bluuebunny/crossref_metadata_2025 huggingface dataset:
Final results of the McCAVE trial: A double-blind, randomized phase 2 study of vanucizumab (VAN) plus FOLFOX vs. bevacizumab (BEV) plus FOLFOX in patients (pts) with previously untreated metastatic colorectal carcinoma (mCRC).
Authors: Bendell Johanna C. , Sauri Tamara , Cubillo Antonio , López-López Carlos , Garcia Alfonso Pilar , Hussein Maen A. , Limon M. Luisa , Cervantes Andres , Montagut Clara , Santos Cristina , Bessudo Alberto , Modiano Manuel R. , Moons Veerle , Andel Johannes , Bennouna Jaafar , Van Der Westhuizen Andre , Samuel Leslie M. , Krieter Oliver , Rossomanno Simona , Hurwitz Herbert ,   McCAVE Study Group
Published: September 2018

3539

Background: VEGF-A and ANG-2 have complementary roles in regulation of tumor angiogenesis. Targeting VEGF-A with BEV in combination chemotherapy (CT) in mCRC has proven to increase PFS and OS. ANG-2 is overexpressed and associated with poor outcome of mCRC pts receiving BEVcontaining treatment. Hence, dual blockade of VEGF-A and ANG-2 by the bispecific mAb VAN with standard CT may improve clinical activity in mCRC. Methods: All pts received mFOLFOX-6 and were randomized 1:1 to also receive intravenous VAN 2000 mg every other week (Q2W) (Arm A) or BEV 5 mg/kg Q2W (Arm B). The primary end point was investigator assessed progression-free survival (PFS). Key eligibility criteria included pts with non-resectable mCRC, no prior therapy for advanced disease, PS 0-1, adequate organ functions, and no history of GI fistula/perforation or intraabdominal abscess within the last 6 months. Results: 192 pts were randomized (Arms A/B, n = 95/97) by 39 sites in 7 countries, between Oct 2014 and May 2016. Median follow-up was 17.6 months (range 2.8 – 20.7). In the ITT population (n = 189; Arms A/B, n = 94/95), median PFS in Arms A and B was 11.3 and 11.0 months (stratified hazard ratio (HR) 1.00 (95%CI 0.64-1.58; p = 0.985)), respectively. Objective response rate was 52.1% vs 57.9%. Relevant prognostic factors incl. RAS/BRAF status and tumor sidedness were balanced between arms and did not significantly influence outcome. Baseline plasma ANG-2 levels were prognostic in both arms but not predictive for response to VAN. The overall incidence of adverse events (AEs) grade ≥ 3 was similar (Arms A/B, 83.9%/82.1%); AEs grade ≥ 3 attributed to the mode of action of VAN/BEV included hypertension (37.6%/18.9%), hemorrhage (2.2%/1.1%), thromboembolic events (venous 6.5%/2.1%; arterial 1.1%/3.2%) and GI perforations incl. GI fistula & abdominal abscess (10.6%/8.4%). Conclusions: The combination of VAN and FOLFOX did not improve PFS and was associated with a marked increase in hypertension compared with BEV plus FOLFOX. Our results strongly suggest that ANG-2 is not a relevant therapeutic target in the setting of first line mCRC. Clinical trial information: NCT02141295.
A phase I/II trial of combined BRAF and EGFR inhibition in patients (pts) with BRAF V600E mutated (BRAFm) metastatic colorectal (mCRC): The EViCT (Erlotinib and Vemurafenib in Combination Trial) study.
Authors: Desai Jayesh , Markman Ben , Ananda Sumitra , Tebbutt Niall C. , Michael Michael , Solomon Benjamin J. , McArthur Grant A. , Tie Jeanne , Gibbs Peter , Ritchie David , Koldej Rachel , Herschtal Alan , Columbus Ruth , Ashley David M. , Lundy Joanne , Kwan Edmond Michael , Waring Paul Michael , Tran Ben
Published: September 2018

3557

Background: Pts with BRAFm mCRC have an exceedingly poor prognosis. Unlike melanoma, BRAF inhibitor monotherapy has limited activity in BRAFm mCRC. Preclinically, BRAF inhibition results in rapid feedback activation of EGFR and ongoing tumor proliferation, which can be readily overcome by combining BRAF and EGFR inhibition. EViCT examined the safety and efficacy of combining two oral agents targeting BRAF with Vemurafenib (Vem) and EGFR with Erlotinib (Erl), in BRAFm mCRC pts. Herein, we report safety and preliminary efficacy data. Methods: EViCT had 2 parts: a Phase I dose escalation of Erl (cohort 1: 100mg qd; cohort 2: 150mg qd) together with Vem 960mg bd, to determine the maximum tolerated dose (MTD). The Phase II component involved dose expansion at MTD using a Simon 2-stage design to treat 9 pts in stage 1 and 15 pts in stage 2. Cycles were 28 days. Eligible pts had ECOG < 1, < 2 lines of systemic therapy for metastatic disease, and acceptable organ function. Staging CT scans were performed every 2 cycles, response assessed using RECIST 1.1. Primary endoint was clinical benefit rate (CR, PR and SD). A number of pharmacodynamics correlates were assessed including serial ctDNA, FDG-PET and optional tumour biopsies. Pts were treated until disease progression or toxicity requiring discontinuation. Results: Between Jul-2014 and Oct-2016, 30 BRAFm mCRC pts were enrolled. The Phase I Lead-in enrolled 4 pts in cohort 1 and 7 pts in cohort 2. There was 1 DLT (grade 3 hand-foot syndrome) in cohort 2. MTD/Recommended Phase 2 Dose was Erl 150mg qd and Vem 960mg bd, the full dose for each agent. The Phase II expansion enrolled 19 pts. Overall, 23 pts are evaluable for this interim analysis. Median age was 61 years, 11 (48%) pts were male. Most pts had 1(50%) or 2 (41%) lines of prior treatment. Overall response rate was 39% (95%CI = [20%, 61%]), including 5 (22%) confirmed PR, 4 (17%) unconfirmed PR, 3 (13%) stable disease and 11 (48%) progressive disease. Conclusions: Vem and Erl can both be given safely at their individual full doses when used in combination. In BRAFm mCRC, this combination resulted in clear clinical activity. Clinical trial information: ACTRN12614000486628.
Primary tumor sidedness associates with prognosis of patients with brain metastases of colorectal cancer.
Authors: Berghoff Anna Sophie , Ferreira Pedro , Plazer Hanna , Widhalm Georg , Birner Peter , Bartsch Rupert , Prager Gerald W. , Zielinski Christoph , Preusser Matthias
Published: September 2018

