Pancreatic Cancer Pts Research Articles

Sindilimab combined with nab-paclitaxel plus gemcitabine as first-line treatment for patients with advanced pancreatic cancer.

e16257 Background: This study aimed to evaluate the efficacy and safety of Sindilimab combined with nab-paclitaxel plus gemcitabine as first-line treatment for advanced pancreatic cancer. Methods: This was a single-arm, simple-center, exploratory trial, which included advanced pancreatic cancer pts. Patients received Sindilimab combined with nab-paclitaxel plus gemcitabine. Combined chemotherapy lasted for no more than 12 cycles. Once chemotherapy intolerance occurred or at end of 12-cycle combined chemotherapy, pts with stable disease or objective response would continue to take Sindilimab as single agent until disease progression or intolerable toxicity. Response was assessed every 8 weeks. Results: 16 eligible patients were enrolled and 14 pts were evaluable for efficacy analysis. Baseline characteristics are shown in Table 2. Conclusions: This study has showed high anti-tumor efficacy and tolerant toxicity in first-line regimen for advanced pancreatic cancer. Furthermore, it is needed to be proved in update results and large scale studies. Efficacy As shown in Table 3, among 14 evaluable pts, unconfirmed ORR was 57.1% and DCR was 92.8%. 8 pts got partial response (PR), 5 pts stable disease (SD) and 1 pts progressive disease(PD) at best. PFS: The primary endpoint 6-month PFS rate was 2%(95% CI 50.4%-72.4%). Which indicated that the primary endpoint of the study was reached. And mPFS was 7.3 months(95% CI 5.9-8.1). OS: Median OS was not reached and 6m-OS rate was 85.7% (95%CI 5%-91.3%). Safety. All 16 pts were included in the safety analysis (Table 4). The overall AE incidence rate was 93.75% .≥Grade 3 irAE included GGT increased (37.5%) and peripheral neuropathy (6.25%). No TRAE led to death.[Table: see text][Table: see text][Table: see text][Table: see text]

A phase Ib trial of ERK inhibition with ulixertinib combined with palbociclib in patients (Pts) with advanced solid tumors.

3103 Background: Activating KRAS mutations are the most frequently detected aberrant oncogenes in pancreatic adenocarcinoma. Combination strategies to target the downstream RAF-MEK-ERK effector pathway are a rational approach. Preclinical data with ERK and CDK4/6 inhibition in both pancreatic cancer cell lines and xenografts demonstrates synergistic cell death and tumor growth suppression. Ulixertinib (BVD-523) is an oral small molecule inhibitor of ERK1/2. This phase 1b study evaluated the safety, pharmacokinetics, and early clinical efficacy of ulixertinib when combined with the oral CDK4/6 inhibitor palbociclib in pts with advanced solid tumors. Methods: Using a 3+3 design, pts received ulixertinib at a starting dose of 300mg (range 300-600mg) twice daily continuously with palbociclib at a starting dose of 75mg (range 75-125mg) on D1-21 out of a 28 day cycle. The primary objective was to establish the maximum tolerated dose (MTD) of the combination. Secondary objectives included characterizing safety and estimating progression free survival (PFS). Dose limiting toxicities (DLTs) were evaluated during the first cycle of treatment. Adverse events were graded by CTCAE v4.03. Response was evaluated after 2 cycles (8 weeks) by RECIST 1.1 criteria. Results: 26 pts were enrolled (13 colorectal, 9 pancreas, 2 melanoma, 1 cholangiocarcinoma, 1 GIST); 16 were evaluable for response. The MTD of the combination was ulixertinib 450mg BID and palbociclib 125mg daily. DLTs included grade 3 fatigue, grade 3 acute kidney injury and grade 3 hyponatremia (Table). Due to toxicity in cohort 3, the protocol was amended to include two additional cohorts (2A and 2B) with a reduced dose of ulixertinib and increasing doses of palbociclib. The most common treatment-related adverse events (TRAEs) (all grades) were fatigue (70%), rash (62%) and nausea (54%). The most common laboratory TRAEs were decreased lymphocyte count (77%), decreased WBC count (73%) and anemia (65%). Grade 3 TRAEs were decreased WBC count, decreased lymphocyte count, anemia and fatigue. No grade 4/5 TRAEs were reported. Three pts demonstrated stable disease (SD). For this heavily pre-treated pt population, PFS was 2.05 months (95% CI 1.87, not determined). PK analysis for ulixertinib and palbociclib was linear and consistent with previously reported data; no drug-drug interactions were observed. Conclusions: The MTD of this phase Ib study of advanced solid tumor pts was ulixertinib 450mg BID combined with palbociclib 125 mg daily. At this dosing, 2 pts demonstrated SD, one with pancreatic cancer and one with cholangiocarcinoma. An expansion cohort of metastatic pancreatic cancer pts is ongoing. Clinical trial information: NCT03454035. [Table: see text]

Masitinib plus gemcitabine as first-line treatment of pancreatic cancer with pain: Results from phase 3 study AB12005.

