substantially less toxic to primary hippocampal rat neurons compared to 6AN, indicating its therapeutic potential in targeting distant metastatic cells.

S3115 Pancreatic Cancer Without Pancreatic Lesion: Pancreatic Acinar Cell Carcinoma (PACC) Presenting as Isolated Hepatic Lesion Without Primary Organ Involvement

Introduction: Pancreatic cancer are diagnosed in advanced stages and by that time the treatment options are often limited. We report a rare case, showing metastatic pancreatic acinar cell carcinoma (PACC) in the liver without any evidence of primary lesion in the pancreas based on imaging studies. Case Description/Methods: A 78-year-old male with a past medical history of prostate cancer, pancreatic insufficiency due to recurrent pancreatitis and irritable bowel syndrome was seen in gastroenterology clinic for epigastric pain. Patient’s family history was significant for prostate cancer and social history was pertinent for alcohol abuse in the past. He underwent endoscopic evaluation with EGD and colonoscopy, both of which were unremarkable. Thereafter, MRI abdomen with contrast revealed a 6 cm right hepatic lobe lesion concerning for malignancy along with multiple cysts approximately 15 mm in size, and no other lesion was identified in the abdomen. Lab work was also unremarkable (see Table 1). Subsequently he underwent IR guided liver biopsy of the mass. The final histopathological diagnosis of the biopsy was acinar cell carcinoma of pancreatic origin and likely metastatic lesion. Looking back at the MRI abdomen there were no findings to suggest of pancreatic lesion, consequently he underwent EUS which showed normal esophagus, stomach and duodenum, the pancreatic parenchyma was consistent with fatty infiltration however no cyst, pseudocyst or mass was identified through the entire pancreas. At this point, patient already followed with medical oncology and was started on systemic pancreatic regimen therapy. He tolerated chemotherapy well and repeat CT scans in subsequent months showed overall stable disease (Figure 1). Discussion: Hepatologists routinely come across liver lesions suspicious for malignancy. Liver is the second most common site of metastasis after lymphatic system. Pancreatic acinar cell carcinomas (PACC) are rare, accounting for 1-2% of adult pancreatic tumors. On MRI, PACC appear as large, oval mass with moderate and heterogenous enhancement after intravenous contrast. Our case is one of its kind due to the detection of significantly sized pancreatic acinar cell tumor in the liver prior to it being detectable in the pancreas itself (see Figure-1 for imaging details). This case highlights the importance of prompt diagnosis and management especially in challenging cases which present with discordance between histopathological and imaging studies.Figure 1.: A, Post-contrast T1-weighted MRI; images showing predominantly peripheral enhancement of segment 6/7 hepatic lesion (red arrows). B, Pre-contrast T1-weighted MRI; images showing predominantly peripheral enhancement of segment 6/7 hepatic lesion (red arrows). C, Post-contrast T1-weighted MRI; Left image marks pancreatic body and tail, Right image marks the uncinate/head, does not show any lesion or mass in pancreas. Table 1. - Diagnostic Lab work up Lab Values/Reference Range &Units Patient Result WBC 4.50-13.50 K/uL 7.06 Hemoglobin 13.0-16.0 g/dL 13.8 Platelets 150-450 K/uL 231 Albumin 3.2-4.7 g/dL 3.3 INR 0.8-1.2 1.1 Total Bilirubin 0.1-1.0 mg/dL 0.9 Alkaline Phosphatase 89-365 U/L 98 AST 10-40 U/L 22 ALT 10-44 U/L 15 Cancer Antigen 19-9 0.0-40.0 U/Ml 13.3 CEA 0.0-5.0 ng/mL 1.7 AFP 0.0-8.4 ng/mL < 2.0 PSA, Screening 0.00-4.00 ng/mL < 0.01

Efficacy of chemotherapy for patients with metastatic or recurrent pancreatic adenosquamous carcinoma: A multicenter retrospective analysis

