Metastatic PDAC Research Articles

The impact of multi-agent chemotherapy in metastatic pancreatic adenocarcinoma: A population-based study utilizing the SEER database.

416 Background: Over the last decade, various landmark trials have demonstrated the impact of multi-agent chemotherapy in the treatment of PDAC. However, the impact in the ‘real world’ has been less clear. The ACCORD trial (2011) was a phase III trial comparing combination chemotherapy (FOLFIRINOX) and single agent (gemcitabine) for advanced disease. The MPACT trial introduced another beneficial regimen (nab-paclitaxel and gemcitabine) in 2013. Subsequently, multi-agent chemotherapy became standard of care for medically appropriate patients. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients diagnosed with PDAC between 1998 and 2017. The cohort was divided into two groups: 1998-2011 (pre-ACCORD) and 2012-2017 (post-ACCORD). We analyzed all patients with metastatic PDAC for overall survival and compared results in the two groups using Kaplan Meier analysis and multivariate Cox proportional hazards models. An interrupted time series analysis was also used to compare the temporal trends in 2-year survival between 1998 and 2017. Results: A total of 47,134 patients were diagnosed with PDAC between 1998 and 2017. Nearly two-third of patients (26,438; 57%) had distant disease. On univariate survival analysis, there was a significant increased overall survival probability in the 2012-17 group compared to the 1998-2011 group (p<0.05). The one- and two-year survival rates were 11% and 3% in the pre-ACCORD period compared to 14% and 4 % after the ACCORD trial respectively. This difference remained significant on multivariate analysis while adjusting for covariates (HR=0.08, 0.78-0.92, p=0.05). On interrupted time series analysis, we observed a steady rise in 2- year survival between 1998 and 2017. There was a significant jump in the two-year survival probability from 16% at 2011 to 20% at 2012 in metastatic PDAC (β=0.02, 0.009-0.03, p<0.0001, Table). Conclusions: Beyond the randomized clinical trial arena, overall survival has increased over time, with a statistically significant jump around the time of the ACCORD trial. However, the absolute increase in the ‘real world’ is smaller than the gains observed in prospective clinical trials. [Table: see text]

A phase II, open-label pilot study evaluating the safety and activity of liposomal irinotecan (Nal-IRI) in combination with 5-FU and oxaliplatin (NALIRIFOX) in preoperative treatment of pancreatic adenocarcinoma (NEO-Nal-IRI Study).

TPS446 Background: Neoadjuvant treatment for potentially curable pancreatic cancer (PDAC) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given neoadjuvantly. Liposomal irinotecan injection (Nal-IRI) is FDA approved with a well-tolerated safety profile in relapsed, refractory metastatic PDAC. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen (NALIRIFOX) and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase II, open-label, multicenter single-arm study focuses on patients (pts) with operable PDAC without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board (resectable vs. borderline), adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive NALIRIFOX regimen as per the table below every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in perioperative setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30 day postoperative complication rate. Clinical trial information: NCT03483038. [Table: see text]

Chemo4MetPanc: A phase II study with combination chemotherapy (gemcitabine and nab-paclitaxel), chemokine (C-X-C) motif receptor 4 inhibitor (motixafortide), and immune checkpoint blockade (cemiplimab) in metastatic treatment naïve pancreas adenocarcinoma (PDAC).

TPS454 Background: Pancreas adenocarcinoma (PDAC) is an aggressive cancer projected to be the second leading cause of cancer-related death in the United States by 2030 for which improved treatment options are desperately needed. Immune checkpoint blockade (ICB) for PDAC has failed as monotherapy in early phase clinical trials likely due to a highly immunosuppressive tumor microenvironment. The CXCR4/CXCL12 axis is a key immune evasion mechanism thought to deter CD8+ T-cells (CTLs) from infiltrating the tumor. We performed a large seven arm survival and biopsy/necropsy study in KPC mice (KrasLSL.G12D/+;p53R172H/+;Pdx1Cretg/+) where we demonstrate that addition of gemcitabine to CXCR4 inhibition in combination with ICB, enhanced tumor stabilization and neoplastic cell death, and improved survival by 50 percent. Multiplex immunofluorescence indicated an increased CTL to regulatory T-cell ratio and clustering of CTLs around neoplastic cells. Presented here is a trial-in progress that will evaluate combination of a CXCR4 inhibitor, ICB, and chemotherapy in treatment naïve patients with PDAC. Methods: This is a multicenter, single arm, open-label phase 2 study of combination motixafortide 1.25mg/kg SC monotherapy for 5 days during priming followed by twice weekly, cemiplimab 350mg IV once every 21 days, gemcitabine 1000mg/m2 IV with nab-paclitaxel 125mg/m2 IV on days 1, 8, and 15 every 28 days. Patients with histologically confirmed metastatic PDAC who have not received prior therapy will be enrolled. The primary endpoint is overall response rate by 16 weeks. A response rate greater than 45% by 16 weeks is considered promising, whereas a response rate of less than 23% is considered not promising. We will use a Simon optimal 2-stage design, where we will enroll 10 patients in the first stage. If 3 or more patients meet the endpoint in the first stage, the study will be expanded to a total of 40 patients. If a total of 14 or more patients achieve CR or PR by 16 weeks, the agent will be considered promising and worthy of further study. Secondary endpoints include safety, mPFS, disease control rate (DCR), and mOS. Correlative aims include analyses of pre- and on-treatment biopsies with quantitative multiplex immunofluorescence, RNA-sequencing, and generation of patient derived organoids for association with clinical benefit and to determine mechanisms of action/resistance. An interim analysis will be performed at the conclusion of the stage I portion of the study. Clinical trial information: NCT04543071.

Molecular Profiling Practices in Pancreatic Adenocarcinoma: Academic vs Community Physicians.