4018 Background: Masitinib (MAS) is a small molecule drug targeting mast cell and macrophage activity, innate immune cells that are critical components of the tumor microenvironment. Proof of concept that MAS in combination with gemcitabine (GEM) improved overall survival (OS) in pancreatic cancer (PC) patients (pts) with pain, was previously shown [doi 10.1093/annonc/mdv133]. The presence of pain in PC is thought to identify pts whose disease is driven in part by a pro-tumoral immune response. Methods: AB12005 was a prospective, placebo (PBO) controlled, double blind, randomized (2:1 MAS:PBO, stratified by disease stage, ECOG and geographic region) phase 3 trial, evaluating oral MAS (6.0 mg/kg/d) in combination with GEM (1000 mg/m²) against PBO plus GEM for the treatment of unresectable locally advanced PC (LAPC) and/or metastatic PC (mPC) pts with pain criteria; i.e. baseline visual analog scale of pain intensity (VAS) > 20 and/or pt treated with an opioid analgesics dose ≥1 mg/kg/d at baseline. Eligible pts were chemo-naïve with histologically or cytologically confirmed inoperable LAPC or mPC and an ECOG status ≤2. The estimated sample size was ̃330 pts to detect an OS hazard ratio (HR) of 0.68 (80% power, 2-sided α = 0.025) after 310 deaths. The study was successful if improvement in median OS (primary endpoint) relative to control reached a 2.5% level of statistical significance for either a targeted subgroup of LAPC with pain criteria, or the overall study cohort. Results: A total of 384 pts were enrolled (safety population n = 383; mITT n = 379; target subgroup n = 92). In the predefined subgroup of unresectable LAPC with pain, MAS-GEM (n = 62) showed significant benefit over PBO-GEM (n = 30) with median OS of 13.0 months (97.5% CI [11.0;18.0]) vs 11.2 months (97.5% CI [7.4;13.0]); p = 0.007. The HR was 0.46 (97.5% CI [0.2;0.9], p = 0.0047), corresponding to a significant 54% reduction in risk of death for MAS-GEM pts relative to control. Secondary analyses in the same subgroup were convergent with this primary outcome. Median PFS showed a 1.8 month between group difference in favor of MAS-GEM (p = 0.039), with a HR of 0.47 (97.5% CI [0.3;0.9], p = 0.014). The 12-month and 18-month OS rates showed a 1.3 fold and 3.4 fold improvement, respectively, in favor of MAS-GEM (53.2% and 33.9% for MAS-GEM vs 40.0% and 10% for PBO-GEM, respectively). In the overall population, comprising LAPC and mPC pts with pain, no survival benefit was observed; median OS for MAS-GEM (n = 244) was 6.9 months vs 8.0 months for PBO-GEM (n = 135); p = 0.461. The MAS-GEM combination was well tolerated with no sign of add-on toxicity. The proportion of patients presenting at least one adverse event (AE) or serious AE was respectively, 96.3% and 19.1% for MAS-GEM (n = 246) vs 99.3% and 21.3% for PBO-GEM (n = 136). Conclusions: The combination MAS (6.0 mg/kg/d) plus GEM may provide a new first line treatment option for unresectable LAPC pts with associated pain. Clinical trial information: NCT03766295.

Impact of pancreatic enzyme replacement therapy (PERT) on clinical outcomes in nonresected pancreatic cancer (PC): Initial results.

400 Background: Current NCCN guidelines recommend PERT use in PC patients (pts) with symptoms of EPI. However, little evidence exists regarding clinical outcomes following PERT use in PC pts, especially those with nonresected disease. We present initial results from PERT use in this pt group regarding disease control and symptom improvement. Methods: Pts with initially nonresected PC were obtained for this study from the Virginia Mason PC Database. Eligibility criteria included:1) pathologically diagnosed nonresected adeno PC from January 2014-December 2019 ; 2) no prior PC anticancer therapy (PCRx) of any kind; 3) ≥2 PGSGA (Patient Generated Global Subjective Assessment ) forms completed with initial PGSGA reporting before 30 days following first PCRx. Pts were stratified by PERT vs non-PERT prescription as validated by the EHR. Clinicians tended to prescribe PERT based on either abnormal fecal elastase and/or clinical symptoms (e.g. diarrhea) as in the PGSGA; no formal criteria for PERT usage existed. Pts were considered to have received PERT if prescribed for the majority of time during the assessment period (i.e. > 30 days) and were analyzed based on an "intent to treat" basis without compliance validation. Results: 344 pts were identified via this method ; 207 (60%)/137 (40%) did/did not receive PERT. > 95% received Creon as PERT. Median time from 1st day PCRx to 1st reassessment was 60 days. 79% pts completed PGSGA prior to and 97% within 2 weeks of 1st day PCRx. Pt characteristics were balanced between PERT/ non PERT groups including race (90% white), age (median 68 yrs), sex (M/F 53%/47%), non-metastatic/metastatic disease 24%/76% . BMI distribution (< 18.5 3%, 18.5-25 40%, 25-30 34%, and >30 23%),and albumin distribution (<3 g/dL 6%, 3-3.4 g/dL 12% and ≥3.5 g/dL 82%). However, mean baseline PGSGA score was higher in the PERT vs non PERT group (9.9 overall, 10.9 (95% CI 10.1-11.7) vs 8.2 (95% CI 7.3 - 9.1), p< 0.01). At 1st reassessment, disease control (PR+SD) (83% overall) was greater in the PERT (87%) vs. non PERT (79%) group (p=0.04).Change from baseline PGSGA was favorable overall (Δ-5.0, 95% CI-5.7--4.3), and in all pt subsets, but with greater improvement in the PERT (Δ-6.0) vs. non PERT (Δ -3.4) group (p< 0.001) and in disease controlled (Δ-5.3) vs. non-disease controlled (Δ- 3.2) pts (p=0.033). Disease controlled vs. non-disease controlled PERT pts did not differ in their PGSGA response (Δ-6.2/-4.8, p=0.98) Conclusions: 1) PERT vs non-PERT pts were similar with respect to basic clinical or nutritional parameters (e.g. BMI, albumin) in this pt cohort. 2) Despite having more adverse baseline PGSGA scores, PERT pts were statistically superior to non PERT pts with respect to both frequency of disease control and magnitude of PGSGA response during initial Rx 3) Further investigation of the detail involving PERT usage and clinical outcomes in nonresected PC is warranted from these data.

Abstract 6478: Circulating stromal cells in resectable pancreatic cancer is associated with high pathological stage and poor clinical outcomes