Background/objectivesPancreatic adenosquamous carcinoma (PASC) is a rare variant of pancreatic ductal adenocarcinoma (PDAC). The usual treatment for metastatic or recurrent PASC is systemic chemotherapy in accordance with the PDAC treatment strategy. This study aimed to investigate the efficacy of chemotherapy, especially the benefit of recent combination therapies, in patients with metastatic or recurrent PASC. MethodsWe conducted a multicenter retrospective analysis of 116 patients with metastatic or recurrent PASC treated with first-line chemotherapy between April 2001 and December 2017 at 24 Japanese institutions. ResultsCombination chemotherapies included gemcitabine + nab-paclitaxel (GnP, n = 28), fluorouracil/leucovorin + irinotecan + oxaliplatin (FFX, n = 10), gemcitabine + S-1 (GS, n = 10), and others (n = 9). Monotherapies included gemcitabine (n = 51) and S-1 (n = 8). The median overall survival (OS) was 6.5, 7.3, and 4.3 months for the whole cohort, the combination therapy group, and the monotherapy group, respectively. Multivariate analysis indicated that combination therapy showed a better trend in OS than monotherapy (hazard ratio = 0.68; 95% confidence interval, 0.38–1.20). GnP or FFX were selected in 58.7% of patients after FFX was approved in Japan, and revealed a median OS, median progression-free survival, and objective response rate of 7.3 months, 2.8 months, and 26.9% in GnP and 7.2 months, 2.3 months, and 20.0% in FFX respectively. ConclusionsThis study suggests that combination therapy may be more effective than monotherapy. GnP and FFX showed similar and clinically meaningful efficacy for patients with metastatic or recurrent PASC.

1296MO PRODIGE 29-UCGI 26(NEOPAN): A phase III randomised trial comparing chemotherapy with folfirinox or gemcitabine in locally advanced pancreatic carcinoma (LAPC)

Pancreatic carcinoma (PC) is an aggressive malignancy and the 4th cause of all cancer deaths worldwide. More than 30% of patients with PC are unresectable because of the local extension with a median overall survival (OS) of less than one year. Folfirinox (FFX) is superior to gemcitabine in the treatment of metastatic PC, in terms of OS and progression-free survival (PFS) but standard of care remains gemcitabine (gem) for LAPC.

The application of the Glasgow prognostic score to predict the survival in patients with metastatic pancreatic carcinoma.

Thither is a more pressing effort to think about chemotherapy (CTx) in second-line and beyond in patients with metastatic pancreatic cancer (mPC). The current work aimed to evaluate the value of the Glasgow prognostic score (GPS) and modified Glasgow prognostic score (mGPS) to predict the survival in patients receiving second-line CTx protocol. We retrospectively reviewed the patients' medical files with mPC who received second-line CTx protocol between September 2013 and December 2017. The GPS/mGPS graded from 0 to 2 based on C-reactive protein and serum albumin. One hundred and sixty-nine patients with mPC were eligible. Survival of patients with Score 0 (GPS/mGPS) was better than that of Score 1 (GPS/mGPS) or Score 2 (GPS/mGPS), which was statistically significant (P < 0.001). Of 78 patients who died, only 16 patients belonged to Score 0 (GPS/mGPS), compared to 30 patients belonged to Score 1 (GPS/mGPS) and 32 patients belonged to Score 2 (GPS/mGPS). Univariate analysis showed that high GPS/mGPS (P < 0.000) as well as poor Eastern Cooperative Oncology Group Performance Status (P < 0.000) and metastasis either to the liver (P < 0.01) or lung (P < 0.04) were linked with worse prognosis. A statistically significant association was detected between the two scores. Cohen's Kappa coefficient (k) was 0.9, SD = 0.03; 95% CI (0.787-0.922; P < 0.001). Our data suggested that GPS/mGPS is an easy and applicable index that may be used in daily practice and may help in the prognostic stratification of mPC patients to avert overtreatment in frail patients and raise the best supportive treatment concept.

A first-in-human phase I dose-escalation trial of the B7-H6/CD3 T-cell engager BI 765049 ± ezabenlimab (BI 754091) in patients with advanced solid tumors expressing B7-H6.