Background: Pancreatic adenocarcinoma (PDAC) is relatively rare but highly aggressive, with most patients diagnosed once they have metastatic or locally invasive disease. Molecular profiling is being explored as a tool for selecting patients for targeted therapy clinical trials and for assessing whether targeted therapies may be effective in PDAC. Whether molecular profiling is being performed at both academic and community oncology clinics has yet to be examined. Here, we characterized the molecular profiling practice patterns in patients with PDAC in academic versus community practices in Denver, Colorado. Methods: We retrospectively reviewed records of all patients with refractory, metastatic PDAC who were referred to a tertiary clinical trials drug development unit in Denver between 2014 and 2019. Results: Of 77 patients, 41 (55%) were men with a mean age of 65 years (SD, 9.3). Fifty-three patients (69%) were referred from the community and 20 (26%) from academic centers; 4 (5%) were self-referred. A total of 51% received profiling prior to referral; 29 of 50 (58%) were from the community and 10 of 21 (47%) from academic settings. Guardant was the most commonly ordered test (47 of 77; 61%); FoundationOne was the second most common (40 of 77; 52%). Twenty-three of 77 patients (30%) received both Guardant and FoundationOne testing, and 3 of 77 (4%) received Caris MI Profile. One patient received a Mocha assay and another received Ascend/Clarient fluorescence in situ hybridization (FISH). Four patients were self-referred, 2 of whom underwent both Guardant and FoundationOne, 1 who underwent Guardant testing only, and 1 who did not receive any molecular profiling testing. Conclusions: This study characterizes molecular profiling practice patterns in individuals with advanced PDAC who were referred to a tertiary clinical trials drug development unit. Both academic and community physicians were found to order profiling about 50% of the time. Further research is needed to determine impact on clinical trial enrollment and detection of PDAC.

Abstract PO-057: Collateral amplification of the PTHrP gene drives pancreatic cancer growth and metastasis and reveals a new therapeutic vulnerability

Abstract Purpose: Metastasis is the leading cause of cancer-related death in PDAC, yet very little is understood regarding the underlying biology. As a result, targeted therapies to inhibit metastasis are lacking. Whole-genome sequencing has established that the squamous/quasi-mesenchymal/basal-like PDAC subtype, which is characterized by its high metastatic proclivity, is annotated by KRAS gene amplification. Here, we report that the squamous lineage gene parathyroid hormone-related protein (PTHrP encoded by PTHLH) is located directly adjacent to KRAS and is co-amplified in metastatic PDAC patients. We hypothesize that this collateral amplification of PTHrP may exert its own oncogenic and pro-metastatic phenotype beyond KRAS and set out to determine if this will confer a novel therapeutic vulnerability. Methods: We generated a novel genetically engineered mouse model whereby we deleted the cytokine Pthlh in the autochthonous KPCY model. To functionally demonstrate the oncogenic and pro-metastatic roles of PTHrP, we further employed genetic deletion and pharmacological inhibition in orthotopic injection, tail vein metastasis assays, mouse hospital pre-clinical trials, and patient-derived 3D organoid models. Results: In silico analysis established that PTHLH is co-amplified along with KRAS in TCGA, is specifically enriched in metastatic patients from the COMPASS trial and correlates with significantly decreased overall survival in both cohorts. Further examination revealed that PTHLH is a squamous/quasi-mesenchymal/basal-like lineage marker. We generated KPCY-PthlhCKO mice and showed that they have significantly reduced primary and metastatic tumor burden and dramatically increased overall survival relative to KPCY controls. In parallel experiments, we treated mice with an anti-PTHrP neutralizing monoclonal antibody, which similarly reduced primary and metastatic tumor growth. Finally, RNA-seq revealed a downstream mechanism whereby PTHrP is important for metastatic competency through induction of EMT, thus facilitating entry into the metastatic cascade. Loss of PTHrP reduced the ability of tumor cells to undergo EMT, resulting in a nearly complete elimination of disseminating cells in KPCY-PthlhCKO mice. Thus, KPCY-PthlhCKO tumors are locked in a well-differentiated epithelial state and are unable to initiate the metastatic process. Conclusions: This work has demonstrated the importance of the previously unappreciated role for PTHrP signaling in pancreatic cancer cell plasticity and metastasis, and future studies will look to translate anti-PTHrP therapy into clinical trials. In a broader sense, we establish a new paradigm of collateral amplification, where an assumed passenger gene (PTHLH) is co-amplified along with a known oncogene (KRAS) and endows the evolving tumor with its own oncogenic and pro-metastatic phenotype. Citation Format: Jason R. Pitarresi, Robert J. Norgard, Anna M. Chiarella, Richard Kremer, Ben Z. Stanger, Anil K. Rustgi. Collateral amplification of the PTHrP gene drives pancreatic cancer growth and metastasis and reveals a new therapeutic vulnerability [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-057.

Abstract PR07: Pancreatic ductal adenocarcinoma requires PI3Kalpha activity to accelerate circulating DNA-positive metastatic disease