Abstract Background: Pancreatic cancer (PC) is a difficult malignancy to diagnosis and properly stage, with extremely poor outcomes even for patients (pts) with resectable disease. Cancer Associated Macrophage-Like cells (CAMLs) are a recently described circulating stromal cell common to the blood of cancer pts, whose presence and size (≥50µm) is a prognostic indicator of poor progression free survival (PFS) and overall survival (OS). However, the clinical value of CAMLs in PC has not been evaluated. We recruited treatment naïve PC pts referred for surgical resection before therapy induction to study CAML association to PFS/OS. We investigate whether a simple blood test can better identify pts with metastatic disease and act as a predictor for PFS and OS. Methods: 68 whole peripheral blood samples were drawn from untreated newly diagnosed PC pts referred for surgical resection prior to induction of therapy. Pts were recruited for a 2 year single blind prospective pilot study testing >5 CAMLs, CAML size (≥50µm), CA19-9, & CEA to clinical stage (CS), pathological stage (PS), and resectability. Pts were referred based on CS with resectable (R) (n=23), borderline resectable (BR) (n=27), or locally advanced (LA)/metastatic (M) (n=16); Stage I (n=50), Stage II (n=12), Stage III (n=0), Stage IV (n=3), and unknown stage (n=2). Blood samples (7.5mL) were taken prior to any neoadjuvant therapy. Blood was filtered by CellSieveTM filtration and CAMLs quantified. Analysis of CAMLs, protein markers, and resectability were used to evaluate PFS and OS significance by log-rank testing. Results: CAMLs were found in 92% (n=61/66) of pt samples and averaged 7.5 CAMLs/7.5 mL blood. In pts that received surgery, 22 pts were upstaged with PS; stage I (n=20), Stage II (n=16), Stage III (n=5), Stage IV (n=18), & 7 pts withdrawing prior to surgery. All early stage pts with ≥12 CAMLs (n=6) were upstaged to metastatic disease after surgical resection. CEA and CA19-9 serum were not significant for PFS (CEA HR 0.9, p=0.639 and CA19-9 HR 0.6, p=0.288). Further, R vs BR was not significant for PFS (HR 0.4 p=0.10) nor was BR vs LA (PFS HR=0.2 p=0.075), though in both comparisons resectability did trend non-significantly toward better PFS. >5 CAMLs was not a significant indicator of PFS or OS (PFS HR 0.6 p=0.175 and OS HR 1.0 p=0.902). However, ≥50µm CAMLs was a highly significant indicator of both PFS and OS (PFS HR 4.0 CI95% 2.0-7.8, p>0.001 and OS HR 2.3 CI95% 1.1-4.7, p=0.035). Conclusions: In PC, accurate staging/resectability is difficult, with 60% of pts being upstaged post-surgery and ~80% recurring in 2 years. There is a need for a better method to stratify surgical candidates that won't benefit from surgical resection. These data suggest that high CAML numbers at diagnosis identifies pts with metastatic disease which are less likely to benefit from surgical resection, and enlarged CAML size correlates to poorer PFS and OS. Citation Format: Kirby P. Gardner, Daniel L. Adams, Mohammed Aldakkak, Cha-Mei Tang, Susan Tsai. Circulating stromal cells in resectable pancreatic cancer is associated with high pathological stage and poor clinical outcomes [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 6478.

Getting rurality right: Investigating cancer across the rural-urban interface.

e19063 Background: Trends in oncology examine the influence of rural characteristics on cancer patient (pt) treatment and outcomes. Current definitions of rurality are broad and varied, with multiple standardized definitions. Few analyses exist to compare definitions and quality in assessing oncologic outcomes. We aim to determine which index is most suitable to define rurality in cancer research. Methods: 1,567 pancreatic cancer pts from the University of Wisconsin Cancer Registry, representing 84 Midwestern counties and 452 zip codes, were assigned rurality codes based on three indices spanning 1983-2013: Rural-Urban Continuum Code (RUCC), Rural-Urban Commuting Areas (RUCA), and Index of Relative Rurality (IRR). RUCC and IRR were assigned to pts at the county level and RUCA at the zip level. Pt rurality was compared across the three indices and over time via the median and interquartile range and inspected visually with violin plots. We compared indices with Spearman’s Rank Order Correlation (SROC). Results: RUCC 2003, RUCA 2004 (zip), and IRR 2000 were concordant in terms of metropolitan, micropolitan, and rural designations for 66.9% (1,049) of pancreatic cancer registry pts. The rural designation for almost one-third (489, 31.2%) of pts was discordant by one or two levels across the three indices (i.e. classified as metropolitan in one index and micropolitan or rural in another). SROC was 0.73 between RUCC 2003 and RUCA 2004 (zip) indices, 0.82 between IRR 2000 and RUCA 2004 (zip), and 0.85 between RUCC 2003 and IRR 2000. Across the 84 counties of registry pts’ residence, the median and interquartile range of RUCC decreased from 6 (3-7) in 1983 to 4 (2.25-6) in 2013 and of IRR decreased from 0.49 (0.44-0.53) in 2000 to 0.49 (0.43-0.53) in 2010. Across the 452 zip codes, RUCA decreased from 4 (1-10) in 1998 to 3 (1-8) in 2004. Pts’ median RUCC decreased from 3 (2-6) in 1983 to 3 (2-4) in 2013, median RUCA (zip) decreased from 2 (1-7) in 1990 to 1 (1-6) in 2000, and IRR remained constant at 0.42 (0.38-0.49) in 2000 and 2010. Conclusions: RUCC is preferable for state-level cancer studies incorporating rurality as it best distributes pts across the rural-urban interface compared to RUCA (skews urban) and IRR (skews central). County boundaries (RUCC) are consistent over time versus zip (RUCA) and census tract (RUCA). Our findings suggest that while the extremes of rural and urban are well-defined, rurality as a continuum is inconsistently measured. Researchers should continue to incorporate other measures of vulnerability to achieve health equity.

Real-world survival outcomes of using neoadjuvant chemotherapy in pancreatic cancer patients: Findings from the PURPLE clinical registry.