TPS3175 Background: B7-H6 is a member of the B7 family of immune receptors, which is expressed in several solid tumors, but with little to no expression detected in normal tissues[Brandt et al. J Exp Med 2009;206.1495–503; Boehringer Ingelheim. Data on file]. BI 765049 is a novel IgG-like bispecific T-cell engager (TcE) designed to bind simultaneously to B7-H6 on tumor cells and CD3 on T cells, resulting in cytolytic synapse formation and tumor lysis. Preclinical studies have demonstrated that BI 765049 monotherapy induced dose-dependent antitumor activity in humanized in vivo CRC tumor models. Consistent with the mode of action, treatment with BI 765049 led to profound infiltration of T cells into the tumor tissue, which correlated with apoptosis and tumor shrinkage. The inflammatory tumor microenvironment created by treatment with the B7-H6/CD3 TcE also led to an increase of PD-1 on T cells and PD-L1 on the tumor cells [Hipp et al. AACR Annual Meeting 2021]. This upregulation of PD-(L)1 provides the rationale for combining BI 765049 with a PD1 inhibitor. Methods: NCT04752215 is a first-in-human, open-label, dose-escalation trial of BI 765049 ± the PD-1 inhibitor, ezabenlimab. Adults with advanced, unresectable and/or metastatic CRC, NSCLC, HNSCC, hepatocellular, gastric or pancreatic carcinoma are eligible. Patients must have progressed on, or be ineligible for, standard therapies. B7-H6 positivity must be confirmed at screening by central review (immunohistochemistry assay) in archived tissues/fresh biopsies (except CRC). Patients must have ≥1 evaluable lesion (modified RECIST 1.1) outside of the central nervous system and adequate organ function. The primary objective is to determine the maximum tolerated dose (MTD) or recommended dose for expansion of BI 765049 ± ezabenlimab, based on dose-limiting toxicities during the MTD evaluation period. Further objectives are to evaluate safety, tolerability, PK/PD, and preliminary efficacy of BI 765049 ± ezabenlimab. The trial will assess up to four intravenous dosing regimens: A (BI 765049 once every 3 weeks [q3w]); B1 (BI 765049 qw); B2 (BI 765049 qw with step-in dosing); C (BI 765049 + ezabenlimab q3w). Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control that will be fitted to binary toxicity outcomes using a hierarchical modelling approach to jointly model all dosing regimens. Treatment will be allowed to continue until confirmed progressive disease, unacceptable toxicity, other withdrawal criteria, or for a maximum duration of 36 months, whichever occurs first. Approximately 150–175 patients will be screened and ̃120 patients enrolled. As of January 2022, eight patients have been recruited in early dose-escalation cohorts. Clinical trial information: NCT04752215.

Study of Gemcitabine Plus Nab-Paclitaxel-Based Chemotherapy Regimen as First-Line Treatment in Metastatic Pancreatic Carcinoma.

Varun GoelBackground The purpose of this study was to study the effectiveness of gemcitabine and nab-paclitaxel combination as first-line chemotherapy regimen for the treatment of metastatic pancreatic cancer. There is scarcity of data regarding efficacy and toxicity profile of this combination in Indian population. Aims and Objectives The primary aim of this study was to assess efficacy of this regimen, for which evaluation done in terms of the objective response rate, progression-free survival (PFS), and overall survival. Safety data were also evaluated. Materials and Methods In this prospective study, gemcitabine plus nab-paclitaxel combination chemotherapy was given as first line in metastatic pancreatic carcinoma patients till progression or appearance of grade 3/4 toxicities with treatment. Results The study was performed in 30 patients comprising 18 (60%) males and 12 (40%) females. The median age was 60 years. Median number of cycles administered were six cycles per patient. Seventeen patients (56.67%) had a partial response and 0% had complete response. A total of seven (23.3%) patients progressed on chemotherapy and six (20%) had stable disease (SD). The disease control rate (responses and SD) was 76.7%. The median PFS was 5.75 months. There was no statistically significant difference in terms of response rates and baseline CA 19-9 levels. Most common toxicities were hematological toxicities with rates of grade 3/4 anemia and neutropenia of 20%. Among nonhematological toxicities, nausea (46.67%) and fatigue (30%) were the commonest. Conclusion Combination of gemcitabine and nab-paclitaxel is active and well tolerated in advanced pancreatic carcinoma. To the best of our knowledge, this is the first such study conducted in India.

Positron emission tomography and computed tomography with [68Ga]Ga-fibroblast activation protein inhibitors improves tumor detection and staging in patients with pancreatic cancer.