3562

Background: Brian metastases (BM) are a rare but devastating complication of colorectal cancer. We aimed to analyse prognostic factors in patients suffering from colorectal cancer (CRC) BM. Methods: Patients with histological proven CRC and BM were identified from the brain metastasis database of the Comprehensive Cancer Center Vienna. Clinical characteristics including established prognostic factors were retrieved by chart review. Established clinical prognostic scores for BM patients including the graded prognostic assessment (GPA) and the GPA for gastrointestinal tumours (GI-GPA) were calculated based on clinical characteristics as previously published. Results: 215 (male: 125/215 (58.1%); female 90/215 (41.9%)) patients with CRC BM were available for this study. The following established clinical prognostic factors showed a significant association with median overall survival (OS) times from BM diagnosis: number of brain metastases (n = 1: 6 months; n = 2-3: 4 months; n > 3: 3 months; p = 0.001), age at BM diagnosis ( < 65 years: 6 months; > 65 years: 4 months; p = 0.047), extracranial disease (present: 4 months; absent: 8 months; p = 0.002) and Karfnofsky performance score (KPS < 70%: 3 months; KPS > 70%: 5 months; p = 0.002), graded prognostic assessment (GPA) class (class I: 15 months; class II: 13 months; class III: 4 months; class IV: 4 months) and the gastro-intestinal disease-specific GI-GPA (class I: 11 months; class II: 6 months; class III: 6 months; class IV: 3 months; p < 0.001). In addition, the location of the primary tumour in the left colon (n = 176 (81.9%); 5 months) was associated with significantly longer median overall survival times from diagnosis of BM than primary tumour location in the right colon (n = 39 (18.1%); 3 months; p = 0.010). Primary tumor sidedness (HR 0.577; 95% CI 0.397-0.841; p = 0.004) remained a strong prognostic factor at multivariate analysis independently of GI-GPA (HR 0.718; 95% CI 0.612-0.842). Conclusions: Primary tumor sidedness is an independent prognostic factor in patients with CRC BM and should be included in disease-specific prognostic scores.
Robotic procedure versus open surgery for simultaneous resection of colorectal cancer with liver metastases: Short-term outcomes of a randomized controlled study.
Authors: Xu Jianmin , Wei Ye , Ye Qinghai , Wang Xiaoying , Chang Wenju , Jian Mi , Ren Li , Zhu Dexiang , Feng Qingyang , Qin Xinyu , Fan Jia
Published: September 2018

3575

Background: The simultaneous resecting both colorectal cancer and liver metastases is a safety and efficacy surgical procedure for treating colorectal cancer patients with liver metastases (CRCLM).The safety and efficacy of robot-assisted simultaneous resection of CRCLM is unclear. Furthermore, what kind of selective CRCLM patients would obtain benefits from robotic procedure need identify. The aim of this study was designed to compare robotic procedure with open surgery, and establish robotic surgery indications to identify benefit population of CRCLM. Methods: CRCLM patients were evaluated and confirmed with surgical indication by multidisciplinary team (MDT), and randomized to two groups, robotic arm (n = 58) and open arm (n = 57). The primary endpoint is 3-year DFS, the second endpoints include short-term surgical outcomes, complications and safety. Results: A total of 115 patients were randomized between September 2013 and September 2016. Despite longer operating time, patients assigned to robot-assisted surgery had less blood loss (100ml vs. 150ml, P < 0.001), a shorter time to pass first flatus (3 d vs. 4 d, P < 0.001) and return to diet (3 d vs. 5 d, P = 0.002), shorter hospital stay with improved sexual function. Furthermore, followed benefits were observed in robotic arm versus open arm: lower serum C reactive protein (CRP) level on postoperative day 1 (POD1) (16 mg/L vs. 37 mg/L,P < 0.001), and POD3 (112 mg/L vs. 160 mg/L, P < 0.001), lower level of liver transaminase on POD5, and lower liver-related complication morbidity(10.3% vs 28.1%, p = 0.016). In addition, we identified and recommended selective CRCLM patients with the number of liver metastases < 3, maximal tumor size < 5cm, tumor not located in segment I to accept robotic procedure. Conclusions: We identified and recommended selective CRCLM patients to accept robotic surgery for treating liver metastases. Robotic surgery result in similar safety as open procedure, with shorter recovery time, decreased morbidity, and improved sexual function. Clinical trial information: NCT02642978.
Not all RAS mutations created equal: Functional and clinical characterization of 80 different KRAS and NRAS mutations.
Authors: Loree Jonathan M. , Miron Ben , Holla Vijaykumar , Overman Michael J. , Pereira Allan Andresson Lima , Lam Michael , Morris Van Karlyle , Raghav Kanwal Pratap Singh , Routbort Mark , Shaw Kenna Rael , Burck Nitza , Sharivkin Revital , Edelheit Oded , Meric-Bernstam Funda , Vidne Michael , Tarcic Gabi , Kopetz Scott
Published: September 2018