e16755 Background: Only a minority of pancreatic cancer patients (pts) are surgical candidates at presentation. Neoadjuvant chemotherapy (NAT) is proposed to increase the proportion of surgical candidates. This study investigates the impact of NAT in routine care of pancreatic cancer. Three cohorts were analysed, patients with early-stage resectable (ER), borderline resectable (BR) and locally advanced (LA) pancreatic cancer. Within these groups, survival outcomes of those undergoing immediate resection (IR) was compared to those receiving NAT with nab-paclitaxel and Gemcitabine (nabPGem) and NAT with FOLFIRINOX. Methods: The PURPLE registry consists of 1492 pancreatic cancer pts from 27 hospitals in Australia, New-Zealand and Singapore, collated between 2016-2019. After exclusion of LA unresectable and metastatic pts (n = 809), 683 pts were included. Kaplan-Meir curves estimated survival between groups with 95% confidence intervals. Multivariable cox proportional hazards models adjusted for age, gender and ECOG performance status. Results: Of 683 pts, 107 received NAT and 576 underwent IR. Those in the NAT group had favourable characteristics, including younger age (mean 63 vs. 66 yrs, p < 0.01) and higher proportion of ECOG 0 vs. ≥1 (64% vs 46%) than those undergoing IR. Of those that received NAT, 64 received FOLFIRINOX and 35 nabPGem. Those receiving FOLFIRINOX were younger (mean: 60 vs. 67 yrs, p < 0.01) and were more likely ECOG 0 compared to those receiving nabPGem (72% vs. 46%, p = 0.02). Resection rates for pts undergoing IR vs. NAT were 88% vs. 50% in ER and 16% vs. 43% in BR. Rates of R0 resection margins in pts undergoing IR vs. NAT were 54% vs. 25% in ER and 6% vs. 21% in BT. Comparing ER to BR, mOS was 29.9 vs. 20.3 mths (HR: 0.54, p < 0.01). Within BR, mOS was 20.3 vs. 17.2 mths for NAT vs. IR (HR: 1.11, p = 0.74). Comparing those receiving FOLFIRINOX vs. nabPGem over all groups, mOS was 22 mths vs. 12 mths (HR: 0.31, p < 0.01). Conclusions: Real-world data confirms the use of NAT remains infrequent in this Asia-Pacific population. The use of FOLFIRINOX was associated with better survival than nabPGem based on this observational study. Improved methods for treatment selection are required. Potential biomarkers including circulating tumor DNA are being explored in the DYNAMIC-Pancreas clinical trial.

Olaparib (O) in patients (pts) with pancreatic cancer with BRCA1/2 inactivating mutations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

4637 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of pancreatic cancer pts with germline or somatic BRCA1/2 inactivating mutations treated with O are reported. Methods: Eligible pts had advanced pancreatic cancer, no standard treatment (tx) options available, measurable disease, ECOG Performance Status (PS) 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received O tablets or capsules dosed at 300 mg (n=27) or 400 mg (n=3), respectively, orally twice daily until disease progression. Simon 2-stage design tested the null disease control (DC) (objective response (OR) or stable disease at 16+ weeks (wks) (SD16+) according to RECIST) rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the tx is worthy of further study. Secondary endpoints are progression-free survival (PFS), overall survival (OS), and safety. Results: Thirty pts with BRCA1/2 inactivating mutations were enrolled from Nov 2016 to Aug 2019; 20 were previously treated with platinum based therapy. Two were not evaluable and excluded from efficacy analyses. Demographics and outcomes are summarized in Table. One partial response (PR) and 7 SD16+ were observed for DC and OR rates of 31% (90% CI: 18% - 40%) and 4% (95% CI: 0% - 18%), respectively. Seven pts had at least one grade 3 AE or SAE at least possibly related to O including anemia, diarrhea, fever, elevated liver enzymes, enterocolitis, increased bilirubin, and oral mucositis. Conclusions: Monotherapy O showed anti-tumor activity in heavily pre-treated pts with pancreatic cancer with germline (5/12 pts with OR or SD16+) or somatic (3/16 pts with OR or SD16+) BRCA1/2 inactivating mutations extending findings of recent studies of O in pts with advanced pancreatic cancer. Clinical trial information: NCT02693535 . [Table: see text]

Germline ATM mutations on survival in metastatic pancreatic cancer patients.

e16746 Background: Ataxia telangiectasia mutated (ATM) protein is a DNA damage repair enzyme and regulates normal cell-cycle mechanisms. Germline ATM mutations are associated with increased risk for developing pancreatic cancer (PC), occurring in approximately 2% of PC patients (pts). The role of germline ATM mutations in PC is not well defined. The objective of this study was to compare survival outcomes in patients with germline ATM mutations compared to somatic ATM mutations in PC. Methods: Tumor genomic profiling was completed in 144 PC patients at a single institution in the US, where pts were included in the analysis if they had either germline ATM mutations or somatic ATM mutations. Clinical outcomes were compared between pts with germline ATM mutations and pts with somatic ATM mutations only. Adjusted Cox regression models were fit to evaluate the impact of ATM mutation on overall survival (OS), calculated from treatment (tx) initiation to death, and progression free survival (PFS) calculated from tx initiation to first progression. Results: From 144 PC pts evaluated, 7 pts (4.9%) had germline ATM mutations, all of whom presented with metastatic disease, and 14 pts (9.7%) with somatic ATM mutations only, of whom 10 presented with metastatic disease and 4 who initially presented with locally advanced PC. The majority of pts (15/21), including all 7 pts with germline ATM mutations and 8 with somatic ATM mutations, were treated with first line gemcitabine and abraxane. Median OS was not reached in patients with germline mutations, and 11 months for patients with somatic mutations. Pts with germline ATM mutations had significantly higher OS (HR: 0.12, 95% CI 0.03-0.62, p = 0.01) and PFS (HR:0.26, 95%CI 0.07-0.91, p = 0.04) compared to patients with somatic ATM mutations only after adjusting for age, sex, and first-line tx. Conclusions: Pts with germline ATM mutations may experience greater survival benefit from tx compared to those with only somatic ATM mutations. Further research into the underlying mechanism is warranted.

DUO-E/GOG-3041/ENGOT-EN10: a randomized phase III trial of first-line carboplatin (carb) and paclitaxel (pac) in combination with durvalumab (durva), followed by maintenance durva with or without olaparib (ola), in patients (pts) with newly diagnosed (nd) advanced or recurrent endometrial cancer (EC).