This study aimed to investigate the diagnostic performance of [68Ga]Ga-FAPI PET/CT for primary and metastatic pancreatic carcinoma lesions and compare the results with those of [18F]-fluorodeoxyglucose ([18F]FDG) PET/CT. Patients with suspected or diagnosed pancreatic malignancy, who underwent contemporaneous [18F]FDG and [68Ga]Ga-FAPI PET/CT between June 2020 and January 2021, were retrospectively analyzed. Routine contrast-enhanced CT (CE-CT) is performed in all patients as standardized care. Findings were confirmed by histopathology or radiographic follow-up. We compared radiotracer uptake, diagnostic performance, and TNM (tumor-node-metastasis) classifications. We evaluated 36 participants (25/36 men; median age, 60years), including 26 patients with pancreatic malignancies and ten patients with pancreatic benign lesions. [68Ga]Ga-FAPI PET/CT showed higher radiotracer uptake and higher sensitivity than [18F]FDG PET/CT in evaluating primary tumors (SUVmax, 21.4 vs. 4.8; sensitivity, 100% vs. 73.1%), involved lymph nodes (SUVmax, 8.6 vs. 2.7; sensitivity, 81.8% vs. 59.1%), and metastases (SUVmax, 7.9 vs. 3.5; sensitivity, 91.5% vs. 44.0%); Compared with [18F]FDG, [68Ga]Ga-FAPI PET/CT upstaged six patients' TNM staging (6/23, 26.1%) and changed two patients' clinical management (2/23, 8.7%). Compared with CE-CT, [68Ga]Ga-FAPI PET/CT upgraded TNM staging in five patients (5/23, 21.7%) and changed the therapeutic regimen in only one patient (1/23, 4.3%). Intense [68Ga]Ga-FAPI uptake was observed throughout the pancreas in 12/26 pancreatic malignancies; dual-time point [68Ga]Ga-FAPI PET/CT may differentiate pancreatitis from malignancy. Compared with [18F]FDG PET/CT, [68Ga]Ga-FAPI PET/CT shows higher sensitivity in detecting primary pancreatic tumors, involved lymph nodes, and metastases and is superior in terms of TNM staging. Prospective trials with larger patient population are needed to evaluate whether [68Ga]Ga-FAPI PET/CT could elicit treatment modification in pancreatic cancer when compared with standard of care imaging.

Pembrolizumab in MSI-high Pancreatic Sarcomatoid Carcinoma

We report the outcome of a patient with MSI-high metastatic pancreatic sarcomatoid carcinoma refractory to multiple lines of chemotherapy treated successfully with pembrolizumab. In November 2015, our patient presented with epigastric pain leading to radiologic workup. A lesion in the pancreas as well as liver metastasis were diagnosed; liver biopsy revealed a poorly differentiated sarcomatoid carcinoma. After having received every approved chemotherapy for pancreatic cancer his disease eventually progressed so that we reached out for novel therapeutic strategies. Because of the tumor being MSI high, treatment with pembrolizumab was commenced in May 2017. Clinical response with better overall quality of life was soon reported and repeated CT scans showed an ongoing partial response leading to a near complete remission in the latest scan obtained. Adverse events during the course of therapy included immune mediated arthralgia grade 1, colitis grade 2 and pneumonitis grade 1 which were managed by administration of glucocorticoids without interruption of immunotherapy. To our knowledge, this is the first case of a patient with MSI high metastatic sarcomatoid carcinoma of the pancreas successfully treated with immunotherapy for more than three years.

Genomic biomarker discovery of first-line gemcitabine/nabpaclitaxel treatment in Chinese advanced pancreatic carcinoma patients.

436 Background: Pancreatic carcinoma is one of the most lethal malignancies worldwide and is characterized by extremely poor prognosis. Gemcitabine plus Nab-paclitaxel (GNp) has been recommended by international guidelines for first-line treatment of locally advanced or metastatic pancreatic carcinoma. However, exploration into molecular biomarkers of GNp treatment is still limited. This study aims to observe and evaluate the efficacy and safety of first-line GNp treatment of pancreatic carcinoma, and to explore potential predictive and prognostic biomarkers to screen advantageous population. Methods: From December 20, 2018 to July 6, 2020, patients with metastatic pancreatic carcinoma, who received first-line GNp treatment, were enrolled. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), overall response rate (ORR), disease control rate (DCR), and adverse events (AE). Patients were collected formalin fixed paraffin embedded (FFPE) samples and sequenced by a next-generation sequencing (NGS)-based 450 gene panel carried out by OrigiMed, a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: In this study, tissue samples from 101 patients were assessed by NGS, including 58 (57.4%) primary tissues and 43 (42.6%) metastasis tissues. So far, 72 patients were available for efficacy analysis, the ORR and DCR were 38.2% and 77.9%, respectively, and were similar between patients sampled from primary lesions and metastasis lesions. The PFS and OS were 176 days and 308 days, respectively. The most frequently mutated genes were KRAS (91.9%), TP53 (76.8%), CDKN2A (32.3%) and SMAD4 (26.3%). Germline pathogenic BRCA2 mutations were detected in 3 (3.0%) patients, while somatic mutations of BRCA2 were found in 2 (2.0%) patients. For KRAS, missense mutations resulted in single amino acid substitutions primarily at G12 (88.1%), and lower frequencies at Q61 (4.0%) and V14 (1.0%). At G12, five different amino acid substitutions have been identified, with G12D (37.6%) the predominant mutation, G12V (32.7%), G12R (11.9%), G12C (3.0%) and G12A (1.0%). The ORR to AG treatment was significantly higher in TP53-alteration (-alt, 47.1%) than in TP53-wild-type (-WT, 11.1%) subgroups (p=0.01). Median OS times in CDKN2B-alt and CDKN2B-WT patients were 180 days and 323 days (p=0.029), respectively. Conclusions: Current evidence indicates that GNp is a valuable option for the first-line treatment of metastatic pancreatic cancer. TP53 may serve as a novel response-predictive gene for GNp treatment in pancreatic carcinoma. Overall survival was significantly prolonged in CDKN2B-WT patients compared with CDKN2B-alt patients. This study provided insights in identifying patients who might potentially benefit from GNp therapy. Clinical trial information: NCT03768687.