3589

Background: Mutations (mts) in RAS predict lack of response to anti-EGFR therapy in colorectal cancer. Outside the “typical RAS” mts ( KRAS/NRAS Codons 12, 13, 59, 61, 117, 146) cited in guidelines and anti-EGFR labeling, clinical impact of other “atypical RAS” mts is uncertain. Methods: Available literature and databases were surveyed to identify 80 KRAS/NRAS mts. We used the NovellusDx Functional Annotation for Cancer Treatment (FACT) to transfect these RAS mts (repeated a mean of 5.5 times/mt) in a cell-based assay that quantifies nuclear ERK localization as a measure of MAPK pathway activation, and normalized to wild type (WT) transfection. In 963 metastatic colorectal cancer patients (pts) with BRAF WT/ KRAS mutant tumors, overall survival (OS) was evaluated by level of RAS signaling activity. Results: Of the surveyed mutations,96% (45/47) of typical mts and 39% (13/33) of atypical mts increased MAPK pathway activation above WT (range: 107%-211% of WT activity). Within the typical RAS mts, mts in NRAS or exon 3, 4 of KRAS had higher activity than mts in exon 2 (codons 12/13) of KRAS, reaffirming the biologic relevance of expanded RAS testing (median activity of 130% vs 178%, P < 0.001). The median activity of atypical RAS mts was lower than typical RAS mts (110% vs 159%, P < 0.001). Several notable exceptions in atypical RAS mts with high activity levels were KRAS V14I, Q22K, D33E, N116S, and F156L (all > 165% of WT activity). Conversely, within the typical RAS mts in the guidelines, KRAS G13C and K117R were not shown to increase activity significantly above WT. Pts with any RAS mt with MAPK activity above the median of typical mts had a worse OS compared to pts below the median in univariate (HR 1.45, 95% CI 1.04-2.32, P = 0.033) and multivariate models (HR 1.96, 95% CI 1.13-3.42, P = 0.017) that controlled for age, gender, sidedness, and synchronous vs metachronous presentation. Conclusions: Functional characterization confirmed activity of RAS mts in the current guidelines, but also suggested that a subset of atypical RAS mutations have similar levels of activation of the MAPK pathway. Within the subset of pts with RAS mts, those mts resulting in high MAPK activity are associated with notably shorter OS.
Impact of patient age on molecular alterations in left-sided colorectal tumors.
Authors: Weinberg Benjamin Adam , Poorman Kelsey , Arguello David , Marshall John , Salem Mohamed E.
Published: September 2018

3592

Background: The incidence of colorectal cancer (CRC) in younger patients (pts) is rising. This increase is most pronounced in tumors arising from the distal colon and rectum. Since tumor sidedness has emerged as an important prognostic and predictive biomarker in CRC, we aim to explore the impact of age on the tumor biology of left-sided colon cancer (LCC). Herein, we compare profiles of LCC from younger (≤ 45 years) and older pts (≥ 65 years). Methods: LCCs (splenic flexure to rectum; n = 1,602) were examined by NextGen sequencing, protein expression, gene amplification, and microsatellite instability fragment analyses. Tumor mutational load (TML) was calculated using only somatic nonsynonymous missense mutations. Chi-square tests were used for comparisons. Results: LCCs from younger (median age 40, range 22-45 years, n = 229) and older (median age 71, range 65-89, n = 503) pts were studied. The most frequently mutated genes included APC, TP53, KRAS, PIK3CA, ARID1A, FBXW7, SMAD4, ATM, BRAF, and NRAS. Comparing younger v. older pts, there were no significant differences in the rates of APC (75.3% v. 82.9%, P = 0.139), TP53 (79.5% v. 73.1%, P = 0.261), KRAS (37.6% v. 43.0%, P = 0.403), PIK3CA (9.4% v. 14.6%, P = 0.234), ARID1A (14.3% v. 13.2%, P = 0.884), FBXW7 (11.4% v. 10.5%, P = 0.830), SMAD4 (13.1% v. 7.4%, P = 0.129), BRAF (4.8% v. 5.7%, P = 0.762), or NRAS (3.5% v. 2.6%, P = 0.680) mutations. Additionally there were no significant differences in protein overexpression. However, there was a trend towards increased HER2 amplification in younger pts (5.7% v. 2.1%, P = 0.05). MSH6 (4.8% v. 0.5%, P = 0.015), MSH2 (2.4% v. 0%, P = 0.032), POLE (2.4% v. 0%, P = 0.032), and NF1 (7.9% v. 0%, P < 0.001) mutations were observed at higher rates in younger pts. High TML (≥ 17 mutations per megabase) was seen more frequently in younger pts (8.2% v. 2.6%, P = 0.02). Conclusions: The molecular differences between LCC in younger and older pts are mostly due to mutations in mismatch repair genes. Higher TML may predict a higher response rate to checkpoint inhibitors in younger pts with LCC. The differences in tumor biology observed here warrant further study and may eventually be used to tailor therapy.
Robotic vs. laparoscopic vs. open abdominoperineal resection for low rectal cancer: Short-term outcomes of a single-center prospective randomized controlled trial.
Authors: Wei Ye , Xu Jianmin , Ren Li , Feng Qingyang , He Guodong , Chen Jingwen , Chang Wenju , Zhu Dexiang , Yi Tuo , Lin Qi
Published: September 2018

3603

Background: Currently, robotic surgery for rectal cancer using da Vinci System is common. However, there is almost no clinical trial reported. This randomized controlled trial aims to compare the safety and efficacy of robotic, laparoscopic and open abdominoperineal resection (APR) for low rectal cancer. Methods: From September 2013 to August 2016, patients aged from 18 to 75 years, with low rectal cancer within 5 cm from anal verge, clinical T1 to T3, no distant metastases, were randomly assigned to receive either robotic procedures (RAP), laparoscopic procedures (LAP) or open surgery (OS) for APR in 1:1:1 ratio. The primary endpoint was postoperative complication rate. This study is registered with ClinicalTrials.gov (NCT01985698). Results: Totally 406 patients were randomly assigned. Actually, 135 finished RAP, 131 finished LAP, and 137 finished OS (including 4 convert from LAP to OS). RAP had significantly lower postoperative complication rate (11.1%) than both LAP (21.4%, P = 0.023) and OS (27.7%, P = 0.001). Also, RAP reduced intraoperative hemorrhage (median [interquartile range], 100 [90-110] ml) than LAP (130 [100-150] ml, P < 0.001) and OS (150 [120-260] ml, P < 0.001). And RAP promoted postoperative recovery, with shorter days to first flatus (1.0 [1.0-2.0] day) than LAP (2.0 [2.0-3.0] day, P < 0.001) and OS (3.0 [2.0-4.0] day, P < 0.001), shorter days to first automatic urination (2.0 [2.0-3.0] day) than LAP (3.0 [2.0-4.0] day, P < 0.001) and OS (3.0 [2.0-4.0] day, P < 0.001), and shorter days to discharge (5.0 [5.0-6.0] days) than LAP (6.0 [5.0-7.0] days, P < 0.001) and OS (6.0 [5.0-7.0] day, P = 0.005). There was no significant difference in open conversion rate, resection margin involvement (including circumferential resection margin), number of lymph node harvested and pathological tumor stage. Conclusions: Robotic APR was safer, and reproduce equivalent surgical quality of conventional laparoscopic and open surgery. Also, it provided less injury and faster functional recovery. Clinical trial information: NCT01985698.
Randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) vs AG in patients (Pts) with untreated, metastatic pancreatic ductal adenocarcinoma (mPDA).
Authors: Hingorani Sunil R. , Bullock Andrea J. , Seery Tara Elisabeth , Zheng Lei , Sigal Darren , Ritch Paul S. , Braiteh Fadi S. , Zalupski Mark , Bahary Nathan , Harris William Proctor , Pu Jie , Aldrich Carrie , Khelifa Sihem , Wu Xionghua W. , Baranda Joaquina , Jiang Ping , Hendifar Andrew Eugene
Published: September 2018

