bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacogenomic blood-based assay to predict chemotherapy response and survival in pancreatic cancer.
Authors: Yu Kenneth H. , McCarthy Brian , Isacoff William H. , Cooper Brandon , Bartlett Andrew , Park Jennifer , Purcell Fay , McCarthy Devan , O'Reilly Eileen Mary
Published: February 2020

738

Background: Pancreatic adenocarcinoma (PDAC) is for most patients a refractory disease. Modern cytotoxic chemotherapeutics (C) are not yet optimal for inducing responses and extending life. We are developing a blood-based pharmacogenomic (PGx) assay profiling circulating tumor and invasive cells (CTICs) to predict sensitivity and resistance to C. Methods: The PGx assay was studied in two cohorts of patients (pts) presenting for frontline C therapy of metastatic PDAC. Cohort 1 is from an ongoing prospective study (planned n=80); pts are enrolled prior to receiving either FOLFIRINOX or gemcitabine (Gem)/nab-paclitaxel (Nab-P). Cohort 2 (n=50) consists of pts enrolled prior to receiving bespoke combinations of C agents informed by the assay. 6 mL of peripheral blood was collected from pts at baseline and while on C therapy. CTICs were isolated by previously described collagen invasion assay, total RNA was extracted and gene-expression analysis was performed. PGx models for seven C agents used in PDAC were applied, and correlated to treatment received. Pts were classified as sensitive if C received were predicted to be effective and resistant if not. Objective endpoints were PFS and OS. Results: Cohort 1 patients who received sensitive first-line C combinations experienced significantly longer time to progression (TTP) v resistant (Table). In Cohort 2, the PGx assay was predictive of TTP and OS when used across multiple lines of therapy, with a two-year survival of 38%. Greater OS was observed in Cohort 2 pts receiving heterogenous C regimens more highly correlated to those predicted by the PGx assay. Conclusions: The PGx assay has promising predictive performance in both standard and personalized C regimens. A prospective, directed trial comparing these approaches is warranted. Clinical trial information: NCT03033927. [Table: see text]
Prognostic utility of inflammation biomarkers in a PDAC trial involving the human anti-CTGF antibody pamrevlumab.
Authors: Sternlicht Mark D. , Li Dongxia , Nguyen Viet-Tam , Carney Mairead , Zhou Duo , Lipson Kenneth E. , Kouchakji Elias , Picozzi Vincent J. , Carrier Ewa , Seeley Todd W.
Published: February 2020

752

Background: Pancreatic ductal adenocarcinomas (PDAC) often exhibit desmoplasia, elevated CTGF (connective tissue growth factor) expression and inflammation. The influence of inflammation on patient outcomes was examined in a dose-ranging trial of the anti-CTGF antibody pamrevlumab in combination with a fixed regimen of gemcitabine and erlotinib in locally advanced or metastatic PDAC patients (NCT01181245; Picozzi et al. J Cancer Clin Trials 2017 2:123; n = 75). Methods: The prognostic utility of pre-treatment plasma levels of C-reactive protein (CRP), transforming growth factor β1 (TGFβ1), albumin, CTGF and CA 19-9 were assessed by univariate and multivariate Cox analysis. Demographic parameters, treatment cohort, and pamrevlumab exposure determined on treatment day 15 were also evaluated, as were changes in biomarker levels over the first four weeks of treatment. Results: Elevated baseline CTGF and CRP were prognostic for shorter overall survival (OS) by univariate analysis (HR = 3.2 for CRP > 10 mg/L, p= 0.00002 and HR = 1.6 for CTGF > 10 ng/mL, p= 0.045). In a five-factor multivariate Cox model that included CRP and TGFβ1 as continuous Ln-transformed variables, performance status, age, and pamrevlumab treatment cohort, cohort assignments associated with increasing pamrevlumab exposure predicted improved OS (HR = 0.87, p= 0.03). Removing CRP from this model reduced the prognostic utility of pamrevlumab cohort assignment and exposure, indicating an important contribution of inflammation to interpretation of treatment outcome. Changes in inflammation biomarkers over the course of treatment were also evaluated, but were not prognostic in this study. Conclusions: In multivariate Cox models, assessment of pre-treatment CRP levels improved ability to detect significant differences in PDAC patient survival outcomes associated with pamrevlumab treatment. Our results emphasize the utility of accounting for pre-treatment CRP levels as an independent prognostic factor in PDAC treatment effect models.
Serum glycoproteomic-based liquid biopsy for the detection of pancreatic ductal adenocarcinoma.
Authors: Kasi Pashtoon Murtaza , Shen Ling , Ramachandran Prasanna , Moser Kaitlynn , Xu Gege , Buckley Padraig , Serie Daniel , Lebrilla Carlito , Xu Hui , Chan Carlos Hou Fai
Published: February 2020