TPS6108 Background: There is a high unmet need for advances in EC treatment that provide progression-free survival (PFS) and overall survival (OS) benefits. EC tumors are sensitive to carb/pac (Pectasides et al. Gynecol Oncol 2008). Maintenance therapy with the poly(ADP-ribose) polymerase inhibitor (PARPi) ola (with or without bevacizumab) led to significant PFS benefits in advanced ovarian cancer pts with either nd (SOLO1, Moore et al. NEJM 2018; PAOLA-1, Ray-Coquard et al. NEJM 2019) or recurrent (SOLO2, Pujade-Lauraine et al. Lancet Oncol 2017; Study 19, Friedlander et al. Br J Cancer 2018) platinum-sensitive disease, regardless of BRCA mutation status (PAOLA-1; Study 19), and in BRCA-mutated metastatic pancreatic cancer pts (POLO, Golan et al. NEJM 2019). Molecular features of EC could predict sensitivity to PARPi (de Jonge et al. Clin Cancer Res 2019; Auguste et al. Mod Pathol 2018). PARPi has been shown to prime the immune microenvironment in a preclinical BRCA1 mutant ovarian model (Higuchi et al. Cancer Immunol Res 2015). Clinical trials have demonstrated antitumor activity of the anti-programmed cell death ligand-1 (anti-PD-L1) blocker durva (Antill et al. J Clin Oncol 2019) and anti-programmed cell death-1 (anti-PD-1) antibody therapies (Makker et al. ESMO 2019; Oaknin et al. SGO 2019) in EC pts. The DUO-E trial (EUDRACT 2019-004112-60, D9311C00001, NCT04269200) will investigate whether the addition of durva to carb/pac, followed by durva (with or without ola) maintenance treatment, improves PFS in pts with nd advanced or recurrent EC. Methods: Eligible pts for this multicenter, double-blind, Phase III trial must have nd Stage III/IV or recurrent EC and be naïve to first-line chemotherapy. Pts will be randomized (1:1:1; n=~233 per arm) to: arm A) carb/pac + placebo (pbo) (q3w for six cycles) followed by pbo maintenance treatment; arm B) carb/pac + durva (1120 mg; q3w for six cycles) followed by maintenance treatment with durva (1500 mg q4w) + pbo (tablets bid); or arm C) carb/pac + durva (1120 mg; q3w for six cycles) followed by maintenance treatment with durva (1500 mg q4w) + ola (300 mg bid tablets). Pts received maintenance treatment until disease progression. Primary endpoint: investigator-assessed PFS (RECIST 1.1) of arm B vs. arm A. Key secondary endpoints: PFS of arm C vs. arm A; OS of arm B vs. arm A, and of arm C vs. arm A. Enrollment began in Q1 2020. Clinical trial information: 2019-004112-60.

Use of a real-world data approach to rapidly generate outcomes data following a case study of a novel treatment combination in pancreatic adenocarcinoma.

e16735 Background: We use a real-world data approach to report on safety and benefits on metastatic pancreatic cancer pts who were treated with a MEK inhibitor plus hydroxychloroquine (HCQ) after exhausting all other treatment options. MEK inhibition acts on the KRAS pathway, which in turn increases autophagy as a resistance mechanism, furthermore, HCQ inhibits autophagy causing a cytotoxic effect. This combination was shown to diminish tumor volume in xenograft mouse models and a partial response in one heavily pre-treated patients was reported. Methods: XCELSIOR is an IRB approved, patient-centric, real-world data and outcomes registry for developing operational and analytic methods in precision oncology. Searching the XCELSIOR database, we identified 14 pts for whom this regimen had been considered. As part of their participation in XCELSIOR, these patients shared access to their full medical records, which were collected, processed, and abstracted into a 21 CFR 11 compliant database for analysis. We additionally collected de-identified data on 12 pts treated with this combination from five academic centers. Three more patients are expected to start treatment soon. Results: Between March 2018 and January 2020, 15 patients treated with the trametinib/HCQ combination and 3 patients treated with cobimetinib/HCQ were identified in XCELSIOR and five academic institutions. The median age at diagnosis was 64 (range 43-74) and 56% were male. For patients treated with trametinib/HCQ, the median time on treatment was 67 days (range 5-172 days), 11 patients were treated for more than 30 days (median time 97 days). The median PFS for this group was 2.9 months and the median OS was 7.4 months. The clinical benefit rate was 60% for the 10 evaluable patients treated with trametinib/HCQ, 1 patient had a partial response (previously published), 5 had stable disease (for at least 8 weeks) and 4 had progressive disease (physician reported). 2/3 patients treated with cobimetinib/HCQ were on treatment for more than 30 days and all three had progressive disease within 7 weeks. The most common side effects were Grade 1 fatigue and Grade 1/2 rash for both combinations. An additional 3 patients will start treatment soon and will be included in the analysis. Conclusions: Combinatorial MEK and autophagy inhibition was well tolerated in heavily treated metastatic pancreatic cancer patients. Trametinib/HCQ demonstrates some clinical benefit for this group. We demonstrate the feasibility of utilizing real-world data in precision oncology. Clinical trial information: NCT03793088 .

Implementation of systematic genetic counseling (GC) and multigene germline testing (MGT) for pancreatic cancer (PC) patients (pts).

678 Background: MGT identifies cancer susceptibility gene variants in 4-10% of unselected PC pts. Such data have prompted national guidelines to recommend GC and MGT of all PC pts, but the benefits and barriers to implementing systematic testing are unknown. This study’s aim was to study the implementation of universal GC for all PC pts seen in an academic oncology practice. Methods: In 12/2016, all Dana-Farber Cancer Institute (DFCI) gastrointestinal oncologists were recommended to refer all PC pts for GC and MGT. In 10/2018, workflows were changed such that PC patients were automatically scheduled for GC consultation on the same day as their initial oncologic evaluation (unless patients opted out), rather than relying on provider referral. Clinical and germline data were collected on a consecutive cohort of PC pts undergoing GC and MGT from 3/1/2017-3/31/2019. Two additional months (4/1/2019-5/31/2019) were collected for clinical quality assessment purposes. Results: 1305 (48.3/month) PC pts were seen for oncologic new patient visits, 318 (25.1%; 12.1/month) of whom underwent GC. Rates of GC/MGT increased significantly after the 10/2018 workflow change (8.2 PC pts/month [17.2% of all new PC pts seen] versus 20.3 PC pts/month, [40.9% of all new PC pts seen]; p<0.01). Of the 318 PC pts who underwent GC, 29 (9.1%; 95% CI 6.4-11.9%; 2.2% of all PC pts seen) were found to carry germline PC susceptibility gene mutations on MGT. Rates of mutation carrier identification increased after the clinical workflow change from 0.79 mutation carriers/month (1.6% of all new PC pts seen) to 1.75 mutation carriers/month (3.5% of all new PC pts seen). The majority of identified mutation carriers have either received therapy targeted towards their germline mutation or are undergoing first-line palliative systemic therapy with potential for future targeted therapy. Conclusions: Clinical implementation of routine GC/MGT in PC pts is feasible and results in the detection of mutations that are actionable for PC pts and at-risk family members. Systematized workflows for GC evaluation not reliant on active referral result in markedly higher uptake of MGT and mutation carrier identification. Clinical trial information: NCT03060720.