4008

Background: Hyaluronan (HA) accumulation in the tumor microenvironment produces elevated tumor pressure, vascular compression, and reduced drug delivery. PEGPH20 degrades HA, increasing the access and therapeutic index of anticancer agents. Methods: In Stage 1 of this phase II study, pts with untreated mPDA were randomized 1:1 to PAG (P; 3 µg/kg IV 2x/wk x 3 wks in C1, then 1x/wk x 3 wks in C2+, plus AG) vs AG every 28 days. An imbalance in thromboembolic (TE) events in the PAG arm led to a clinical hold (~40% of pts discontinued PEGPH20), exclusion of pts at high risk for TE events and enoxaparin prophylaxis in both study arms. In Stage 2, randomization was 2:1 to PAG vs AG. Tumor HA was tested using a novel assay (VENTANA HA RxDx). Primary endpoints were PFS (evaluable pts) and TE event rate (Stage 2). Secondary endpoints were PFS by HA level and ORR. Results: 279 pts were randomized; 231 are evaluable for efficacy. Of 246 pts with HA data, 84 (34%) were HA-High. As of December 16, 2016, the primary PFS endpoint was statistically significant for PAG vs AG (HR 0.73, 95% CI 0.53-1.00; p = 0.048) (Table). PFS in HA-High pts was also statistically significant in the PAG vs AG arm (HR 0.51; 95% CI 0.26-1.00; p = 0.048). ORR in HA-High pts was 46% (PAG) vs 34% (AG). Overall survival in HA-High pts (exploratory) was 11.5 months (mo) (PAG) and 8.5 mo (AG) (HR 0.96, 95% CI 0.57-1.61). TE events were similar (PAG 14% vs AG 10%) following enoxaparin initiation. All grade treatment-related AE included peripheral edema (PAG 63% vs AG 26%), muscle spasms (56% vs 3%), neutropenia (34% vs 19%), and myalgia (26% vs 7%). Conclusions: Randomized Phase II study met both primary endpoints (PFS and TE event rate), with the largest improvement in the secondary endpoint of PFS in HA-High pts. These data support HA as a potential predictive biomarker for patient selection of PEGPH20, currently investigated in the ongoing global Phase III HALO 301 study with PFS and OS as co-primary endpoints. Clinical trial information: NCT01839487. [Table: see text]
Phase I study of AG-120, an IDH1 mutant enzyme inhibitor: Results from the cholangiocarcinoma dose escalation and expansion cohorts.
Authors: Lowery Maeve Aine , Abou-Alfa Ghassan K. , Burris Howard A. , Janku Filip , Shroff Rachna T. , Cleary James M. , Azad Nilofer Saba , Goyal Lipika , Maher Elizabeth A. , Gore Lia , Hollebecque Antoine , Beeram Muralidhar , Trent Jonathan C. , Jiang Liewen , Ishii Yuko , Auer Julia , Gliser Camelia , Agresta Samuel V. , Pandya Shuchi Sumant , Zhu Andrew X.
Published: September 2018

4015

Background: Mutations in the metabolic enzyme isocitrate dehydrogenase 1 (mIDH1) occur in patients (pts) with cholangiocarcinoma (CC) and are detected in up to 25% of intrahepatic CC. mIDH1 produce the oncometabolite, D-2-hydroxyglutarate (2-HG), resulting in epigenetic and genetic dysregulation and oncogenesis. AG-120 is a first-in-class, potent, oral inhibitor of mIDH1 tested in this phase I study in mIDH1 solid tumors, including CC. Methods: AG-120 was escalated in a 3+3 design from 100 mg twice daily to 1200 mg once daily (QD) in 28-day cycles (N = 60, mIDH1 advanced solid tumors). Key eligibility for CC: recurrence of progressive mIDH1 CC following standard therapy (dose escalation) or at least a prior gemcitabine-based regimen (expansion cohort). Response (RECIST 1.1) was assessed every 8 weeks. Plasma and tumor tissue were collected for exploratory analyses. Results: Based on the safety, pharmacokinetic, and pharmacodynamic data from dose escalation, the 500 mg QD dose was selected for expansion in mIDH1 CC and other mIDH1 solid tumors. As of Dec 16, 2016, 73 pts with mIDH1 CC had been dosed in the dose escalation (n = 24) and expansion (n = 49) cohorts. Demographics: M/F = 24/49, median number of prior therapies = 2 (range 1–5), ECOG 0–1 = 26/47. There were no dose-limiting toxicities. Treatment-related adverse events (AEs) in ≥5% pts: fatigue (21%), nausea (18%), vomiting (12%), diarrhea (10%), decreased appetite (8%), dysgeusia (5%), QT prolongation (5%). Two (3%) pts experienced related grade 3 AEs: fatigue and low phosphorus. There were no AG-120-related AEs leading to discontinuation. Among the 72 efficacy evaluable (≥1 post baseline response assessment or discontinued prematurely) mIDH1 CC pts (24 in escalation and 48 in expansion cohort), 6% (n = 4) had a confirmed partial response and 56% (n = 40) experienced stable disease. The progression-free survival rate at 6 months was 40%, and 8 pts have been treated with AG-120 for ≥1 year. Conclusions: In this pretreated mIDH1 CC population, AG-120 was associated with a favorable safety profile and prolonged stable disease. A global, phase III, randomized, placebo-controlled study of AG-120 in mIDH1 CC has been initiated (ClarIDHy). Clinical trial information: NCT02073994.
Impact of chemoradiotherapy on PD1/PDL1 expression and clinical outcomes in gastroesophageal cancers.
Authors: Osipov Arsen , Li Quanlin , Thomassian Shant , Annamalai Lakshmanan , Yearley Jennifer Holmes , Rutgers Joanne K , Hendifar Andrew Eugene , Tuli Richard
Published: September 2018