763

Background: Non-invasive biomarkers with high sensitivity and specificity would be of great value for patients with Pancreatic Ductal Adenocarcinoma (PDAC). This would aid in early detection and serve other purposes that 'liquid biopsies' are being explored in. Besides circulating tumor DNA (ctDNA) and methylation markers, glycosylation markers hold great potential promise. We developed a novel workflow using high-resolution quantification of site-specific protein glycosylation by liquid chromatography and tandem mass spectrometry to evaluate the clinical utility of glycoprotemics signature for patients with PDAC. Methods: Serum samples from newly diagnosed PDAC patients and controls were obtained from a commercial biobank (Indivumed, Hamburg, Germany), and a panel of 504 glycan motifs, representing 73 previously reported proteomic markers, was determined. Age-adjusted generalized linear regression models were used to evaluate the differential abundance of each marker, and stepwise variable selection was used for model construction. Results: We analyzed 45 PDAC and 136 control samples. PDAC patients (60% male) had a mean age of 67 (±11) years. with 4.4%, 71.1%, 4.4%, and 20% at stage 1, 2, 3,4, respectively. Controls were women with benign histology after pelvic mass surgery; with a mean age of 61 (±11) years. Twenty-six glycoproteomic markers showed statistically highly significant differential abundance among cases and controls (p<1e-4 each) and were highly reproducible(Pearson’s r > 0.85), which were glycoforms in proteins that have previously been found to be associated with PDAC. Fourteen of these markers displayed >0.8 area under the curve of the receiver operating characteristic (AUC). Multivariate logistic regression modeling with backward selection yielded a classification model with an AUC of 0.94 (95% CI: 0.89-0.99), sensitivity of 91% (95% CI: 75-97%) and specificity of 86% (95% CI: 81-92%). Conclusions: Circulating glycoproteomic biomarkers may be useful in the early detection and clinical management of PDAC patients; offering a new platform to explore and validate.
Survival outcomes of pancreatic intraepithelial neoplasm (PanIN) versus intraductal papillary mucinous neoplasm (IPMN) associated pancreatic adenocarcinoma.
Authors: McGinnis Timothy , Bantis Leonidas , Madan Rashna , Dandawate Prasad , Kumer Sean , Schmitt Timothy , Paluri Ravi Kumar , Saeed Anwaar , Kasi Anup
Published: February 2020

766

Background: Pancreatic intraepithelial neoplasms (PanINs) and intraductal papillary mucinous neoplasms (IPMNs) are common pancreatic adenocarcinoma precursor lesions. However, data regarding their respective associations with prognosis is lacking. Methods: We retrospectively evaluated 72 resected pancreatic adenocarcinoma cases at the KU Cancer Center between Aug 2009 and March 2019. Patients were divided into either one of two groups, PanIN or IPMN, based on the results of the surgical path report. We compared baseline characteristics, overall and progression free survival between the two groups, as well as OS and PFS based on local or distant tumor recurrence. Results: 52 patients had PanIN and 20 patients had IPMN. Demographic and baseline characteristics are as follows (PanIN/IPMN): Median age 62.5/69; Gender (male) 63%/65%; ECOG status (0-1) 98%/85%; pancreatic head tumors 87%/70%; pancreatic body tumors 6%/15%; pancreatic tail tumors 7%/15%; Abnormal CA19-9 at diagnosis 79%/67%; Comorbidity Index 5/5 respectively. Median PFS was 26.2 months (95% CI: 21.4-31.0) for PanIN and 74.3 months (95% CI: 15.7-132.9) for IPMN [p = 0.004]. Median OS was 70.3 months (95% CI: 35.4-105.2) for PanIN and 78.8 months (95% CI: 33.2-124.4) for IPMN [p = 0.013]. Within the PanIN group, median OS after recurrence was 71.3 months (95% CI: 68.8.-73.4) for local recurrence and 46.7 months (95% CI: 39.2-54.2) for distant recurrence [p = 0.330]. Conclusions: Patients who had a IPMN associated pancreatic cancer had better PFS and OS when compared to patients with PanIN associated pancreatic cancer. In patients with PanIN associated cancer that recurred, OS was better with local recurrence compared to distant recurrence but did not meet statistical significance. The results need to be validated in a larger cohort. [Table: see text]
Young-onset pancreas cancer (PC) in patients less than or equal to 50 years old at Memorial Sloan Kettering (MSK): Descriptors, genomics, and outcomes.
Authors: Varghese Anna M. , Singh Isha , Singh Ritu Raj , Capanu Marinela , Chou Joanne F. , Wong Winston , Stadler Zsofia Kinga , Salo-Mullen Erin E. , Iacobuzio-Donahue Christine A , Kelsen David Paul , Park Wungki , Yu Kenneth H. , O'Reilly Eileen Mary
Published: February 2020

774

Background: For individuals ≤ 50 years old, cancer incidence is increasing, particularly gastrointestinal and obesity related cancers (Sung, Lancet Public Health 2019). Limited details are known about young onset PC. Herein, we report the epidemiologic, pathologic, and molecular characteristics of PC in patients (pts) ≤ 50 years. Methods: MSK institutional database was queried for medical and treatment history, genomics, and outcomes in pts ≤ 50 years old diagnosed with PC between January 2008 and July 2018. Neuroendocrine cancers were excluded. Overall survival (OS) from date of PC diagnosis was estimated using Kaplan-Meier methods. Results: N = 450 pts ≤ 50 years old with a diagnosis of PC were identified. Ninety-six percent had adenocarcinoma, and 4% had acinar cell carcinoma/other histologies. Table summarizes demographics. Median OS was 16 months in the entire cohort and 11.3 months in stage IV disease. For N = 236 pts diagnosed after 2014, 119 (50%) underwent successful somatic testing with at least one alteration identified, and 21/119 tumors were RAS wild-type with identification of several actionable alterations (NRG1 fusions (n=2), NTRK fusions (n=2), IDH1 R132C (n=1), and microsatellite unstable tumors (n=1) ). N = 114 pts had germline testing (routine after 2015), and 33/114 (29%) had pathologic germline alterations, including BRCA1/2 (n=18), CHEK2 (n=3), PALB2 (n=3), ATM (n=2), MLH1 (n=1), and MSH3 (n=1). Conclusions: Pathogenic germline alterations are present in a substantial percentage of pts with young onset PC, and actionable somatic alterations were seen frequently in the subgroup of young onset PC RAS-wild type tumors. These observations underpin the need for germline and somatic profiling in PC. [Table: see text]
Encorafenib plus cetuximab with or without binimetinib for BRAF V600E-mutant metastatic colorectal cancer: Quality-of-life results from a randomized, three-arm, phase III study versus the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC).
Authors: Kopetz Scott , Grothey Axel , Van Cutsem Eric , Yaeger Rona , Wasan Harpreet Singh , Yoshino Takayuki , Desai Jayesh , Ciardiello Fortunato , Loupakis Fotios , Hong Yong Sang , Steeghs Neeltje , Guren Tormod Kyrre , Arkenau Hendrik-Tobias , Garcia-Alfonso Pilar , Gollerkeri Ashwin , Maharry Kati , Christy-Bittel Janna , Keir Christopher Hunt , Pickard Michael D , Tabernero Josep
Published: February 2020