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a paradigmatic model of micrometastatic disease, characterized by both relapse of surgery and failure of long-term disease control with chemotherapies in resected, locally advanced unresectable and metastatic patients. Molecular characterization of large cohorts of PDAC patients failed to identify actionable pathways associated with mutations except for oncogenic Kras, found in more than 80% of all patients. Class I PI3K being a key regulator of both cell survival and cell migration, we questioned if nonmutated PI3K activity downstream oncogenic Kras is a clinically relevant target for this pathology. To achieve this goal, we devised a novel preclinical protocol in a genetically engineered mouse model (GEMM) including a noninvasive monitoring using circulating cell-free DNA (cfDNA) level as a novel biomarker of micrometastatic disease. We previously showed that, downstream Kras, nonmutant ubiquitous PI3Kalpha is crucial for PDAC development. Among all the mRNA expression-based hallmarks of biologic pathways, we now show that PI3K/Akt/mTOR hallmark is significantly increased in PDAC patients with advanced metastatic disease. High scoring of PI3Kalpha activation, based on expression levels of PI3Kalpha-regulated curated genes, is correlated to a poor prognosis, and is found in metastatic PDAC cell lines and in patient-derived ex vivo cultures of locally invasive PDAC cancer cells. When testing global or isoform-selective inhibitors in GEMM and human cell lines, we show that biologically efficient PI3K inhibitors annihilate PI3Kalpha strongly, but not necessarily specifically, among the four class I PI3K isoforms, resulting in Akt2 inactivation. Similar results are obtained with siRNA and in PIK3CA oncogenic cell lines. PI3Kalpha controls pancreatic tumor cell line motility and migration. In a GEMM model of PDAC, mice with high level of cfDNA present a shorter survival and develop a metastatic disease. Genetic or pharmacologic inhibition of PI3Kalpha in these mice decreases tumor volume, metastasis, ascitic fluid development, cfDNA quantity and M2 macrophage infiltration. Here, we used GEMMs to define a cfDNA-positive aggressive subtype of PDAC and identify a pharmacologically actionable prometastatic feature driven by PI3Kalpha. We propose PI3K as a therapeutic strategy to suppress PDAC progression and metastasis by scavenging peritumoral CD206-positive macrophages. Our data demonstrate that PI3K agents could be efficient on micrometastatic disease (measured by cfDNA), resulting in delay on macrometastatic dissemination. This abstract is also being presented as Poster B04. Citation Format: Benoit Thibault, Fernanda Ramos-Delgado, Elvire Pons-Tostivint, Nicole Therville, Gabriella Reyes-Castellanos, Marie Tosolini, Jean-Pierre Delord, Dieter Saur, Alice Carrier, Pierre Cordelier, Céline Basset, Julie Guillermet-Guibert. Pancreatic ductal adenocarcinoma requires PI3Kalpha activity to accelerate circulating DNA-positive metastatic disease [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr PR07.

Pancreatic circulating tumor cell detection by targeted single-cell next-generation sequencing.

Single-cell next-generation sequencing (scNGS) technology has been widely used in genomic profiling, which relies on whole-genome amplification (WGA). However, WGA introduces errors and is especially less accurate when applied to single nucleotide variant (SNV) analysis. Targeted scNGS for SNV without WGA has not been described. We aimed to develop a method to detect circulating tumor cells (CTCs) with DNA SNVs. We tested this targeted scNGS method with three driver mutant genes (KRAS/TP53/SMAD4) on one pancreatic cancer cell line AsPC-1 and then applied it to patients with metastatic PDAC for the validation. All single-cell of AsPC-1 and spiked-in AsPC-1cells in healthy donor blood, which were isolated by the filtration with size or by flow cytometry, were detected by targeted scNGS method. All blood samples from six patients with metastatic PDAC, for the validation of target scNGS method, showed CTCs with SNVs of KRAS/TP53/SMAD4 and the positive confirmation of immunofluorescent stainings with Pan-CK/Vimentin/CD45. Four patients with early stage disease, one patient with benign pancreatic cyst and a healthy control sample all showed concordant results between targeted scNGS and CTC enumeration. The novel technique of targeted scNGS for SNV analysis, without pre-amplification, is a promising method for identifying and characterizing circulating tumor cells.

1559P Chemotherapy related changes of peripheral blood lymphocytes in advanced and metastatic PDAC

Immunotherapeutic approaches pointed out promising results in different solid tumors but remain worthless in PDAC. Immune system and TME of pts suffering from PDAC are explored widely. We conduct one institution clinical trial to evaluate impact of different treatment modalities on T lymphocyte and other cells in the peripheral blood as possible predictive and prognostic biomarkers for PDAC patients. Cohort of 77 pts with inoperable locally advanced or metastatic PDAC was evaluated in this analysis. Blood samples were collected for analysis of T cell subsets, including CD19, CD3+ CD56+, CD8+ CD57+, CD3+ CD57+, CD3, CD3+ CD4+, CD3+ CD8+, CD3+ CD4- CD8-, CD3- CD56+ CD16+, CD3- CD56+ CD16-, CD4+ CD25+ CD127+/-, CD4+ FOXP3+, CD8+ CD25+ CD127+/-, CD8+ FOXP3+ T cells by flow cytometry at initial diagnosis before chemotherapy and after two months. Results were estimated according to the age, sex, disease volume (locally advanced or metastatic, differentiation rate, regimen received (FOLFIRINOX or gemcitabine), CA 19-9 values. Student t, Mann-Whitney U and Wilcoxon Singed Rank tests were used for statistical analysis. After evaluating parameters at first visit statistically significant difference was seen in T helper subpopulation CD3+ CD4+, comparing <65 years age group and >65 years old group. The same tendency is seen comparing good/ moderately differentiated and poor diferentiated groups. Metastatic pts. tend to have lower CD3+ CD4- CD8- and CD3- CD56+ CD16- subpopulation rates before treatment. There were no significant difference of meassured parameters between groups concerning CA 19-9 elevation and sex, Initial parameters between FOLFIRINOX and gemcitabine gruops did not differ either. After 2 months on chemotherapy T lymphocytes CD3+ CD56+, NK cells CD3- CD56+ CD16+ and CD3- CD56+ CD16- as well as Treg CD4+ FOXP3+ revealed some changes. Those changes differ according to disease volume and differentiation rate. Gemcitabine showes greater impact on CD3- CD56+ CD16- fall after 2 months of chemotherapy then FOLFIRINOX. T cells subpopulations in advanced and metastatic PDAC pts vary during treatment and may be considered as potential biomarkers for evaluating pts‘ status and response to therapy.