4031

Background: Expression of the immune modulating proteins, programmed death receptor-1 (PD1) and its ligand (PDL1), in gastrointestinal malignancies is associated with poor prognosis. PD1/PDL1 expression levels have also been identified as predictors of response to checkpoint inhibition. Minimal data is available on how expression of PD1 and PDL1 is influenced by chemoradiotherapy (CRT). In this study, we investigated the relationship between PDL1/PD1 expression, CRT, and clinical outcomes in gastroesophageal (GE) cancer. Methods: With IRB approval, we identified 28 patients with gastric cardia or GE junction tumors who underwent neoadjuvant standard CRT followed by surgical resection. Pre-CRT biopsies and post-CRT surgical specimens were analyzed using quantitative immunohistochemistry for the expression of PDL1 and PD1. Samples were categorized as trace-low (TL) or moderate-high (MH) expressors of PDL1 and PD1. The impact of these and other clinical and pathologic variables on overall survival (OS) was assessed using multivariate cox proportional hazards modeling. Co-expression of PDL1 and PD1 in matched samples was determined by regression analysis. Results: Following CRT, PDL1 and PD1 expression increased in 54% and 32% of patients, respectively. On multivariate analysis, patients with MH expression of PD1 after CRT irrespective of pre-CRT expression levels had a significant decrease in OS compared to those with TL expression (median survival 23.1 vs 74.1 months; HR,3.31; CI,1.05-10.35; p = 0.039). In patients with gastric confined tumors, an increase in PD1 expression from TL to MH after CRT was associated with significantly lower OS rates (p = 0.003). Regression analysis of PD1 to PDL1 was significant (p < 0.01) both before and after CRT, with a correlation coefficient of 0.34 in pre-CRT and 0.49 in post-CRT specimens. Conclusions: Elevated expression of PD1 is associated with poor OS in patients with GE cancer. Neoadjuvant CRT upregulates both PDL1 and PD1. In gastric cancer patients, this led to significantly worse survival. These data identify potential mechanisms of resistance and suggest a role for checkpoint inhibitors in combination with CRT.
Expression of Claudin 18.2 and HER2 in gastric, gastroesophageal junction, and esophageal cancers: Results from the FAST study.
Authors: Schuler Martin H. , Al-Batran Salah-Eddin , Zvirbule Zanete , Manikhas Georgy , Lordick Florian , Rusyn Andriy V. , Vynnychenko Ihor , Dudov Assen , Bazin Igor , Melichar Bohuslav , Dhaene Karl , Wiechen Kai , Maurus Daniel , Tureci Özlem , Sahin Ugur
Published: September 2018

4038

Background: Claudin 18.2 (CLDN18.2), a gastric mucosa tight junction protein, is aberrantly expressed in various cancers. In the FAST Phase 2 trial (NCT01630083), IMAB362, an anti-CLDN18.2 monoclonal antibody, administered in combination with EOX chemotherapy, prolonged survival compared to EOX alone in patients with advanced/recurrent gastric, gastroesophageal junction (GEJ), and esophageal cancers ineligible for trastuzumab. The aim of the present analysis was to assess tumor CLDN18.2 expression and co-expression with HER2 in the FAST population. Methods: Tumor tissue samples from patients screened for inclusion into the FAST trial were analyzed for CLDN18.2 expression using a CE-marked, validated immunohistochemistry (IHC) assay. CLDN18.2 expression was centrally scored based on staining intensity and percentage of stained tumor cells. In a subset of tissue samples with known HER2 status, overall HER2 expression and co-expression with CLDN18.2 were determined. Results: Tissue samples from 730 patients with gastric, GEJ, and esophageal cancer were screened for the FAST study. Of these 730 samples, 685 (94%) were assessed by central IHC; 49% (n=333/685) met the FAST CLDN18.2 expression criterion (≥2+ intensity in ≥40% of tumor cells) for inclusion. Across the 154 tissue samples with known HER2 status, the majority (84%; n=129/154) were HER2–. Furthermore, 94 of these 154 samples (61%) met the FAST CLDN18.2 expression criterion, of which 14% (n=13/94) co-expressed HER2 (Table). Conclusions: In tissue samples from patients screened for the FAST trial, nearly half met CLDN18.2 expression inclusion criterion. In samples with known HER2 status, co-expression of CLDN18.2 and HER2 occurred in 14% of the samples that met study eligibility. These data suggest CLDN18.2 may serve as a non-HER2 overlapping targetable alteration in a distinct subpopulation of patients with gastric, GEJ, or esophageal cancers. Clinical trial information: NCT01630083. [Table: see text]
Cardiac death rates after irradiation for esophageal cancer: An epidemiologic study among esophageal cancer survivors.
Authors: Molenaar Remco Jurriaan , Radivoyevitch Tomas , Hulshof Maarten , Van Laarhoven Hanneke W.M.
Published: September 2018