8

Background: In the BEACON CRC study, the triplet regimen of encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) significantly improved overall survival (OS, HR:0.52, P < 0.0001) and objective response rates (ORR, 26% vs 2%, P < 0.0001) in patients (pts) with BRAF V600E metastatic colorectal cancer (mCRC) compared with current standard of care. This analysis focuses on the patient-reported quality of life (QOL) assessments from this study. Methods: The BEACON CRC study was a randomized, open-label, 3-arm, phase 3 global study which evaluated triplet (ENCO+BINI+CETUX) or doublet (ENCO+CETUX) vs. investigator’s choice of irinotecan + CETUX or FOLFIRI + CETUX in pts with BRAFV600E mCRC. QOL assessments (secondary endpoints in the trial) included the EORTC QOL Questionnaire (QLQ C30), Functional Assessment of Cancer Therapy Colon Cancer (FACT C), EuroQol 5D 5L, and Patient Global Impression of Change (PGIC). The primary assessment for the QOL variables was the time to definitive 10% deterioration between arms. Results: 665 pts were randomly assigned to receive either triplet (n = 224), doublet (n = 220), or control (n = 221). Reduction in the risk of QOL deterioration was an estimated 45% (HR 0.55, 95% CI: 0.43, 0.70) and 44% (HR 0.56, 95% CI: 0.44, 0.71) in EORTC QLQ C30 and FACT C assessments, respectively, in favor of the triplet regimen over control. For the doublet vs. control, reduction in risk of QOL deterioration was an estimated 46% (HR 0.54, 95% CI: 0.43, 0.69) and 43% (HR 0.57, 95% CI: 0.45, 0.72) in EORTC QLQ C30 and FACT C, respectively in favor of the doublet. Similar results were observed in EuroQol 5D 5L and PGIC assessments. There were no overall differences in QOL between triplet and doublet across the 4 instruments. Conclusions: In BEACON CRC, triplet and doublet demonstrated substantial improvement in patient-reported QOL assessments over the current standard of care in pts with BRAF V600E-mutant metastatic CRC whose disease had progressed after 1 or 2 prior regimens. Clinical trial information: NCT02928224.
Declining use of red blood cell transfusions for gastrointestinal cancer surgery: A population-based analysis.
Authors: Zuckerman Jesse , Coburn Natalie , Callum Jeannie , Mahar Alyson , Zuk Victoria , Lin Yulia , McLeod Robin , Turgeon Alexis F. , Pearsall Emily , Martel Guillaume , Hallet Julie
Published: February 2020

802

Background: Perioperative anemia is common in gastrointestinal (GI) cancer surgery patients and is often treated with red blood cell transfusion (RBCT), which carries risks for inferior oncologic outcomes. Despite level-1 evidence for restrictive transfusion strategies, RBCT use is often not consistent with guidelines leading to a high rate of unnecessary transfusions. Understanding of RBCT use at the population-level is necessary to develop system-level efforts to minimize perioperative RBCT for cancer. We sought to evaluate the secular trends of transfusion in a large North American population. Methods: We conducted a population-based retrospective cohort study of patients undergoing GI cancer resection between 2007-2018 using linked administrative health datasets in Ontario, Canada. Primary outcome was administration of any RBCT during the hospitalization. Temporal RBCT trends were analyzed with Cochran-Armittage tests for trend. Modified Poisson regression assessed trends while controlling for potential confounders. Results: Of 79,764 patients undergoing GI cancer resection, median age was 69 (IQR: 60-78) years old and 55.5% were male. The most frequent cancer site was colorectal cancer (n = 63,243), followed by esophago-gastric (n = 7,307), hepato-pancreato-biliary (n = 6,510), and small bowel (n = 2,704). 30% of patients received RBCT. The proportion of patients transfused decreased from 26.5% in 2007 to 18.9% in 2018 (p < 0.001). This trend remained consistent when stratified by sex, age, cancer type, operative approach, procedure setting, and institution teaching status. After adjusting for patient and institution factors, the time period was associated with receipt of RBCT with a relative risk of 0.94 (95% CI 0.91-0.96) for 2011-14 and 0.75 (95% CI 0.73-0.78) for 2015-2018 compared to the period of 2007-10. Conclusions: Over the 11-year study period, we observed a decrease in RBCT for GI cancer resection. These findings may reflect the dissemination of clinical guidelines and implementation of patient blood management programs. An evaluation of institutional variation and the relationship with outcomes is warranted to identify opportunities for further improvement.
The cost of chemotherapy administration: A systematic review and meta-analysis.
Authors: Sohi Gursharan Kaur , Levy Jordan , Delibasic Victoria , Davis Laura , Mahar Alyson , Amirazodi Elmira , Earle Craig , Hallet Julie , Hammad Ahmed , Mittmann Nicole , Coburn Natalie
Published: February 2020