Abstract CT135: A phase 1b study of palbociclib + nab-paclitaxel in patients (pts) with metastatic adenocarcinoma of the pancreas (PDAC)

Abstract Palbociclib (P), an oral cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, has shown antitumor activity in preclinical PDAC models. In Avatar PDAC models, P+ nab-paclitaxel (A) was more effective than either agent alone and similar to P+A+gemcitabine. This study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), preliminary efficacy, and maximum tolerated dose (MTD) of P+A in pts with advanced PDAC. Pts with metastatic PDAC, Karnofsky performance status ≥70 and adequate organ function were eligible. In the dose escalation phase, P was administered orally once daily at doses ranging from 75-125 mg/d for 21 of every 28 days (3/1 schedule). A was administered intravenously at 100-125 mg on days 1, 8 and 15 every 28 days. Additional cohorts were P 75 mg (3/1 schedule or continuously) with A (100- and 125-mg dose, biweekly). The prespecified efficacy target was 12-month survival probability &amp;gt;65% at MTD. In total, 76 pts (median age 61 years [range 39-75], 45% female) received a median of 4 treatment cycles (range 1-21); 44 (57.9%) pts had liver disease and 61 (80.3%) had prior treatment for advanced disease. Four dose-limiting toxicities were observed: grade 3 mucositis (1), grade 4 neutropenia (2), and febrile neutropenia (1). Grade 3/4 adverse events were reported in 67 (88.2%) pts; events reported for ≥5% of pts were neutropenia (61.8%), leukopenia (26.3%), anemia (22.4%), asthenia (9.2%), lymphopenia (7.9%), and peripheral neuropathy (5.3%). PK demonstrated no significant drug-drug interactions. MTD was P 100 mg (3/1 schedule) and A 125 mg (days 1, 8 and 15 every 28 days). Objective response rate and disease control rate in the 23 pts treated at MTD were 13% and 65.2%, respectively. In these pts, median progression-free survival, median overall survival, and survival probability at 12 months were 5.3 months (95% CI: 3.5-9.7), 12.1 months (95% CI: 6.4-14.8), and 50% (95% CI: 29.9%-67.2%), respectively. Thirty of 57 analyzed pts (52.6%) had an on-treatment maximum Ca 19-9 reduction &amp;gt;50% from baseline. In paired skin punch biopsies (26 pts at any dose level, including 13 pts at MTD), pRb decreased during P dosing, increased above baseline during the week off P, and decreased again following P dosing, demonstrating PD modulation of Rb phosphorylation. CDKN2A, RAS, and TP53 mutations were analyzed in plasma DNA; clinical outcome of pts without alterations detected (n=58, 26, and 28, respectively) was superior to those with alterations detected (n=12, 44, and 42 pts, respectively). In conclusion, P+A was tolerated, with side effects as expected based on single agent profiles, and no significant PK interactions. MTD was P 100 mg (3/1 schedule) + A 125 mg (days 1, 8, and 15 every 28 days). PD observations were consistent with CDK4/6 inhibition. The combination regimen did not meet the prespecified efficacy threshold.Pfizer (NCT02501902) Citation Format: Manuel Hidalgo, Rocio Garcia Carbonero, Kian-Huat Lim, Wells Messersmith, Ignacio Garrido-Laguna, Erkut Borazanci, Andrew Lowy, Laura Medina Rodriguez, Daniel Laheru, Xin Huang, Meggan Tammaro, Jean-François Martini, Arthur Kudla, Kenneth Kern, Teresa Macarulla. A phase 1b study of palbociclib + nab-paclitaxel in patients (pts) with metastatic adenocarcinoma of the pancreas (PDAC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT135.

Abstract LB-203: The mRNA binding protein Human Antigen R (HuR, ELAVL1) is a novel regulator in pancreatic ductal adenocarcinoma metastatic progression and persistence

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death with a five-year survival rate of 10%. Yet, for the majority of patients who present with metastatic burden (50-60%), this rate drops to a mere 3%. Systemic chemotherapeutic regimens such as FOLFIRINOX or gemcitabine abraxane, have only shown marginal efficacy in delaying tumor growth and metastatic progression. Thus, there is a dire need for more robust treatment options to effectively target metastatic PDAC. Work by Iacobuzio-Donahue et al. and others have interrogated genetic drivers of patient metastases. They have demonstrated through genomic sequencing of matched primary and metastatic tumors that no single genetic event can account for driving metastasis. Therefore, metastatic progression is most likely driven by mechanisms beyond genomic mutations. Our lab has characterized one such alternative, the RNA binding protein Human Antigen R (HuR). HuR is a major regulator of pleiotropic gene regulation in response to demands from the pancreatic tumor microenvironment (e.g. nutrient deprivation, hypoxia). HuR generally stabilizes and enhances the translation of pro-survival mRNA transcripts (e.g., PIM1, IDH1, WEE1, DCK, PARG, etc.). Outside of this role, published data has implicated HuR to regulate epithelial-to-mesenchymal transition diving genes (e.g. SNAI1, PLAU, CTTNB1, MMP9) necessary for migration and invasion. We have been able to demonstrate that HuR is important for the migration and invasion of PDAC cells, in vitro. Through use of short hairpin RNA and CRISPR technology, inhibition of HuR decreased the ability of PDAC cells to migrate and invade in a transwell assay. Additionally, both knockdown and knockout of HuR slowed wound healing and colony formation. To evaluate the role of HuR in metastasis in vivo, we utilized a luciferase-expressing humanized PDAC orthotopic model to monitor tumor growth and spread. Either parental or HuR knockout luciferase-expressing PDAC cells were injected into the tail of the pancreas of NRG mice. A month after tumor engraftment, the majority of mice bearing parental tumors harbored liver and lung metastases (liver-5/5, lung 4/5) while HuR knockout tumor-bearing mice showed little to no evidence of metastasis (liver 2/4, lung 0/4). Employing ribonucleoprotein immunoprecipitation assays identified metastatic-associated mRNA transcripts bound to HuR (i.e., CTNNB1 (beta-catenin) and YAP1 mRNAs). Validation of these findings demonstrated that silencing or knocking out HuR induces a robust loss of beta-catenin and YAP1 expression (p&amp;lt;0.001). Ongoing work will further uncover known and novel pathways that HuR is modulating for the pro-metastatic phenotype often seen in PDAC. Taken together, these data supports our continuing work of developing novel therapeutic strategies to target HuR in PDAC. Citation Format: Grace A. McCarthy, Aditi Jain, Samantha Z. Brown, Charles J. Yeo, Jonathan Brody. The mRNA binding protein Human Antigen R (HuR, ELAVL1) is a novel regulator in pancreatic ductal adenocarcinoma metastatic progression and persistence [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-203.