4049

Background: Esophageal cancer is frequently treated with radiation in addition to surgery and/or chemotherapy. Long-term survivors that received radiation may be at risk for radiation-induced cardiotoxicity. Methods: Esophageal cancer survivors (defined as surviving > 5 yrs after diagnosis) from all 18 Surveillance Epidemiology and End Results (SEER) registries from 1973 to 2013 were queried for irradiation status, cause of death and survival using SEERaBomb, a package for the R statistical programming language. Results: 6,514 esophageal cancer survivors were identified, of whom 2,892 (44%) received no radiation therapy and 3,448 (53%) received external beam radiotherapy. Mean age at the time of esophageal cancer diagnosis was 64.0 yrs in the no radiation group and 63.0 yrs in the radiation group. Median person years of follow up after esophageal cancer diagnosis was 8.6 yrs (interquartile range [IQR]: 7-12) in pts receiving no radiation and 7.9 yrs (6-11) in pts receiving radiation. A total of 590 esophageal cancer survivors died of cardiac disease; 254 received no radiation and 336 did receive radiation. Median time to cardiac death after esophageal cancer diagnosis was 32.2 yrs (IQR: 19-38) in pts that received no radiation and 25.3 years (15-30) in pts that received radiation (log-rank P< 0.001). Compared with unirradiated pts, irradiated pts had an increased risk of dying of cardiac disease (hazard ratio [HR] = 1.47; 95% confidence interval [CI]: 1.2-1.7, Cox regression P< 0.001). The association between radiation and cardiac death was the strongest in esophageal cancer pts diagnosed before 1995 (HR = 1.75; 95% CI: 1.4-2.2, P< 0.001) and in squamous cell carcinoma of the esophagus (HR = 1.9; 95% CI: 1.4-2.6, P< 0.001) but not in adenocarcinoma (HR = 1.04; 95% CI: 0.8-1.4, P= 0.8). Conclusions: 5-year esophageal cancer survivors that were treated with radiotherapy have an increased risk of dying of cardiac disease, compared with unirradiated counterparts. This association was strongest in pts treated before 1995 and in squamous cell carcinoma pts. This may be due to late radiation-induced cardiotoxicity, decreasing with the use of heart-sparing radiation techniques after 1995.
Pathophysiology and therapeutic strategies for peritoneal recurrence after gastric cancer surgery.
Authors: Murata Satoshi , Takebayashi Katsushi , Yamamoto Hiroshi , Yamaguchi Tsuyoshi , Kaida Sachiko , Kodama Hirokazu , Ohtake Reiko , Shimizu Tomoharu , Mori Tsuyoshi , Kawai Yuki , Kitamura Naomi , Miyake Toru , Akabori Hiroya , Iida Hiroya , Ueki Tomoyuki , Sonoda Hiromichi , Mori Haruki , Nitta Nobuhito , Naka Shigeyuki , Tani Masaji
Published: September 2018

4050

Background: We recently showed that cancer cells, with proliferative and tumorigenic potential, can spill into the peritoneal cavity during curative (R0) gastric cancer (GC) surgery, which is associated with peritoneal recurrence (PM). To elucidate the pathophysiology of PM, the relationship between spilled cancer cells and cancer stem cells was evaluated. Furthermore, to identify a therapeutic strategy for PM, the prognostic impact of hyperthermic intraperitoneal chemotherapy (HIPEC) following GC surgery with spillage of cancer cells was evaluated. Methods: Patients with advanced GC (≥pT2 [MP]) who underwent R0 gastrectomy between 2010 and 2015 were enrolled. Ninety-four consecutive patients with negative results in peritoneal cytology and cancer cell culture (CCC [-]) following peritoneal washing (PW) before GC surgery were included. Spilled cancer cells in PW after GC surgery (PW-Post) were examined to identify any CD44-positive cancer stem-like cells associated with cancer metastasis. Based on the PW-Post CCC results, associations between HIPEC and recurrence-free survival (RFS), or overall survival (OS) were evaluated. HIPEC was performed following GC surgery using CDDP, MMC, and 5-FU in 5 L saline maintained at 42˚C for 30 min. Results: Spilled cancer cells included CD44+ cancer stem-like cells. In 48 patients with PW-Post positive CCC (CCC [+]), the number of patients with pStage I, II, and III were 4, 7, and 15, respectively, in those who received HIPEC (n = 26), and 3, 9, and 10, respectively, in those who did not (n = 22). Among patients with CCC (+), the 5-year peritoneal RFS, hepatic RFS, and lymph node RFS rates were 93.3%, 100%, and 68.5%, respectively, in patients who received HIPEC, and 56.7%, 35.6%, and 66.7%, respectively, in those who did not ( P = 0.008, P = 0.008, and P= 0.24, respectively). Among patients with PW-Post CCC (-), none developed recurrence, regardless of whether they received HIPEC (n = 28) or not (n = 18). Conclusions: The results show that PW-Post CCC is a promising predictive biomarker for recurrence after R0 GC surgery. Adjuvant HIPEC performed with R0 GC surgery showed preventive effects on peritoneal and hepatic recurrence and survival benefits for patients with PW-Post CCC (+).
Long-term outcomes with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from appendiceal cancer: An 18-year experience.
Authors: Munoz-Zuluaga Carlos A. , Sardi Armando , Sittig Michelle , Eskay Victoria , Nieroda Carol Ann , El-Sharkawy Farah , Sipok Arkadii , Gushchin Vadim
Published: September 2018