810

Background: Cancer treatment is a significant driver of healthcare costs worldwide, however, the economic impact of treating patients with anti-neoplastic agents is poorly elucidated. Hence, we conducted a systematic review and meta-analysis to estimate the direct costs associated with administering intravenous chemotherapy in an outpatient setting. Methods: We systematically searched four databases from 2010 to present and extracted hourly administration costs and the respective components of each estimate. Separate analyses were conducted of Canadian and United States (US) studies, respectively, to address a priori hypotheses regarding heterogeneity amongst administration cost estimates. The Drummond checklist was used to assess risk-of-bias. Data were summarized using medians with interquartile ranges and five outliers were identified; costs were presented in 2019 USD. Results: A total of 44 studies were analyzed, including sub-analyses of 19 US and seven Canadian studies. 26/44 studies were of moderate or high quality. When components of administration cost were evaluated, physician costs were reported most frequently (24 studies), followed by lab tests (13) and overhead costs (9). The median cost estimate when outliers were excluded was $142/hour (IQR = $103-166). Sensitivity analyses determined the median administration cost in the US was $149/hour (IQR = $118-158), and was $128/hour (IQR = $102-137) in Canada. Conclusions: There is currently a paucity of literature addressing the costs of chemotherapy administration, and existing studies utilize a patchwork of reporting methodologies which renders direct comparison challenging. Our results demonstrate that the cost of administering chemotherapy is approximately $125-150/hour, globally. This value is dependent upon the region of analysis, inclusiveness of cost subcomponents as well as the methodology used to estimate unit prices, as described here.
First analysis of same-day pegfilgrastim use with concurrent capecitabine-based regimens in pts with GI malignancies.
Authors: Hakim Nausheen , Chi Jeffrey , Rehman Hasan , Goyal Shreya Prasad , Olazagasti Coral , Moriarty Linda , Jose Jyothi , Lamont Carol , Saif Wasif M.
Published: February 2020

817

Background: Pegfilgastrim is administered 24 hrs after chemotherapy to reduce risks of myelosuppression. This requires an additional clinic visit, which can be difficult for some patients (pts) due to work and transportation issues. In GI malignancies, pts receiving capecitabine-based regimens also require pegfilgastrim to reduce myelotoxicity. Capecitabine is converted to active 5-FU by cytidine deaminase which is present in humans in low levels and generally does not cause severe myelosupression. Therefore, administering pefilgastrim concurrently with chemotherapy may be an option. We present here the first study to analyze safety and efficacy of administering pegfilgrastim on the same day as capecitabine-based regimens in patients with GI malignancies. Methods: We evaluated 157 pts with GI malignancies who received a capecitabine-based chemotherapy regimens, including XELOX, EOX, ECX, XELIRI, MIXE, gemcitabine-capecitabine and same-day pegfilgrastim (6 mg) within 1 hr of completion of systemic agents. As per institutional guidelines, pts were counseled on risks of same-day pegfilgrastim prior to its administration. Pts were followed to determine the degree of neutropenia and toxicity. Results: A total of 914 chemotherapy cycles in 157 pts were analyzed. Median ANC nadir for all cycles was 5634/uL (range: 450-23800). Grade 1 and 2 neutropenia developed in 11 of 914 cycles. Bone pain reported in 9 pts. There was 1 episode of grade >3 neutropenia resulting in infection and antibiotic use. No other pt required dose reductions, chemotherapy delays, or hospitalizations. No increased toxicity of capecitabine was noticed. Conclusions: We believe our study is the first in GI malignancies to report that same-day pegfilgrastim administration with capecitabine-based regimens may be as effective and safe as next-day administration. Additionally, given the absence of CD in human bone marrow, it appears capecitabine can be used concurrently with pegfilgastrim. Prospective studies should be done to further investigate, as this practice can benefit pts clinically, decrease office visits, increase pt satisfaction and reduce healthcare costs.
Glycogen synthase kinase-3 beta (GSK-3β) blockade with 9-ing-41 in gastrointestinal cancers: The 1801 phase Ib/II study.
Authors: Safran Howard , Dhawan Mallika Sachdev , Cavalcante Ludimila , De Souza Andre Luiz , Powell Steven Francis , Billadeau Daniel D. , Giles Francis J. , Munster Pamela N. , Carneiro Benedito A.
Published: February 2020

827

Background: 9-ING-41 is a selective GSK-3β inhibitor with significant pre-clinical antitumor activity in a broad spectrum of malignancies as a single agent and in combination with cytotoxic agents. GSK-3β is a serine/threonine kinase whose overexpression is associated with advanced stage, aggressive tumor growth, and chemotherapy resistance. We report the preliminary results of patients (pts) with gastrointestinal (GI) malignancies. Methods: Phase 1b/2 study evaluating safety and efficacy of 9-ING-41 as monotherapy and combination therapy in pts with refractory cancers. 9-ING-41 is administered intravenously twice-weekly as a single agent (21-day-cycle) or combined with chemotherapy agents, including gemcitabine (GEM), nab-paclitaxel + GEM, carboplatin, or paclitaxel. Study parts 1 and 2 evaluate the safety, describe dose-limiting toxicities (DLTs), determine the maximum tolerated dose and the recommended phase 2 study dose (RP2D) for 9-ING-41 as monotherapy (Part 1) and as combination therapy (Part 2). Part 3 (Simon 2-Stage Phase 2) assess clinical benefit in pts treated with 9-ING-41-based combinations at the RP2D established in Part 2. Response is assessed by RECIST 1.1 criteria in the evaluable lesions. Results: To date, the study accrued 63 pts. Five dose levels (1, 2, 3.3, 5 and 7 mg/kg) have been completed without DLTs. Part 2 of the study evaluating 9-ING-41-based chemotherapy combinations is ongoing. Five out of nine pts with pancreas cancer (PCa) enrolled had stable disease (SD) as the best response; 2 out of 9 pts had a 40-45% decline of CA 19-9. One pt completed 6 cycles with 9-ING-41, two pts completed 4 cycles with 9-ING-41/GEM. Two active pts are receiving 9-ING-41/GEM with SD after 3 and 4 cycles. Three out of four pts with adenocarcinoma of the appendix enrolled had SD as the best response; two pts in active treatment are receiving cycles 5 and 6. One out of 13 pts with colorectal cancer had SD. 9-ING-41-attributable AE to date are reversible grade 1 transient visual changes (color perception). Conclusions: 9-ING-41 is well-tolerated with encouraging SD among heavily pretreated pts with carcinoma of the pancreas and appendix. Clinical trial information: NCT03678883.
Prospective study for comprehensive genomic profiling (GP) in cancer of unknown primary (CUP): Feasibility, molecular landscape, and clinical utility in current era.
Authors: Raghav Kanwal Pratap Singh , Willett Anneleis , Huey Ryan , Dhillon Nishat , Modha Jignesh , Matamoros Aurelio Aurelio , Estrella Jeannelyn , Sanghavi Kunal , Antov Andrey , Choquette Linda , Statz Cara , Kelly Kevin , Rowe Shannon , Liu Edison T. , Rueter Jens , Kopetz Scott , Overman Michael J. , Varadhachary Gauri Rajani
Published: February 2020