Long Term Survival and Prognostic Factors in Metastatic Pancreatic Adenocarcinoma Undergone Pancreatic Resection after Downstaging

Background: Patients with metastatic pancreatic adenocarcinoma receive palliative chemotherapy to control disease progression and related symptoms.Surgical resection of primary tumor has been proposed, best after a course of neoadjuvant chemotherapy with a benefit in survival if compared to CHT alone. Early recurrence or long disease-free survival occurs, regardless of therapy, histology or other known factors. Aim: Investigate long term survival and recurrence of disease in patients undergone surgical resection after downstaging of liver metastatic pancreatic carcinoma and eventually factors associated to best/worst survival. Patients and Methods: A prospective collected database from two centers, Pederzoli Hospital(PH) and The Pancreas Institute(IP) was retrospectively reviewed. All patients undergone pancreatic resection for PDAC after a complete downstaging of liver lesions were considered for survival analysis using Kaplan-Meier method. Results: Between 2008 and 2020 a total of 1129 patients with PDAC and liver mets were observed in the two centers. 54(4.8%) experienced downstaging of liver lesions after chemotherapy (63% FLX, 31% Gem-Abr, 6% Gem alone) and received resection of primary tumor (PD 69%, DP 29%, TP 2 %) with no mortality. Ca19.9 decreased from 1142U/mL at diagnosis to 50U/mL after CHT(p< 0,005). Median interval between diagnosis, surgery and recurrence was 12 and 10 months respectively.Site of recurrence was liver (35 %), peritoneum (7%), local (9%) or multiple sites (16%). DFS and OS were 10 (1-19) and 35 (14-56) months. PD combined with vascular resection and persistent high Ca19.9 post CHT, were associated to overall survival <18 months (p=0.02 and p=0.005, respectively) versus pancreatic resection alone. Conclusions: In patients with liver mPDAC at diagnosis, when downstaging seems to occur, surgery should be considered as an option in very selected cases. Simple tools like Ca19.9 or vascular involvement assessment may help to force or deny surgical resection, despite the apparences, with appropriate criteria.

Association between neutropenia and survival to nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer

Neutropenia is a common side effect associated with nab-paclitaxel gemcitabine (Nab-Gem) therapy. We retrospectively investigated the association between neutropenia induced by first-line Nab-Gem and survival in metastatic pancreatic carcinoma patients. Metastatic pancreatic patients treated with first-line Nab-Gem were included in this retrospective analysis. Neutropenia was categorized using the National Cancer Institute Common Toxicity Criteria scale. Outcome measures were overall survival (OS), progression-free survival (PFS) and response rate. 115 patients were analyzed. Median PFS was 7 months (95% CI 5–8) for patients with grade ≥ 3 neutropenia and 6 months (95% CI 5–6) for patients with grade < 3 neutropenia [p = 0.08; hazard ratio (HR 0.68)]. Median OS was 13 months (95% CI 10–18) for patients with grade ≥ 3 neutropenia and 10 months (95% CI 8–13) for patients with grade < 3 neutropenia (p = 0.04; HR 0.44). In multivariate analysis, the occurrence of grade ≥ 3 neutropenia showed a statistically significant association with OS (HR 0.62; 95% CI 0.09–0.86; p = 0.05). Nab-Gem-induced neutropenia is associated with longer survival in metastatic pancreatic cancer patients.