Genome-wide profiling of circulating tumor DNA depicts landscape of copy number alterations in pancreatic cancer with liver metastasis.

Cell-free DNA (cfDNA) offers an alternative to tissue biopsies for genomic profiling in tumors. Here, we sought to evaluate copy number alterations in PDAC through whole-genome sequencing (WGS) of cfDNA and determine their clinical significance. Using shallow WGS across 90 plasma samples from 70 pancreatic cancer patients, we detected somatic copy number alterations (CNAs) in 34 subjects (48.6%). Additionally, a higher tumor fraction (TFx) was associated with increased carbohydrate antigen 19-9 (CA19-9), metastasis, and a worse prognosis. Serial cfDNA analysis suggested that CNAs were highly concordant even for progressive disease after chemotherapy. TFx dynamics were largely in line with changed CA19-9 levels and tumor burden following chemotherapy. Notably, patients with more abundant, baseline CNAs exhibited a better response to chemotherapy. In conclusion, shallow WGS for cfDNA enables a high-throughput characterization of CNAs and an estimation of tumor burden in metastatic pancreatic cancer. These findings reinforce our understanding of the genomic evolution of metastatic PDAC and might have clinical relevance for guiding treatment.

Study protocol for an open-label, single-arm, phase Ib/II study of combination of toripalimab, nab-paclitaxel, and gemcitabine as the first-line treatment for patients with unresectable pancreatic ductal adenocarcinoma

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a fatal disease with a dismal response to single-use of immune checkpoint inhibitors (ICIs). ICIs combined with systemic therapy has shown efficacy and safety in various solid tumors. Nab-paclitaxel and gemcitabine (AG), as the standard first-line treatment for advanced PDAC, has been widely used in recent years. The combination of ICIs and AG chemotherapy appears to be a promising option in the treatment of PDAC.MethodsThis is an open-label, single-arm, and single-center phase Ib/II trial. The enrolled subjects are the unresectable (locally advanced or metastatic) PDAC patients without previous systemic treatments. All subjects receive an intravenous injection of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on day 1 and day 8, along with toripalimab 240 mg at day 1 every 3 weeks. The subjects may discontinue the treatment because of progression disease (PD), intolerable toxicities, requirements of patients or researchers. For local advanced patients who are evaluated as partial response (PR), surgeons need to assess the surgical possibility. The primary objective of this trial is to evaluate the safety and overall survival (OS) of this combination therapy; and the secondary objective is related to the assessment of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and the rate of resection or R0 resection after receiving toripalimab plus AG treatment. Besides, we expect to identify the predictive biomarkers (such as MMR protein and PD-L1 expression, the number of TILs, the small RNA of EBV and so on) and explore the correlation between these biomarkers and tumor response to this combined regimen.DiscussionThis trial is the first attempt to evaluate the efficacy and safety of the combination of toripalimab plus AG chemotherapy as a first-line treatment for unresectable PDAC patients. The results of this phase Ib/II study will provide preliminary evidence for further assessment of this combined therapeutic regimen for unresectable PDAC patients.Trial registrationTrial registration: ChiCTR (ChiCTR2000032293). Registered 25 April 2020 - Retrospectively registered.

Liver metastases from pancreatic ductal adenocarcinoma: is there a place for surgery in the modern era?

Abstract Pancreatic ductal adenocarcinoma (PDAC) represents one of the most aggressive malignancies, and the majority of patients with PDAC present with metastatic disease, mainly in the liver, at the time of diagnosis. Surgical resection is the only treatment that can offer prolonged survival and possible cure. However, the indications for surgery for patients with PDAC metastases remain extremely limited to highly selected patients with localized disease, and metastatic disease is generally regarded as a contraindication to surgery. Recently, however, the advent of more effective chemotherapy has changed the treatment strategy for metastatic PDAC. In fact, cases in which resection of synchronous or metachronous PDAC liver metastases lead to prolonged survival in highly selected patients have been reported. In this review, we provide current data regarding survival outcomes after surgery, and discuss the role of surgical resection and selection criteria for patients with PDAC liver metastases in the modern era.

A phase II trial of cabozantinib and erlotinib for patients with EGFR and c-Met co-expressing metastatic pancreatic adenocarcinoma (PDAC).