834

Background: CUP presents a unique niche and challenge for application of GP. Absence of a primary limits consensus regarding site-directed and availability of tissue specific targeted therapy. We evaluated the real time feasibility and clinical utility of GP in CUP. Methods: Treatment eligible CUP pts were prospectively enrolled. A novel next-gen targeted sequencing (NGS) assay (ActionSeq/FusionSeq) was used to find genomic alterations (GAs) (somatic mutations in 212 and fusions in 53 cancer-associated genes). The primary objective was to determine prevalence of GAs and to assess the clinical impact via change in pre-test planned therapy (either referral to biomarker pertinent clinical trial (CT) or off label use of FDA approved drugs). With 54 pts we achieved 80% power (α 0.05) to a treatment change in 10% (5% to 15%) pts. Results: Between 9/2016 and 8/2019, 150 pts were consented. Tissue for GP was available in 59 (39%) pts (for 91 pts, samples had exhausted or insufficient tissue). Test was successfully performed on 54 (92%) pts. Cohort characteristics include: median age: 58 yr, male 43%, ECOG PS ≤1 96%, median IHC 8 (range 2-26), median survival 33 m (95% CI 18-47). Median reporting time was 23 days. Four (7%) pts had no identifiable GAs. A fusion ( PTRPK) was seen in 1 (2%) pt. Among 50 pts, total number of GAs were 487; 123 (26%) were “clinically relevant” (median 2.5/pt, range 1-11) while 364 (76%) were variants of unknown significance. Of the 123 GAs, 94 were mutations and 29 were amplifications. The 5 most common mutations were TP53, KRAS, PIK3CA, ARID1A, and NRAS and amplifications were CCND1, FGFR3, ERBB2, EGFR, and MYC. Planned therapy change post ActionSeq occurred in 13 pts (22%, 95% CI 13-34) (2 received an off-label drug; 9 were CT eligible [2 enrolled, 5 had PS decline, 2 pending]; 2 were lost to follow-up). Responses were seen in 2 of 4 pts who received GP based treatment. Conclusions: Comprehensive GP should be offered early to CUP pts. GP can help identify novel therapy and clinical trial options. Given the high rate of insufficient tissue cases, integrating a tissue sensitive algorithm involving IHC and GP in therapeutic management of CUP is merited.
Characteristics of gastrointestinal stromal tumors incidentally discovered during abdominal surgery.
Authors: Garg Meera , Hitscherich Kyle Joseph , Bennett Joseph J.
Published: February 2020

835

Background: Gastrointestinal Stromal Tumors (GISTs) are rare sarcomas with 5000 new cases each year. Despite their low incidence, surgeons should be familiar with this pathology since GISTs can be encountered incidentally during abdominal surgery. Methods: A retrospective series was conducted by querying pathology and operative reports from a community cancer center between 2005 and 2019 for all GIST diagnoses. Patients identified to have incidental GISTs discovered intra-operatively while undergoing surgery for another diagnosis were the focus of this study. Patient and tumor characteristics were evaluated. Results: A total of 195 patients had a diagnosis of a resected GIST during our study period. Of these 195, 48 patients were incidentally discovered to have a GIST excised during another index operation. The average age of these patients was 62 years old, 27 were female and 21 male. The primary location of these incidental GISTs in descending frequency was stomach (62.5%, n = 30), small bowel (31.3%, n = 15), colon (4.2%, n = 2) and esophagus (2.1%, n = 1). The average GIST size for the cohort was 1.7cm, with stomach, small bowel, colon and esophagus measured at 1.8cm, 1.7cm, 0.65cm and 0.30cm, respectively. Mitotic rate was < 5 mitosis/50 HPF in 96% of patients. Incidental GISTs were identified during the following surgery: colon (n = 14), bariatric (n = 13), non-bariatric gastric (n = 10), hernia (n = 4), pancreatic (n = 3), esophageal (n = 2) and other (n = 2). Most incidental GISTs were discovered during elective surgery (81.3%, n = 39) compared to emergency surgery (18.8%, n = 9), and for benign disease (n = 33) compared to malignant (n = 15). Conclusions: Approximately one quarter of all GISTs resected at our community cancer center in 15 years were discovered incidentally, and during a wide variety of abdominal surgeries for both benign and malignant disease. Almost all these GISTs were < 2cm, benign, and should be cured with the incidental resection. Abdominal surgeons should be aware of unexpectedly finding small GISTs and should not be apprehensive about resecting since they have indolent characteristics. Larger lesions should trigger expert surgical oncology consultation.
Effect of weight loss in patients with metastatic colorectal cancer treated within the randomized phase III FIRE-3 trial (AIO KRK 0306).
Authors: Liu Lian , Erickson Nicole Tonya , Holch Julian W. , Ricard Ingrid , Gesenhues Alena Britta , Theurich Sebastian , Stintzing Sebastian , Heinemann Volker
Published: February 2020