Changing the landscape of germline testing in patients with pancreatic adenocarcinoma.

676 Background: Results from the POLO trial demonstrated the benefits of PARP inhibition in patients (pts) with germline BRCA-mutated metastatic pancreatic cancer (PC). In 2018, ASCO and NCCN updated their guidelines to recommend that pts with a personal history of PC undergo germline testing. We examined referral patterns and frequency of germline pathogenic variants in pts with PC. Methods: A retrospective review was performed of PC pts seen at the Levine Cancer Institute (LCI) Center for Genetics between January 2010 and September 2019. Descriptive analyses were completed on demographics and appointment outcomes. Results: A total of 201 PC pts were referred; 20 canceled and 14 no-showed their appointment. The remaining 167 were seen and included in this analysis. Most pts (59%) were referred after July 2018. The median age was 65 years (range 32-90) and 19% were < 50 years. The majority of pts were female (61%). Race was most often reported as white (72%) followed by black (20%). Reported family histories were as follows: 28 (17%) claimed at least one first-degree relative with PC; 54 (32%) claimed a first, second, or third-degree relative with PC; 24 (14%) had no known family history of PC; and 95 (57%) claimed a first-degree relative with another cancer (breast [37], prostate [25], colon [18], ovarian [9], uterine [6], and gastric [2]). Germline testing was pursued by 138 (83%) pts: 25 (18%) were found to have a pathogenic variant and 50 (36%) a variant of uncertain significance. Pathogenic variants were most commonly identified in ATM (24%), BRCA2 (20%), PALB2 (12%), and CDKN2A (8%). Variants were also observed in DIS3L2, HOXB13, MITF, MUTYH (heterozygote), NTHL1 (compound heterozygote), RAD50, PRSS1, and SDHA. Among pts that had a pathogenic variant, cascade testing was performed in 11 families (44%) for 29 individuals. Conclusions: Our data suggest that the referral of PC pts to genetics has increased following updated ASCO/NCCN guidelines. However, improved adherence to genetic counseling is needed. ATM and BRCA2 were the most common germline mutations observed. More effort to increase awareness of genetic testing and its potential implications for pts and their families is warranted and might reduce cancellations and missed visits.

Utilization of somatic comprehensive genomic profiling (CGP) to identify patients (pts) with pancreatic cancer (PC) that harbor germline DNA damage repair (DDR) gene alterations.

760 Background: Somatic and germline DDR gene alterations in PC have been postulated to positively predict response to DNA damaging cytotoxic agents. Due to the relatively high prevalence of germline DDR gene alterations, germline testing is recommended in all pts with PC. We examined whether somatic CGP can be used to reliably identify PC pts that merit germline testing. Methods: We retrospectively reviewed the electronic medical records of PC pts who underwent both somatic CGP (utilizing the Foundation One assay) and germline testing. DDR gene mutations were categorized as somatic-pathogenic, somatic-variant of uncertain significance (VUS), germline-pathogenic and germline-VUS. For somatic testing, DNA was extracted from formalin fixed paraffin embedded (FFPE) clinical specimens and CGP was done on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of > 600 for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer. Germline genetic testing was performed on submitted blood or saliva samples, utilizing commercial assays; next generation or Sanger sequencing of all coding regions and adjacent intronic nucleotides were performed. Results: Ninety-three pts had somatic CGP data, 51 (55%) pts had both somatic CGP and germline data available. Among the 51 pts with both germline and somatic data available, DDR gene alterations that were somatic-pathogenic, germline-pathogenic, somatic-VUS and germline-VUS were present in 7 (13.7%), 7 (13.7%), 23 (45.1%) and 16 (31.4%) pts, respectively. Of the 7 pts with somatic-pathogenic alterations, 5 (71%) had a concordant germline alteration and of the 7 pts with germline-pathogenic alterations, 5 (71%) had a concordant somatic alteration. Of the 23 pts with somatic-VUSs, 12 (52%) had a concordant germline VUS and of the 16 pts with germline-VUSs, 12 (75%) had a concordant somatic VUS. Conclusions: Both somatic and germline DDR gene alterations are common in PC pts. Despite the relatively high concordance rate between somatic and germline pathogenic DDR gene alterations, somatic CGP will miss approximately one fourth of the germline DDR gene alterations.

Modified FOLFIRINOX in pancreatic cancer patients Age 75 or older

BackgroundAlthough FOLFIRINOX (5-Fluorouracil + leucovorin + irinotecan + oxaliplatin) is now the standard of care for patients (pts) with metastatic pancreatic cancer (PC) based on the 2011 study by Conroy et al. which demonstrated improved median overall survival (mOS), pts > 75 yrs old were excluded from this study. The purpose of this study was to assess the safety and efficacy of modified FOLFIRINOX (mFOLFIRINOX) in this population. MethodsWe retrospectively analyzed unresectable PC pts, age ≥ 75, treated with mFOLFIRINOX at MD Anderson from 2011 to 2017. Primary outcome was rate of grade 3 or 4 hematologic toxicity (HT). Results24 pts were included. Grade 3 or 4 HT occurred in 11 pts 6 pts required hospitalization for any toxicity, and 10 stopped mFOLFIRINOX due to toxicity. The most frequently used starting doses of infusional 5-FU, irinotecan and oxaliplatin were 2400, 150 and 75 mg/m2, respectively. Median PFS was 3.7 months (95% CI: 3.0–5.7) with a median OS of 11.6 months (95% CI: 6.14–15.7). For first line pts, median PFS and OS were 5.1 (95% CI: 2.0–12.8) and 12.2 months (95% CI: 4.8–30.8), respectively. ConclusionsIn this single-center retrospective analysis of unresectable PC pts age 75 or older given mFOLFIRINOX, toxicities and survival outcomes were similar to those reported in the initial study. These data indicate that the use of modified dosing FOLFIRINOX in advanced PC pts older than 75 appears to maintain similar toxicity and efficacy when compared to younger pts.