e16764 Background: Both EGFR and the c-MET receptors are overexpressed in a majority of PDACs. Inhibition of both receptors simultaneously may be required for anti-tumor activity. Erlotinib, an EGFR inhibitor, has modest activity in metastatic PDAC and is approved by the FDA in combination with gemcitabine. Cabozantinib is a tyrosine kinase inhibitor targeting AXL, FLT-3, KIT, MER, MET, RET, ROS1, TIE-2, TRKB, TYRO3, and VEGFR-1, -2, and -3. Preclinical data suggests that the addition of cabozantinib to erlotinib leads to tumor shrinkage and improvement in survival in a KPC PDAC mouse model compared to gemcitabine alone. This phase II study tests this hypothesis in patients with metastatic PDAC that co-express c-MET and EGFR. Methods: Key eligibility includes patients (pts) with metastatic PDAC with EGFR and c-MET overexpression (as determined by centrally tested IHC of 2+ or greater) that have progression on one prior chemotherapy regimen. Patients were treated with cabozantinib (40mg daily) and erlotinib (100mg daily) continuously. This dosing is based on previous combination data in NSCLC. This is a single arm two-stage phase II study with a primary endpoint of overall response rate. Secondary endpoints include of PFS, DCR and OS. Results: From October 2017 to October 2019, 43 pts were screened with 7 pts (median age 62 [range 51-76)] enrolled and treated on study. Pts had a median of 1 line of prior systemic chemotherapy. Most common reason for screen failure was due to lack of co-expression of c-MET and EGFR. EGFR IHC expression was +2 in 4 pts, +3 in 3 pts; c-MET IHC expression was +2 in 5 pts and +3 in 2 pts. Most common any-grade adverse events attributable to cabozantinib and erlotinib include: diarrhea (71%), AST increase (43%), fatigue (43%), nausea (43%), and rash (43%). Only one grade 3 event of fatigue occurred. All pts had clinical and/or radiographic progression within 1-2 months after initiating study therapy. Conclusions: The combination of cabozantinib and erlotinib was well tolerated with manageable toxicity. Due to lack of clinical responses, this study has been terminated due to futility. Clinical trial information: NCT03213626 .

Exceptional sustained responses to ipilimumab/nivolumab (ipi/nivo) in patients (pts) with advanced pancreaticobiliary cancers and germline DNA damage repair (DDR) mutations.

e16757 Background: Immune checkpoint inhibitors (ICIs) have not shown meaningful clinical activity in unselected pts with pancreaticobiliary cancer. DDR-deficient tumors have increased genomic instability, including increased tumor mutation burden (TMB), more tumor-infiltrating immune cells, and enrichment of a T cell-inflamed signature. We hypothesized that pts with DDR deficiency may be sensitive to ICIs. Methods: Utilizing the IRB-approved database at the University of Miami, we identified pts with advanced pancreaticobiliary cancer with germline DDR mutations who were treated with dual ICI. Results: Eleven pts were identified (3 BRCA1, 4 BRCA2, 1 RAD51C, 1 RAD51D, 1 ATM, and 1 PALB2). There were two complete responses (CR), one partial response (PR), three stable disease (SD), two progressive disease (PD), and three pending evaluation. Evaluable responses are sustained for 22 months (m), 19m, and 7m, respectively. All pts had microsatellite stable tumors and none had high TMB. Among pts with responses, TMB was 4, 8, and 8 mut/Mb, respectively. One pt with a CR had gBRCA1 with pancreatic adenocarcinoma (PDAC) s/p distal pancreatectomy/splenectomy, adjuvant gemcitabine (gem)/capecitabine, biopsy-proven recurrence in lung and retroperitoneum 12m later, initiated ipi/nivo, and achieved a CR ongoing for 22m on nivo maintenance. Second pt with a CR had gBRCA1 and unresectable cholangiocarcinoma (CC), with disease progression after gem/cisplatin (cis), therapy switched to ipi/nivo. After 4 doses, an incidental cerebellar lesion was found which was biopsy-proven CC, therefore taken off treatment. Pt has been in CR for 19m without further therapy. The pt with a PR had RAD51C and metastatic PDAC s/p FOLFIRINOX for 6m, followed by olaparib for 12m. At progression, disease rapidly progressed through 5-fluorouracil/nanoliposomal irinotecan, gem/nab-paclitaxel/cis, and FOLFIRINOX. Pt was initiated on ipi/nivo with immediate improvement in pain and tumor markers; PR ongoing for 7m with continued clinical and tumor marker improvement on nivo maintenance. Additional correlative studies (RNA sequencing, Hyperion Imaging, mutation allele fraction analysis) among responders vs. nonresponders will be reported at the meeting. Conclusions: In this series, 6 out of 8 evaluable pts with advanced pancreaticobiliary cancers had disease control with ipi/nivo. This series suggests that tumors with germline DDR mutations may be responsive to ICIs. Further evaluation is warranted.

Phase Ib/II open-label, randomized evaluation of 2L atezolizumab (atezo) + PEGPH20 versus control in MORPHEUS-pancreatic ductal adenocarcinoma (M-PDAC) and MORPHEUS-gastric cancer (M-GC).

4540 Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to identify early efficacy signals and safety of treatment (tx) combinations across cancers. Within MORPHEUS, atezo (anti–PD-L1) was tested with PEGylated recombinant human hyaluronidase (PEGPH20), an anti–stromal and extracellular matrix modulator, in patients (pts) with metastatic (m) PDAC or advanced/mGC. Methods: In 2 separate randomized trials, eligible pts with 2L mPDAC or mGC received atezo (1200 mg IV q3w) + PEGPH20 (3 µg/kg IV on D1, 8, 15). Control tx for M-PDAC (NCT03193190) was mFOLFOX6 or gemcitabine + nab-paclitaxel. In M-GC (NCT03281369), control tx was ramucirumab + paclitaxel. Primary endpoints were ORR (investigator-assessed RECIST 1.1) and safety. Results: Pts were followed up for ≥ 18 wk in M-PDAC (data cutoff: Aug 5, 2019) and ≥ 24 wk in M-GC (data cutoff, Jul 11, 2019). In M-PDAC, 66 pts received atezo + PEGPH20 and 42 received control in both preliminary and expansion phases. Confirmed ORRs were 6.1% (95% CI: 1.7, 14.8) and 2.4% (95% CI: 0.06, 12.6), respectively. Duration of response ranged from 5.3 to 11.3 mo in tx arm and was 3.9 mo in control. Median PFS was 1.5 mo (95% CI: 1.4, 2.6) and 2.3 mo (95% CI: 1.6, 4.0), respectively. Median OS was 7.1 mo (95% CI: 4.6, 9.5) and 6.8 mo (95% CI: 5.6, 8.3). Updated survival data will be presented. Respectively, 62.2% and 59.5% of pts had Gr 3-4 AEs; Gr 5 AEs were seen in 4.5% and 2.4% of pts; serious AEs (SAEs) occurred in 45.5% and 45.2% of pts; 16.7% and 4.8% of pts had tx-related AEs leading to tx withdrawal. The most common tx-related AEs were myalgia (65.2%) and peripheral edema (28.8%) in the combination arm. In M-GC, 13 pts received atezo + PEGPH20 and 12 received control. Confirmed ORRs were 0% (95% CI: 0, 24.7) and 16.7% (95% CI: 2.1, 48.4), respectively. Gr 3-4 AEs were seen in 30.8% and 75.0% of pts, respectively. No Gr 5 AEs occurred in either arm. SAEs occurred in 7.7% and 50.0% of pts, respectively. Only 1 pt in the control arm had a tx-related AE leading to tx withdrawal. While tumor hyaluronan (HA) appears to be associated with poor prognosis in the M-PDAC control, there was no clear association between HA levels and response to atezo + PEGPH20. PK data will also be presented. Conclusions: Limited efficacy was seen with the chemotherapy-free combination of atezo + PEGPH20 in PDAC. No efficacy was seen in GC. The safety of atezo + PEGPH20 was consistent with each agent’s known safety profile; no new safety signals were identified. Clinical trial information: NCT03193190 .