87

Background: A subgroup of RAS wild-type metastatic colorectal cancer patients within the FIRE-3 study consisted of 400 patients. Gaining insight into frequency and effects of weight change among patients treated with FOLFIRI plus either cetuximab or bevacizumab was aim of this analysis. Methods: A subgroup of 400 RAS wild-type metastatic colorectal cancer (mCRC) patients of the FIRE-3 trial were evaluated. Linear mixed effect models were fitted to explore the mean evolution of weight over time. The presence of a breakpoint at month 1 was investigated by the addition of an adequate parameter into the model. A linear evolution was supposed from month 1. In this exploratory analysis, patients were grouped into cohorts according to weight change using the cut off ≥ 5%. Kaplan-Meier estimations and median survival times were analyzed using log-rank testing. Hazard ratios and corresponding 95% confidence interval from univariate Cox proportional hazards were followed by a multivariate analysis. Results: Patients lost in average 0.75 kg during the first month of treatment, whereas body weight increased hereafter 0.43 kg per month. Of note, patients older than 65 years lost most body weight at month one (1.35kg) and gained least hereafter (0.20kg per month). Within this population a weight loss of ≥ 5% was observed to be an independent prognostic factor for both PFS after 3 months (HR 1.72, 95% CI 1.26-2.34, P = 0.001) and OS after 3 months (HR 1.754, 95% CI 1.29-2.39, P < 0.001). This remained significant when adjusted for age, sex, ECOG score, primary tumor side and treatment arm. Conclusions: In the overall RAS wild-type population, weight loss is an independent prognostic factor for survival in patients with RAS wild-type metastatic colorectal cancer patients and may predict the frequency of adverse events. Therefore, we assume that early preventative measures targeted at weight maintenance might contribute to improved outcomes among this population.
Feasibility of using fitness tracker to assess activity level and toxicities in colorectal cancer (CRC) patients (Pts).
Authors: Holden Thomas , Hill Maureen , Ward William Harrell , Meeker Caitlin R. , Handorf Elizabeth A. , Hall Michael J. , Sigurdson Elin R. , Astsaturov Igor A. , Denlinger Crystal S. , Reddy Sanjay S. , Meyer Joshua E. , Zibelman Matthew R. , Dotan Efrat , Farma Jeffrey M. , Vijayvergia Namrata
Published: February 2020

91

Background: Performance status (PS) is used to predict tolerance and morbidity associated with CRC treatment. Monitoring activity level at the start of therapy using a wearable fitness tracker Fitbit (Fb) may provide a more accurate estimate of a pt’s overall PS and help predict treatment related toxicity (T). Methods: With IRB approval, we prospectively enrolled CRC pts undergoing therapy into 2 cohorts, medical undergoing chemotherapy (M) and surgical undergoing definitive surgery (S). Our objective was to assess feasibility of using Fb to track pt activity level and secondarily correlate with T. After documenting baseline ECOG PS, M and S pts wore Fb for 4 days while receiving chemotherapy or prior to surgery, respectively. Pts’ mean steps per day (SPD) were calculated excluding days Fb was worn <12 hours. To stratify prediction of toxicity risk, a cutoff of 5000 SPD was selected and any post-operative complication (S pts) or ≥grade 3 toxicity (M pts) was counted as T. The study met accrual of 80 pts. Results: On final analysis, 80 pts were evaluated for the primary aim. 68 pts had at least 3 days with ≥12 hours of Fb usage, meeting the 75% feasibility endpoint. 76 pts had at least 1 day with ≥12 hours of Fb usage with data for analysis. SPD correlated with PS and the SPD and active minutes (read by device) for PS 0 and PS 1 pts was 6313 steps and 122 min and 2925 steps and 55 min, respectively (p=0.0003). Rate of T was 25% in pts with PS 0 and 33% in pts with PS 1. With SPD, rate of T was numerically lower in pts with >5000 SPD compared to pts with <5000 SPD (21% vs 32%, p = NS). Conclusions: We observed high rates of compliance with Fb in CRC pts. SPD cutoff of 5000 correlated with ECOG PS 0 vs 1. We observed usefulness of SPD as an identifier for toxicities and suggestion that it may be more reliable compared to PS alone in this small sample of pts. These findings provide rationale to study SPD in conjunction with PS for risk stratification of pts undergoing therapy, and can possibly be incorporated into pre-habilitation selection in high risk groups.

[Table: see text]
A phase II study of savolitinib (volitinib, AZD6094, HMPL-504) in subjects with MET amplified metastatic colorectal cancer (mCRC) detected by cell-free (cf)DNA.
Authors: Jia Jingquan , Niedzwiecki Donna , Arrowood Christy , Garett-Mead Nancy , Nagy Rebecca , Lanman Richard B. , Wright John , Nixon Andrew B. , Strickler John H.
Published: February 2020