711P - The analysis of genomic signatures of head and body/tail of pancreatic cancer in Chinese patients

BackgroundThe incidence of pancreatic cancer (PAC) has continued to rise in recent years. PAC can be divided into head of PAC (HPAC) and body/tail of PAC (BTPAC) by the anatomical location. The patients (pts) with BTPAC are usually diagnosed at relatively advanced stage and had worse survival than those with HPAC. The comparative molecular signatures between different locations in Chinese PAC pts remain unclear. Methods154 tumor specimens (HPAC, N=85; BTPAC, N=69) and matched normal blood samples of Chinese PAC pts were detected and analyzed in a CAP&CLIA certified laboratory (OrigiMed company) with Yuansu panel including 450 genes. Total 100 males (65%) and 54 females (35%) with a mean age of 61 years old (yrs) were enrolled. We measured the somatic variations and calculated tumor mutational burden (TMB) after filtering known driver mutations (muts). Meanwhile, germline muts were analyzed among the tumor susceptibility genes. Fisher tests were used for comparative analyses. ResultsThe median age in HPAC and BTPAC was 60 yrs and 62 yrs. Pts with stage 3&4 accounted for 40% and 60% in HPAC and BTPAC (P<0.05). Genomic alterations of KRAS and SMAD4 were significantly more prevalent in BTPAC (KRAS in BTPAC vs. HPAC= 97% vs. 82%, P=0.004; SMAD4 in BTPAC vs. HPAC= 42% vs. 21%, P=0.008). 2 NTRK3 fusions (3%) were found in BTPAC but 0 in HPAC. Additionally, muts frequency in Wnt pathway was 57% in BTPAC, whereas 37% in HPAC (P=0.02). No significant difference was found in TP53 (83% vs. 81%), CDKN2A (32% vs. 27%) and germline muts frequency (12% vs. 14%) between BTPAC and HPAC, nor in the mean TMB value (3.22 muts/Mb vs. 3.59 muts/Mb). For HPAC, there were more muts in HR pathway genes (24% vs. 19%), although the difference was not statistical significance. 2 BRCA2 germline muts were found in HPAC but neither BRCA1 nor BRCA2 was found in BTPAC. ConclusionsGenomic pattern did not show apparent difference between the anatomic locations of PAC. However, we found more driver muts in KRAS and SMAD4 and more Wnt pathway muts related to proliferation and metastasis in BTPAC. Further research should be done to better understand the cancer biology among the locations and identify more therapy targets for precision medicine. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Abstract 401: Clinical impact of viable circulating tumor cells (v-CTC) detection and PD-L1 expression on v-CTC in the patients with resectable pancreatic cancer

Abstract [Introduction] The capture and analysis of CTCs as “liquid biopsy” provides the possibility to avoid invasive biopsies, obvious implications in cancer diagnosis and staging. We tested novel methods for viable CTCs (v-CTC) isolation in the patients (pts) with pancreatic cancer (PC), and investigated the clinical potential of v-CTCs in prognosis. We analyzed the PD-L1(L1) expression in both PC tumors and v-CTCs. [Pts and Methods] 7.5 ml of venous blood was collected prospectively from 39 PC pts, either surgery first (S group) or pre-treatment, consisted of Gem:800mg/m2; and S-1:80mg/m2 given concurrently with IMRT to 60Gy (NACRT:N group). To detect v-CTCs, we employed a telomerase-specific replication-selective adenovirous expressing GFP. For S group, samples were obtained before/after resection. For N group, samples were obtained before/after NACRT and after resection. To distinguish between leucocyte and cells with either epithelial or mesenchymal origin, cells were stained by anti-CD45, anti-Cytokeratin and anti-Vimentin Abs. GFP-positive and CD45-negative cells were counted as v-CTC. To assess L1 expression in PC tissues (IHC) and v-CTCs, L1 IHC kit (22C3, for tissues) and anti-human L1 mAb(MIH1,for CTCs) were employed. [Results]S group: 24 pts aged 53~85 years (male/female=12/12) were enrolled. 24 pts underwent curative resection. No v-CTCs were detected in 6 pts at both before and after resection, and 5 of 6 pts survived without recurrence. V-CTCs were identified in 18 of 24 pts, and 13 of 18 pts developed liver metastasis. Marked decrease of CTC counts were seen after resection in 10 of 18 pts, but 9 pts developed recurrence. N group: 15 PC pts aged 44~77 years (male/female=4/11) were enrolled. 15 pts underwent curative resection. No v-CTCs were detected in 5 pts, and 5 pts survived without recurrence. V-CTCs was identified in 10 of 15 pts, and only 3 out of 10 pts developed disease recurrence. Marked increase in CTC counts was observed after NACRT in 5 of 6 CTC-positive pts before NACRT, and 3 of 5 pts developed liver metastasis and died. NACRT may induce tumor cell dissemination into the blood circulation for CTC-positive pts. PD-L1 expression: L1 expression were assessed for 21 pts (S group:18, N group: 3). No patients with IHC-L1 high expression (≥50%) were observed (&amp;lt;1% [negative]:9, 10%:6, 20%:4, 40%:2). For S group, IHC-L1 low +/CTC-L1 + were detected in 12/18 pts (66%). IHC-L1-/CTC-L1+ were detected in 3/18 pts (17%). IHC-L1 - /no detectable CTCs were detected in 3/18 pts (17%). For N group, IHC-L1 - were detected in 3 pts, but CTCs-L1 + were detected in 2 pts (1 pt had no CTCs). The majority of detectable v-CTCs were positive for L1-expression (89% [92/103 CTCs]), despite L1-negative or -low expression in PC tissues. [Conclusions] Viable CTC detection appears as a promising prognostic marker. Immunotherapy with anti-PD-1/PD-L1 Abs may effectively target v-CTCs. Note: This abstract was not presented at the meeting. Citation Format: Masahiro Tanemura, Kenta Furukawa, Manabu Mikamori, Takurou Saito, Masahisa Otsuka, Yozo Suzuki, Kentaro Kishi, Hironao Yasuoka, Masahiko Tsujimoto, Yasuo Urata, Hiroki Akamatsu. Clinical impact of viable circulating tumor cells (v-CTC) detection and PD-L1 expression on v-CTC in the patients with resectable pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 401.