Population-based analysis of treatment patterns and outcomes for pancreas cancer in Victoria.

The Victorian Pancreas Cancer summit 2017 analysed state-wide data on management of Victorians with pancreas cancer between 2011 and 2015 to identify variations in care and outcomes. Pancreas cancer remains a formidable disease but systemic therapies are increasingly effective. Surgery remains essential but insufficient alone for cure. Understanding patterns of care and identifying variations in treatment is critical to improving outcomes. This population-based study analysed data collected prospectively by Department of Health and Human services (Victorian state government). Data were extracted from Victorian Cancer Registry (covering all Victorian cancer diagnoses), Victorian Admitted-Episodes Dataset (all inpatient data), Victorian Radiotherapy Minimum Dataset and Victorian Death Index providing demographics, tumour and treatment characteristics, age-standardized incidence, overall and median survival. Of 3962 Victorian patients with any form of pancreatic malignancy, 82% were ductal adenocarcinoma (PDAC), of whom 67% had metastases at diagnosis. One-year overall survival for PDAC was 30% (60% non-metastatic, 15% if metastatic). Median survival with metastases increased from 2.7 to 3.9 months, and from 13.3 to 15.9 months for non-metastatic PDAC between 2011 and 2015. Thirty-one percent of non-metastatic patients underwent pancreatectomy. About 1.5% were treated with neoadjuvant chemotherapy/chemoradiation. Of patients undergoing intended curative resection, 77% proceeded to adjuvant therapy. Fifty-one percent of metastatic PDAC patients never received anti-tumour therapy. Nearly one-fourth of surgically treated patients never received systemic therapy. More than two-thirds of non-metastatic patients never proceeded to surgery. Further consideration of neoadjuvant therapy should be given to borderline resectable patients. Most patients with PDAC still die soon after diagnosis, but median survival is increasing.

Abstract A46: CD73 inhibition enhances the effect of anti-PD-1 therapy on KRAS-mutated pancreatic cancer model

Abstract Background: CD73 catalyzes the extracellular generation of adenosine (ADO) from adenosine monophosphate (AMP). High levels of ADO, found in the tumor microenvironment (TME), have been shown to suppress immune responses and curtail T-cell activation in the presence of anti-PD-1/PD-L1 blocking antibodies. Oncogenic drivers resulting from activating mutations, such as KRAS, BRAF, and EGFR mutations, are commonly treated with tyrosine kinase inhibitors that result in robust but nondurable responses. We show here that KRAS mutations, of which 60% were derived from pancreatic adenocarcinoma (PDAC) samples, significantly upregulated CD73 expression and resulted in worsening prognosis. In a murine model of pancreatic cancer bearing KRASG12C mutation, coadministration of CD73 inhibitor with anti-PD-1 in established tumors resulted in significant tumor growth retardation, comparable to KRAS inhibitor alone. These data support the rationale for the clinical development of CD73 inhibitors in pancreatic cancer. Methods: Linear models were used to evaluate the ability of 299 pan-cancer consensus oncogenic drivers to predict CD73 expression independent of tumor type in the TCGA dataset. Immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded (FFPE) samples was performed using CD73 (Cell Signaling, D7F9A) primary antibody and detected using anti-rabbit HRP. CD73 expressing cells were detected by DAB chromogen and quantified using QuPath Software. CD73 activity in fresh frozen tissues were detected using the Wachstein-Meisel method. C57BL/6J mice bearing established KP4662-G12C tumors (&amp;gt;150 mm3) were treated with A0001421 (CD73i), 30 mg/kg; once a day; s.c. and anti-PD1 (Clone RMP 1-14): 10 mg/kg; twice a week; i.p. Mice were treated for two weeks starting from day 10 post-tumor. Treatment efficacy was monitored using micro-computed tomography (Genisys PET/CT G8 (Sofie Biosciences). All small-molecule inhibitors were synthesized by Arcus Biosciences, Inc. Results: Out of the 299 oncogenes, alterations in KRAS, BRAF, and EGFR were the top 3 oncogenes upregulating CD73 expression. Increase in CD73 expression in KRAS-mutated tumors was further confirmed by IHC. Data extrapolated from Koyama et al. suggest that PD-1 nonresponsive mice express higher levels of adenosine pathway genes, including CD73 and CD39. Coadministration of CD73 inhibitor with anti-PD-1 was superior to anti-PD-1 alone in limiting tumor growth of an aggressive model of pancreatic cancer. Global changes in immune contexture and TME were also observed, consistent with the immune modulatory effects of inhibiting CD73 activity. Conclusion: CD73 is a highly efficient ecto-enzyme that catalyzes the hydrolysis of AMP to immune-suppressive ADO and is associated with worsening prognosis across multiple malignancies. AB680, a potent and selective CD73 inhibitor with excellent safely and pharmacokinetic profile, is currently undergoing clinical evaluation in 1L metastatic PDAC in combination with AB122 and chemotherapy. Citation Format: Thuc M. Le, Akshata Udyavar, Woosuk Kim, Arthur E. Cho, Luyi Li, Daniel DiRenzo, Brandon Rosen, Matthew J. Walters, Joanne B.L. Tan, Caius G. Radu. CD73 inhibition enhances the effect of anti-PD-1 therapy on KRAS-mutated pancreatic cancer model [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A46.