TPS270

Background: MET amplification (amp) is a well-described driver of acquired EGFR antibody (Ab) resistance and is found in 10-20% of pts with KRAS and NRAS wild-type mCRC treated with anti-EGFR Abs. Blood-based genomic profiling of cfDNA is a non-invasive and efficient means of identifying acquired MET amp in mCRC. Although the activity of anti-MET tyrosine kinase inhibitors (TKIs) in EGFR Ab refractory mCRC has been shown in preclinical and clinical studies, the clinical efficacy of anti-MET TKIs in pts with MET amplified mCRC is not well established. Savolitinib is a potent and highly selective oral small molecule anti-MET TKI that is currently under clinical development for MET-driven papillary renal cell carcinoma, NSCLC and gastric cancer. Methods: This single-arm phase II study will evaluate the clinical efficacy and tolerability of savolitinib in pts with MET amplified mCRC. Eligible pts include those with RAS wild-type mCRC who have been previously treated with 5-FU, oxaliplatin, irinotecan, an anti-VEGF Ab and an anti-EGFR Ab. Pts must have MET amp detected by Guardant360 (G360) cfDNA screening assay. Up to 150 patients will be screened to identify at least 15 pts for study accrual. Prior treatment with an anti-MET TKI or monoclonal Ab against c-MET or HGF is excluded. The primary objective is to estimate the objective response rate (ORR) for savolitinib. In this heavily pre-treated cohort an observed ORR of 20% is considered clinically meaningful and worthy of further study. Secondary objectives are to evaluate the efficacy (progression-free survival, duration of response), safety and tolerability. Correlation between tissue and blood-based biomarkers and clinical outcomes will be explored. Blood will be collected at baseline and each restaging to determine if savolitinib eliminates MET amp in cfDNA. Subjects will receive savolitinib at a dose of 600mg by mouth daily on 28-day cycles. Response will be assessed every 2 cycles (8 weeks) per RECIST version 1.1. This study was initiated on 1/30/2019. Recruitment is ongoing in the NCI Experimental Therapeutics Clinical Trials Network (ETCTN). Clinical trial information: NCT03592641.
NuTide: 302—A phase Ib study of the ProTide NUC-3373 in combination with standard therapies in advanced colorectal cancer.
Authors: Ciombor Kristen Keon , Graham Janet Shirley , Aroldi Francesca , Coveler Andrew L. , Schlechter Benjamin L. , Clark Jeffrey William , Graham Jill , Rodgers Lisa Jane , De Gramont Aimery , Tabernero Josep , Berlin Jordan , Blagden Sarah Patricia , Evans T.R. Jeffry
Published: February 2020

TPS274

Background: Although 5-FU-based regimens such as FOLFOX and FOLFIRI remain the cornerstone of treatment for patients (pts) with colorectal cancer (CRC), their clinical utility is limited by resistance mechanisms and toxicity. Anti-cancer activity of 5-FU is dependent on conversion to an active metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), which binds to and inhibits thymidylate synthase (TS), a critical enzyme in de novo nucleotide synthesis and cell survival. However, due to multiple limitations including: reliance on enzymatic activation; catabolism by dihydropyrimidine dehydrogenase (DPD) and a short plasma half-life, 5-FU is not efficiently converted to FUDR-MP. NUC-3373, a phosphoramidate transformation of FUDR-MP, was designed to bypass the key resistance mechanisms that limit the clinical utility of 5-FU. NUC-3373 demonstrated a favorable PK/PD profile and promising efficacy signals in the first-in-human study (NuTide:301) in pts with advanced solid tumors. NUC-3373 has a longer plasma t1/2 (9.7 hours) than 5-FU (8-14 minutes) and generates high intracellular levels of FUDR-MP (Ghazaly et al ESMO, 2017). TS is efficiently inhibited and sequestered into TS-ternary complexes, depleting the pool of deoxythymidine monophosphate (dTMP) within 2-4 hours. Methods: NuTide:302 is a three-part, Phase Ib study in pts with advanced CRC who have relapsed after ≥2 prior lines of 5-FU-containing therapies. Primary objective is to identify a RP2D of NUC-3373 when administered weekly and q2w in combination with standard agents used in CRC treatment. Secondary objectives include safety, PK/PD and anti‐tumor activity. In Part 1, patients are receiving NUC-3373 with leucovorin (LV) to determine if LV augments TS inhibition. In Part 2, NUC-3373 (±LV) will be administered in dose escalating cohorts, in a modified 3+3 design, with either oxaliplatin (NUFOX) or irinotecan (NUFIRI). In Part 3, the NUFOX and NUFIRI regimens selected in Part 2 will be combined with biologics targeting VEGF or EGFR pathways. To date, 22 pts have received study treatment. Recruitment is ongoing in the US and Europe. Clinical trial information: NCT03428958.
KEYNOTE-811 pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction cancer (mG/GEJc): A double-blind, randomized, placebo-controlled phase III study.
Authors: Chung Hyun Cheol , Bang Yung-Jue , Fuchs Charles S. , Qin Shukui , Satoh Taroh , Shitara Kohei , Tabernero Josep , Van Cutsem Eric , Alsina Maria , Cao Z. Alexander , Chen Xinqun , Bhagia Pooja , Shih Chie-Schin , Janjigian Yelena Yuriy
Published: February 2020

TPS463

Background: Combination therapy with the anti-HER2 antibody trastuzumab plus fluoropyrimidine and platinum is the current standard of care for patients with HER2+ mG/GEJc. We hypothesize that combination anti–PD-1 and anti-HER2 therapy will result in T-cell activation, augment antibody-dependent, cell-mediated cytotoxicity, and potentiate antitumor immune response in HER2+ patients. A phase 2 study in HER2+ mG/GEJc demonstrated the safety and preliminary efficacy of trastuzumab/pembrolizumab/chemotherapy; the objective response rate was 87%, and the disease control rate was 100% (Janjigian YY, ASCO GI 2019). KEYNOTE-811 (ClinicalTrials.gov, NCT03615326), a global, multicenter, randomized, placebo-controlled, phase 3 study, is underway. Methods: Key eligibility criteria are age ≥18 years; previously untreated unresectable or metastatic HER2+ (centrally confirmed IHC 3+ or IHC 2+/ISH > 2.0) G/GEJ cancer; life expectancy > 6 months with RECIST v1.1 measurable disease; and adequate organ function and performance status (ECOG PS of 0 or 1). Patients will be randomly assigned 1:1 to receive chemotherapy with pembrolizumab 200 mg intravenously (IV) or placebo with trastuzumab 6 mg/kg (after 8 mg/kg load) every 3 weeks (Q3W) up to 2 years or until intolerable toxicity or disease progression. Investigator-choice chemotherapy will include day 1 cisplatin 80 mg/m2 IV and 5-fluorouracil 800 mg/m2/day IV (days 1-5) or oxaliplatin 130 mg/m2 IV and capecitabine 1000 mg/m2 BID days 1-14 (Q3W). Primary end points are progression-free survival and overall survival. Secondary end points are objective response rate, duration of response, and safety and tolerability. Adverse events are graded per CTCAE v4.0 and will be monitored for 30 or 90 days after treatment. Patients will be followed up for survival. Planned enrollment is approximately 692 patients. Clinical trial information: NCT03615326.
Margetuximab (M) combined with anti-PD-1 (MGA012) or anti-PD-1/LAG-3 (MGD013) +/- chemotherapy (CTX) in first-line therapy of advanced/metastatic HER2+ gastroesophageal junction (GEJ) or gastric cancer (GC).
Authors: Catenacci Daniel V.T. , Rosales Minori Koshiji , Wigginton Jon M. , Chung Hyun Cheol , Yoon Harry H. , Shen Lin , Moehler Markus H. , Kang Yoon-Koo
Published: February 2020