Goals of care designation associated with improved survival and indicators of quality end-of-life care in pancreatic cancer (PC) patients (pts) undergoing palliative chemotherapy.

11532 Background: Discussion of goals of care (GoC) is a key part of quality care for pts with palliative cancer. Numerous studies have shown that documentation of GoC in this population remains low. Here we describe changes in GoC documentation and other indicators of quality end-of-life care in PC pts undergoing palliative chemotherapy during a health-system wide initiative to improve advanced care planning (ACP). Methods: This is a retrospective cohort analysis of 106 pts with locally advanced or metastatic PC treated with palliative chemotherapy from 2012-2015 in Northern Alberta (Canada). In 2014, an initiative was launched to provide pts with hard copies of their GoC designation intended to be available at all health-system interactions. Data were obtained from outpatient medical oncology (MO) and palliative care (PAL) notes and the provincial cancer registry. Survival analysis used a multivariate Cox-regression. All other tests were Chi-squared. Results: 50% (53/106) of pts had a documented GoC discussion, with 45% (48/106) receiving a specific GoC designation. In 2012, 31% (6/19) of pts had a GoC designation, which increased to 61% (20/33) in 2015. Of 84 individual GoC discussions documented, 34% (29/84) were by MO, 62% (52/84) were by PAL, and at least 8% (7/84) referenced prior discussions with a family physician or discussion while admitted to hospital. Pts with a GoC designation had increased median overall survival (287 vs 216 days; HR = 0.62; p = 0.041), and were less likely to receive chemotherapy in the last two weeks of life (p = 0.016). Conclusions: Rates of GoC discussions for PC pts undergoing palliative chemotherapy increased during a health-system wide ACP initiative. Having a GoC designation was associated with greater overall survival and indicators of higher quality end-of-life care.

Impact of no treatment vs other nonsurgical treatments in Pancreatic Adenocarcinoma National Cancer Database: 2004-2014.

e15795 Background: Surgery remains the only curative treatment option in pancreatic adenocarcinoma, yet in more than 50% of the patients (pts) the disease is too advanced or at very high risk and considered inoperable. They are either managed with no treatment or other nonsurgical methods. Hence, we analyzed a large cohort of pancreatic adenocarcinoma pts undergoing No Treatment vs Chemotherapy, Radiation or Chemoradiation to determine their impact on survival. Methods: Only pancreatic adenocarcinoma pts who had no surgery in the National Cancer Database (NCDB) from 2004–2014 were included. Of that group, patients with unknown or missing data about chemotherapy or radiation treatment or less than 3 years of survival data were excluded. Pts were stratified into 4 groups: Chemotherapy, Radiation Therapy, Chemoradiation and No Treatment. Overall 1-, 2- and 3-year survival was calculated and the groups were compared using Pearson’s chi-squared. Results: Of the total 309,709 pancreatic cancer pts in the NCDB 2004–2014, 111,421 (36.0%) remained after application of the study criteria. Of these, 43,203 (38.8%) received chemotherapy only, 2,453 (2.2%) received radiation only, 15,764 (14.1%) received chemoradiation and 50,001 (40.0%) had no treatment. Overall survival for 1, 2, and 3 years was best in the chemoradiation group with a 1 year survival of (40.0%) compared to chemotherapy only (22.4%), radiation only (14.9%) and no treatment (9.6%). Overall, only (19.0%) of pts survived for 1 year, (5.4%) survived for 2 years and (2.3%) survived for 3 years. (Table) Conclusions: Survival in pancreatic adenocarcinoma pts remains dismal without surgery. Best survival in nonsurgical pts was seen after combination Chemoradiation therapy and worst survival in No Treatment group. Hence, whenever possible, a combination Chemoradiation should be offered even as palliation in non-surgical pancreatic adenocarcinoma pts.[Table: see text]

A retrospective analysis of antibiotics usage and effect on overall survival and progressive free survival in patients with metastatic pancreatic cancer.

e15781 Background: Recent studies have shown that the pancreatic ductal adenocarcinoma (PDAC)-associated gut microbiome can play a major in modulating responses to therapies. Antibiotics (ATB) can potentially alter the tumor and gut microbiota diversity and composition leading to modified responses to chemotherapeutic/immune therapy regimens and hence the survival. Methods: We retrospectively analyzed the clinical data of 148 patients (pts) with documented metastatic PDAC seen at MD Anderson Cancer (MDACC) from 2009 to 2017. Along with demographic and chemotherapy regimen details the duration, type and reason for antibiotic consumption for more than 3 days were recorded. Overall survival (OS) and Progression free survival (PFS) were calculated. Log-rank test and Gehan-Breslow-Wilcoxon test were used to check the statistical significance for OS and PFS. Confounding variables were also accounted. Results: We analyzed the data of 148 metastatic pancreatic cancer pts[mean age 62.73, 50.67% males 49.32% females, 75.6% white] out of which 135 patients received antibiotics. The infectious sources consisted of intraabdominal (n = 68), urinary (n = 36), respiratory (n = 57), skin/soft tissue infections (n = 26), blood related (n = 24), and others (n = 76). Beta lactams (n = 96) and Quinolones (n = 96) were the most commonly prescribed antibiotics. When comparing outcomes, we found out that the median OS for pts taking macrolides (n = 24) was 541 days compared to 341 days for pts not taking macrolides (n = 144) (HR = 0.6384, p value = 0.0191) . Median PFS for pts taking macrolides was 178 days versus 124 days in those not taking macrolides (HR = 0.6331, p value = 0.0188). The potential confounders were having a respiratory infection or the type of chemotherapy regimen. Conclusions: Macrolide consumption for &gt; 3 days leads to a prolonged OS and PFS. Consistent with the preclinical evidence our data suggests a potential role for some antibiotics in modulating PDAC-associated gut microbiome. Hence, having implications on the survival of PDAC pts. [Table: see text]