Tyme-88-Panc Part 2: A randomized phase II/III of SM-88 with MPS as third-line in metastatic PDAC.

TPS789 Background: Patients with metastatic pancreatic cancer who have progressed on two prior lines of therapy have a poor prognosis with an overall survival in the range of 2-2.5 months. (Manax, et al. J Clin Oncol 37, 2019 suppl 4; abstr 226). There is currently no standard of care for these patients that has demonstrated improved outcomes. SM-88 (D,L-alpha-metyrosine; racemetyrosine [USAN]) is a proprietary dysfunctional tyrosine derivative and is the backbone of SM-88 used with MPS (Methoxsalen 10mg, Phenytoin 50mg and Sirolimus 0.5mg; all administered daily). SM-88 monotherapy was relatively well tolerated, with improvement in survival in select patients with heavily pretreated PDAC who achieved stable disease on therapy (HR 0.08, p = 0.02). Circulating tumor cells (CTC’s) were prognostic and decreased on therapy with SM-88 potentially identifying a subgroup of PDAC that may be most likely to benefit from therapy (Noel et al. Annal Oncol V30, Suppl 4, 2019). Preliminary radiomic analysis of the largest metastases at baseline suggested the same benefits including a correlation with baseline CTCs, changes in CTCs on therapy and OS (Ocean et al, Annal Oncol, V30, Suppl 5, 2019). Here, we describe a randomized, open-label, phase 2/3 trial evaluating the efficacy of SM-88 + MPS vs physician’s choice treatment as third line therapy for patients with metastatic PDAC. Methods: This is a multi-center Phase 3 study of patients ≥18 years with metastatic PDAC that progressed after 2 lines of chemotherapy (gemcitabine [gem] and 5-fluorouracil [5-FU] based) with an ECOG &lt;2. Randomization will be 1:1 with 250 patients being stratified by site, ECOG, and choice of chemotherapy. SM-88 will be administered at a dose of 460mg twice daily (920 mg/day). Primary end point is Overall Survival (OS). Secondary end points include progression free survival, response rate, duration of response, pharmacokinetics, safety and CTCs. Clinical trial information: NCT03512756.

Efficacy and safety of nab-paclitaxel plus S-1(nab-P/S-1) versus nab-paclitaxel plus gemcitabine (nab-P/Gem) for first-line chemotherapy in advanced pancreatic ductal adenocarcinoma (aPDAC): A randomized study.

717 Background: Nab-P/Gem significantly improved survival compared with gem in patients (pts) with metastatic PDAC, but the ORR was limited to 23% with increased myelosuppression. Two phase II trials demonstrated high ORR of 50.0-53.1% with nab-P/S-1 and showed less hematologic toxicity. Methods: A randomized (1:1) phase II trial was conducted. Eligibility required treatment-naïve pts with unresectable PDAC. Pts received nab-P 125mg/m2on day 1 + S-1 80-120mg orally per day on day 1-7 every 2 weeks or nab-P 125mg/m2+ Gem 1000mg/m2 on days 1,8 every 3 weeks. With an increase of ORR from 25% to 50%, 100 pts were required for 90% power at a two-sided significance level of 0.05. We enrolled 40 pts for a pilot study. Primary endpoints were ORR and 6-month PFS rate. Secondary endpoints were ORR of primary lesion, DCR, PFS, OS and safety. Results: 40 pts were enrolled between 06/2018 and 06/2019, including locally advanced (27.5%) and metastatic (72.5%) PDACs. 42.5% were male and the median age was 61 (range, 36-75) years old. The median duration of treatment was 2.3 months in nab-P/S-1 (n = 20) and 2.7 months in nab-P/Gem (n = 20). In the intention-to-treat (ITT) population, the ORR and DCR were 35.0% vs 25.0% ( P= 0.49) and 70.0% vs 70.0%, respectively.The ORR of primary lesion was 30.0% vs 25.0% ( P= 0.72). In the evaluable pts (nab-P/S-1 n = 18, nab-P/Gem n = 18), the ORR, DCR and the ORR of primary lesion were 38.9% vs 27.8%, 77.8% vs 77.8% and 35.3% vs 29.4%, respectively.With the median follow-up of 5.0 (range 0.3-11.4) months, the median PFS and 6-month PFS rate was 6.3 vs 5.7 months and 56.1% vs 36.2%( P= 0.61) for nab-P/S-1 and nab-P/Gem, respectively. The median OS have not reached. Grade 3/4 toxicities occurred in 30.0% nab-P/S-1 and 30.0% nab-P/Gem: leukopenia/neutropenia(15.0% vs 25.0%), febrile neutropenia (0 vs 5.0%), rash (0 vs 5.0%) and diarrhea (10.0% vs 0). Conclusions: Compared with nab-P/Gem, nab-P/S-1 had higher ORR, ORR of primary lesion and longer PFS without significant difference. Nab-P/S-1 developed a trend towards less hematologic toxicity. Follow up for survival is ongoing. Clinical trial information: 03636308.