TPS468

Background: Trastuzumab (T), a monoclonal antibody (mAb) targeting HER2, is standard of care palliative 1st-line therapy for advanced HER2+ GEJ/GC patients (pts). M, an Fc-engineered anti-HER2 mAb, targets the same HER2 epitope but with higher affinity for both 158V (high binding) and 158F (low binding) alleles of activating Fc receptor CD16A. M coordinately enhanced both innate and adaptive immunity, including antigen-specific T-cell responses to HER2. PD-1 and LAG-3 are T-cell checkpoint molecules that suppress T-cell function. MGA012 (INCMGA00012) is a humanized, hinge-stabilized, IgG4 κ anti-PD-1 mAb blocking binding of PD-L1 or PD-L2 to PD-1. MGD013 is a humanized Fc-bearing bispecific tetravalent protein that binds to both PD-1 and LAG-3, inhibiting their respective ligand binding. We previously reported that a CTX-free regimen of M+PD-1 blockade was well tolerated in GEJ/GC pts, and induced a 30% objective response rate (ORR). This was 2- to 3-fold greater than in historical controls with checkpoint inhibitors alone. This registration-directed trial assesses efficacy, safety, and tolerability of M+checkpoint inhibition ± CTX in metastatic/locally advanced, treatment-naïve, HER2+ GEJ/GC pts. Methods: This is a 2-cohort, adaptive open-label phase 2/3 study. The first single arm, CTX-free cohort A evaluates M+MGA012 in HER2+ (immunohistochemistry [IHC] 3+) and PD-L1+ (excluding microsatellite instability high) pts. After 40 pts are evaluated for response/safety, 60 more pts will be enrolled if the threshold for continuation is met. In randomized cohort B, HER2+ (IHC 3+ or 2+/fluorescent in situ hybridization+) pts are enrolled irrespective of PD-L1 status. Part 1 randomizes pts to 1 of 4 arms (50 pts each): control arm (T+CTX) or 1 experimental arm (M+CTX; M+CTX+MGA012; M+CTX+MGD013). CTX is investigator’s choice XELOX or mFOLFOX-6. Part 2 consists of control (T+CTX) vs 1 experimental arm (M+CTX) + either MGA012 or MGD013, depending on results from part 1; with 250 pts each. The primary efficacy endpoint for cohort A (both parts) is ORR per RECIST 1.1; for cohort B part 2 it is overall survival.
A pilot study of avelumab in Epstein-Barr virus-associated gastric cancer.
Authors: Mc Laughlin Ronan Andrew , Aird John , McCormack Orla , DeGascun C. , Hussein R. , Molloy B. , Malara A. , Galligan M. , Kelly Catherine Margaret , Doran Peter , Duffy Austin G.
Published: February 2020

TPS473

Background: Gastric Cancer (GC) is the third most common cause of cancer related deaths worldwide. The median overall survival of patients with stage 4 disease is approximately 1 year. Current accepted treatment approach with chemotherapy is applied with little consideration for known genetic or biologic heterogeneity. Whilst immune-based approaches in GC look promising it is clear that single-agent PD1/PDL1 inhibition benefit a minority. We must clarify a means of identifying prospectively those patients who may benefit from this treatment. A recent landmark paper by The Cancer Genome Atlas (TCGA) proposed a classification of GC into four subtypes: Epstein-Barr-virus (EBV)-positive, microsatellite instable (MSI), chromosomal instable (CI), and genomically stable (GS). Two of the four – EBV and MSI subtypes – are likely to be immunogenic and amenable to PD1/PDL1 inhibition. Recent advances have shown EBV-positive tumors to be infiltrated by lymphocytes and be enriched for PDL1. Methods: This single centre single-arm pilot study in gastric or junctional adenocarcinoma will explore the hypothesis that administering anti-PDL1 therapy (Avelumab) in a prospectively identified population enriched for potential responders will result in improved outcomes. The anticipated frequency of EBV associated-GC (c10%) means that approximately N = 100 patients will be screened to identify N = 10 participants. If a positive signal for efficacy is seen this will provide a basis for a larger, multicentre study. Previously treated Patients with confirmation of stage 4 EBV- positive gastric or oesophago-gastric adenocarcinoma meeting eligibility criteria will be enrolled. Avelumab will be administered at a dose of 10mg/kg IV every 14days. Primary endpoint is to determine the 6-month progression free survival (PFS) of Avelumab in EBV-associated GC. Secondary endpoints include overall response rate, overall survival, median PFS time and feasibility/accrual rate at 12 months. Exploratory endpoints will be to evaluate changes in immune parameters in the peripheral blood over time. Kaplan-Meier methods for primary efficacy endpoint with two-tailed one-sample proportion test will be used to evaluate the evidence to reject the null hypothesis. Clinical trial information: 2018-002085-39.