4098

Background: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) have become standard of care for patients with peritoneal carcinomatosis (PC) from appendiceal cancer (AC). We reviewed our experience and outcomes. Methods: A retrospective review of 614 CRS/HIPEC procedures from 1998-2016 was performed. Patient characteristics, surgical variables, and postoperative outcomes of first CRS/HIPEC were analyzed. Results: Two hundred ninety patients with PC from AC underwent 334 CRS/HIPEC’s. Median age at diagnosis and surgery was 52 (22-79) and 53 (23-81) years, respectively; 65% (187) were female. Prior surgical score was 0, 1, 2, and 3 in 20%, 38%, 37%, and 5%, respectively. Prior systemic chemotherapy was reported in 30% of patients. Median time from diagnosis to CRS/HIPEC was 4 months (0-182). Pre-operative tumor markers (CEA, CA-125, CA-19-9) were positive in 48% with one, two, and three positive markers in 21%, 15%, and 13% patients, respectively. Median Peritoneal Cancer Index was 29. Mitomycin-C was the HIPEC agent of choice. Mean operative time was 10 hours (R: 4-19) and median length of stay was 10 days (R: 4-93). Histology included 59% (171) peritoneal mucinous carcinomatosis (PMCA), 41% (119) disseminated peritoneal adenomucinosis (DPAM). Lymph nodes were positive in 47% PMCA. Complete cytoreduction rate was 87% (84% PMCA, 92% DPAM [p = 0.048]). Grade III-V complications occurred in 21%, with one 30-day mortality (0.3%). Overall, median progression-free survival (PFS) was 84 months with 5-year PFS of 56%. Median PFS was 43 months in PMCA and not reached in DPAM. Five year PFS was 40% PMCA and 82% DPAM (p < 0.001). Median overall survival (MOS) was 139 months with 61% 5-year OS. MOS was 53 months in PMCA and not reached in DPAM. Five year OS was 47% PMCA and 85% DPAM (p < 0.001). At 42-month median follow-up, 68% were alive (92 PMCA/103 DPAM) with 84% disease free (72 PMCA/92 DPAM), 28% died of disease (73 PMCA/7 DPAM). Conclusions: CRS/HIPEC is an effective treatment for patients with PC from AC providing meaningful long term survival in low and high grade tumors and should be considered the standard of care.
Potential role of circulating tumor DNA (ctDNA) in the early diagnosis and post-operative management of localised pancreatic cancer.
Authors: Lee Belinda , Cohen Joshua , Lipton Lara Rachel , Tie Jeanne , Javed Ammar Asrar , Li Lu , Goldstein David , Cooray Prasad , Nagrial Adnan , Burge Matthew E. , Tebbutt Niall C. , Nikfarjam Mehrdad , Harris Marion , O'Broin-Lennon Anne Marie , Wolfgang Christopher Lee , Tomasetti Cristian , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Gibbs Peter
Published: September 2018

4101

Background: Pancreatic cancer remains a devastating disease, with the diagnosis typically being made late. ctDNA has shown promise as a screening test for various tumor types. The detection of ctDNA post curative intent surgery has been associated with a high risk of recurrence in multiple solid tumors. We explored the potential of ctDNA to improve pancreatic cancer outcomes. Methods: Data from separate US and Australian series were combined. Plasma samples were collected prior to surgery in both studies and post-operative samples were collected in Australia from cases undergoing curative intent surgery. Clinicians were blinded to ctDNA results and adjuvant therapy was at clinician discretion. Tissue samples from both series were analyzed at Johns Hopkins University. Next generation sequencing was used to search for somatic KRAS mutations in the primary tumors and in cell-free DNA in the plasma. Clinico-pathologic, treatment and outcome data were collected. Results: 119 pts had a ctDNA sample at diagnosis (median age 67 years, 56.3% male). Sixty six pts (55.5 %) had detectable ctDNA, including 3/7 (42.9%) with stage I disease, 54/99 (54.5%) with stage II disease, 4/8 (50%) with stage III disease and 5/5 (100%) with metastases. Specific codon 12 KRAS (G12D, G12V or G12R) mutations were identified in the tumor tissue of 12/16 (75%) patients who had a ctDNA sample collected post-surgery. At a median follow-up of 15.2 months, 7/12 (58.3%) pts had recurred, including 3/8 (37.5%) with no detectable ctDNA and 4/4 (100%) with detectable ctDNA post-surgery (HR 4.9, p = 0.04). Detectable ctDNA post-surgery was significantly associated with poor overall survival (HR 6.93, p = 0.006), with a median of 8 months for pts with detectable ctDNA. Conclusions: ctDNA shows promise as a pancreatic cancer screening test, being detectable in a high proportion of pts with early stage disease. The detection of ctDNA post operatively predicts a very high risk of recurrence. The clinical utility of ctDNA to guide adjuvant therapy decision making, and its potential as a real-time marker of treatment effect, are being explored in further studies. Clinical trial information: ACTRN12612000763842.
Preliminary safety data from a randomized multicenter phase Ib/II study of neoadjuvant chemoradiation therapy (CRT) alone or in combination with pembrolizumab in patients with resectable or borderline resectable pancreatic cancer.
Authors: Katz Matthew H. G. , Varadhachary Gauri R. , Bauer Todd W. , Acquavella Nicolas , Merchant Nipun B. , Le Tri Minh , Javle Milind M. , Shroff Rachna T. , Overman Michael J. , Fogelman David R. , Petroni Gina R. , Slingluff Craig L. , Rahma Osama E.
Published: September 2018

4125

Background: Pancreatic cancer (PC) is a challenging target for immunotherapy.Tumor-infiltrating lymphocytes (TILs) do not reach the PC cells in significant numbers due to the presence of stroma and a suppressive microenvironment. Neoadjuvant chemoradiation (CRT) can increase the presence of TILs in the PC microenvironment. We hypothesized that combination of CRT and pembrolizumab can lead to further increase in TILs and their activation. Methods: Patients with resectable or borderline resectable PC have been randomized 2:1 to the investigational treatment (Arm A) to receive pembrolizumab 200mg IV every 3 weeks on days 1, 22, and 43 during concurrent CRT with capecitabine (825 mg/m2 orally twice daily, Monday-Friday, on days of radiation only) and radiation (50.4 Gy in 28 fractions over 28 days) or Arm B to receive only concurrent CRT with capecitabine. Restaging CT scan or MRI is performed at 4-6 weeks after completion of neoadjuvant treatment, and patients with resectable disease will undergo surgical resection. Here we report the preliminary safety data based on 22 enrolled patients. Results: As of February 3-2017,22 patients have been enrolled (14 Arm A and 8 Arm B). 50% of the patients had resectable disease (7 arm A; 4 arm B) and the other 50% had borderline resectable disease (7 Arm A; 4 arm B). Post-neoadjuvant therapy, 6 patients had unresectable disease (3 on each arm), and 14 patients underwent surgery (10 arm A and 4 arm B). There were 7 grade 3 treatment-related toxicities in Arm A (5 patients): 2 grade 3 diarrhea attributed to CRT; 4 grade 3 lymphopenias attributed to pembrolizumab, CRT or the combination; and one patient had elevated alkaline phosphatase probably related to the combination that met the definition of DLT and resolved after holding the treatment and receiving steroids. There was only one grade 3 toxicity on Arm B: lymphopenia attributed to CRT. No grade 4 toxicities have been reported on either arm. There were no major surgical complications reported within 30 days post-surgery. Conclusions: The combination of CRT and pembrolizuamb is safe based on the presented data. Clinical trial information: NCT02305186.
Biomarker findings and mature clinical results from KEYNOTE-052: First-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC).
Authors: O'Donnell Peter H. , Grivas Petros , Balar Arjun Vasant , Bellmunt Joaquim , Vuky Jacqueline , Powles Thomas , Plimack Elizabeth R. , Hahn Noah M. , De Wit Ronald , Pang Lei , Savage Mary J. , Lunceford Jared K. , Keefe Stephen Michael , Bajorin Dean F. , Castellano Daniel
Published: September 2018

4502

Background: Comorbidities and renal impairment preclude many with advanced UC from receiving chemotherapy. Initial results from the phase 2 KEYNOTE-052 (NCT02335424) trial suggested first-line pembro is active and safe in cisplatin-ineligible advanced UC. We present updated efficacy and safety data (all pts have ≥6 mo follow-up) and evaluate biomarkers correlated with outcomes. Methods: Eligibility criteria included cisplatin-ineligible (ECOG PS 2, CrCl ≥30- < 60 mL/min, grade ≥2 neuropathy/hearing loss, NYHA Class 3 heart failure), advanced UC, and no prior systemic chemotherapy. Pts received pembro 200 mg IV Q3W. Imaging was performed at wk 9, then Q6W for the first year, and Q12W thereafter. Primary end point was confirmed ORR (RECIST v1.1, independent review). Efficacy and safety were assessed in the 370 pts with ≥1 pembro dose. The associations of an 18-gene expression profile (GEP) and IHC PD-L1 combined positive score (CPS) with ORR were evaluated. Results: As of the Dec 19, 2016, data cutoff, ORR was 29% (95% CI, 24-34): 25 (7%) and 81 (22%) pts achieved complete and partial responses. Another 69 pts (19%) had stable disease as best response, for a clinical benefit rate of 47%. Median time to response was 2 mo (range, 1-5). At a median follow-up of 8 mo (range, 0.1-20) across all pts, median duration of response was not reached (range, 1+-18+ mo). 74% of responses were ongoing. Any-grade and grade ≥3 drug-related AEs occurred in 239 (65%) and 68 (18%) pts. Immune-mediated AEs occurred in 76 (21%) pts. Evidence supporting a positive association with response was seen in the first 100 pts for both biomarkers (GEP, n = 72, P = 0.007, ROC AUC 0.69; CPS, n = 96, P= 0.111, ROC AUC 0.58); biomarker data for all pts will be presented. ORR in the 110 pts with CPS ≥10% was 47% (95% CI, 38-57). Conclusions: Results confirm that pembro elicits clinically meaningful, durable responses in cisplatin-ineligible advanced UC. Consistent with PD-1 pathway biology, biomarkers (GEP and CPS) showed the expected trends of positive association with response to pembro. Pembro was well tolerated across cisplatin-ineligible pts, including elderly and pts with poor performance status. Clinical trial information: NCT02335424.
Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: Preliminary phase I/II results of ECHO-202/KEYNOTE-037.
Authors: Smith David C. , Gajewski Thomas , Hamid Omid , Wasser Jeffrey S. , Olszanski Anthony J. , Patel Sandip P. , Mamtani Ronac , Schmidt Emmett V. , Zhao Yufan , Maleski Janet E. , Gangadhar Tara C.
Published: September 2018

4503

Background: Pembrolizumab (P), a PD-1 inhibitor, is active and well tolerated in platinum-treated, advanced urothelial carcinoma (UC). Epacadostat (E) potently and selectively inhibits indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan-catabolizing enzyme that suppresses T-cell–mediated immune surveillance. IDO1 overexpression is associated with tumor progression and shortened patient (pt) survival. ECHO-202/KEYNOTE-037 is an open-label, phase I/II study of E + P in pts with advanced tumors. We report phase I/II efficacy and safety outcomes for the UC cohort at an October 29, 2016 data cutoff. Methods: Adult pts with advanced UC, prior platinum therapy (adjuvant or advanced disease setting) or alternative therapy (if platinum was not appropriate), and no prior checkpoint inhibitor therapy were eligible to participate. In phase I, pts received E (25, 50, 100, or 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) dosing was selected for phase II. Response was assessed in RECIST 1.1–evaluable pts. Safety was assessed in pts receiving ≥1 E + P dose. Results: A total of 40 pts (phase I, n = 5; phase II, n = 35) were evaluated. Median age was 67 years, 75% were men, 88% were white, 100% had prior platinum therapy, and 75% had 0–1 prior line of therapy for advanced disease. Preliminary ORR (CR+PR) and DCR (CR+PR+SD) for all efficacy-evaluable pts were 35% (13/37; all PR) and 57% (21/37; 13 PR, 8 SD), respectively; for pts with 0–1 prior line of therapy for advanced disease, ORR and DCR were 37% (10/27) and 63% (17/27). At data cutoff, 12/13 responses were ongoing (range, 1+ to 652+ days). PFS and biomarker analyses are ongoing. The most common TRAEs (≥10% of 40 pts) were fatigue (28%), rash (18%), and increased amylase (10%; asymptomatic). Grade ≥3 TRAEs occurred in 20% of pts (rash was the only grade ≥3 TRAE to occur in > 1 pt [n = 3]). Three pts discontinued due to TRAEs (grade 3 rash [n = 1]; grade 3 COPD exacerbation [n = 1], grade 2 diarrhea [n = 1]). Conclusions: E + P was generally well tolerated and associated with increased response compared with previously reported PD-1 inhibitor monotherapy in pts with advanced UC. A phase III UC study is planned. Clinical trial information: NCT02178722.