bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating free tumor DNA copy number index (CNI) as a predictor of therapeutic response in pancreatic ductal adenocarcinomas (PDAC).
Authors: Kundranda Madappa N. , Beck Julia , Bergelin Jana , Dragovich Tomislav , Lucente Patricia , Conn Marie , Naraev Boris , Chang John , Urnovitz Howard , Schütz Ekkehard
Published: January 2019

261

Background: Cell-free tumor DNA (cfDNA) has potential to provide minimally invasive patient specific biomarkers to monitor tumor burden. Tumor-specific copy number instability (CNI) are used to quantify tumor-derived cfDNA in the plasma. We prospectively computed CNI Scores of cfDNA to compare with radiological and Ca 19-9 responses. Methods: In a laboratory blinded, prospective single-institution study, 119 plasma samples from 33 patients (pts) with PDAC were analyzed. Time-points were at baseline (C1), 2nd (C2) and 3rd (C3) cycle of systemic therapy. Tumor cfDNA was measured with a CNI scoring assay that quantifies cfDNA with somatic macro-alterations. CNI Score (CNIs) of 31 was defined as ref. range (97.5 % - control group; N = 135), pts below this threshold were censored. Progression of disease (PD) defined as C3 CNIs > 93 (3-fold threshold) and difference to the baseline > 31 (dispersion of reference population). Mutant KRAS in plasma was measured using ddPCR in a subset 22 pts. Pts with an increase of > 0.06% (critical difference) were classified PD. Radiologic imaging results were compared with CNIs and CA19-9 changes from baseline to C3, respectively. Results: By standard radiological imaging 33 pts were classified as: 14 PR/CR, 10 SD, 9 PD. 27/33 pts (81%) were evaluable by CNIs which ranged from decrease of 2017 - increase of 645. The C3 CNI classifier yielded a sensitivity of 86% for predicting PD and 95% for SD/PR/CR. KRAS classification yielded an accuracy of 72%, and only 3/9 PD were accurately predicted (33%). 26/33 pts were secretors evaluable by CA19-9. Only 2/8 PD pts showed increasing values in CA19-9 and 6/8 of evaluable by CNI; 5/6 showed increasing CNI scores. 3/20 deemed as SD on imaging with increasing values of CA19-9 were noted to have decreasing CNIs. CNI Score classification was significantly better than CA19-9 (P = 0.001 and 0.63, respectively). Conclusions: Our evaluation of a comparative study on cfDNA and CA19-9 versus imaging suggest that CNI quantification is potentially a more reliable blood-based marker for early assessment of efficacy to systemic therapy in PDAC. Furthermore, for patients not expressing CA19-9 it could serve as an alternative monitoring aid.
The impact of the immune microenvironment in patients with GEP-NETs.
Authors: Baretti Marina , Zhu Qingfeng , Zahurak Marianna , Pawlik Timothy M. , Anders Robert A , De Jesus-Acosta Ana
Published: January 2019

267

Background: The immune microenvironment in neuroendocrine tumors (NETs) remains largely unexplored with very limited data evaluating its impact on survival. We aimed to characterize the immune microenvironment and lymphocytic infiltrate in patients with gastroenteropancreatic (GEP) NET. Methods: We performed comprehensive immune profiling for CD3, CD8, PD-1, IDO, and PD-L1 expression in two cohorts of patients with primary GEP-NET: patients who had short progression free survival (PFS) ≤ 4 years (n = 12) or long PFS > 4 years (n = 14) following surgical resection. Tumor associated immune infiltrates in the tumor, inner and outer invasive front were recorded and quantified. The percentage of PD-L1 membranous expression was manually counted in tumor, stroma and invasive front. To account for the correlation among multiple samples within the same patient, generalized estimating equations (GEE) were used for model estimation and hypothesis testing. Results: Patients with shorter PFS had larger primary tumor size compared to patients with longer PFS (Wilcoxon p value = 0.02), with no statistically significant differences in Ki-67 expression. For all patients univariate GEE results showed a higher mean expression of CD3+, CD8+, and PD-1+ cells at the interface (inner and outer) as compared to the tumor region: 1.28 (95% CI: 0.98, 1.58, p < 0.0001), 0.99 (95% CI: 0.67, 1.32, p = 0.0005) and 1.38 (95% CI: 0.90, 1.38, p < 0.0001) respectively. Comparison between the two groups showed that tumors from patients with a longer PFS had higher intratumoral CD3+ TILs densities than did those from patients who had a shortened PFS (0.88, 95% CI: 0.44, 1.31, p = 0.004). Intratumoral expression of CD8+TILs, and IDO+ cells tended to be higher in the long PFS group (p = 0.143 and 0.29 respectively). While the probability of positive PD-L1 expression did not differ according to location, it was higher in patients with shortened PFS (odds ratio = 1.96; 95% CI: 0.64, 5.93), though not significant. Conclusions: Higher intratumoral T cell infiltrate (CD3+) is associated with a favorable outcome and longer PFS following resection for GEP-NETs. Immune escape is a potential mechanism for disease progression and warrants further investigation as a therapeutic strategy for this disease.
Phase II pharmacokinetics of oral SM-88 in heavily pretreated advanced pancreatic ductal adenocarcinoma (PC).
Authors: Noel Marcus Smith , Fernandez-Zapico Martin , Sokol Gerald H. , Del Priore Giuseppe
Published: January 2019

277

Background: SM88 is an oral tyrosine isomer ( TI) and repurposed drugs (CYP3a4 inducer, mTOR inhibitor, oxidative stress catalyst). This regimen has reported no drug related grade 3, 4 or 5 adverse events (JCO 2013 31: e22095) and potential clinical activity in PC (JCO 2018 36: TPS 4156). PC patients have risk factors for malabsorption and a cachexia syndrome rendering some oral therapies potential unreliable. We present PK data from the completely enrolled first stage of an ongoing dose finding phase II in PC. Methods: Open label randomized TI (control – 230 mg bid vs. experimental - 430 mg bid) along with the lowest approved doses of the other agents. Samples were drawn from four patients at pre-dose and up to six h post dosing on cycle day one for two cycles after a single dose of all four components. Results: Mean age: 71.3 (59 – 80), BMI = 25.3 (21.9 – 28.8) and median three prior chemo lines, two post-pancreas surgery and one s/p RT. There was no evidence that the combination altered the expected PKs at C2. There were no serious drug related adverse events. Favorable RECIST, PERCIST or biomarker activity was documented at both TI dose levels. The PK results of the repurposed drugs were consistent with the published data for these agents, despite the combination use and lower than typical label doses; data will be provided. These results were consistent with previous animal and healthier patient PK of SM88. Conclusions: Single dose C1 and C2 TI PKs are consistent with preclinical predictions (ESMO 2016. Ann Oncol (2016) 27 (supp_6): 1605P) and those previously reported in a healthier population of cancer patients (JCO 2018 36: TPS 4156). Based on these results and PK ones from the repurposed drugs, additional data is being collected in order to define the ongoing phase II expansion cohort dose. SM-88 appears to have predictable PK even in heavily pretreated PC patient with prior radiotherapy and surgery. Clinical trial information: NCT03512756. [Table: see text]
Ligand-inducible, prostate stem cell antigen (PSCA)-directed GoCAR-T cells in advanced solid tumors: Preliminary results from a dose escalation.
Authors: Becerra Carlos Roberto , Hoof Pamela , Paulson Andrew Scott , Manji Gulam Abbas , Gardner Olivia , Malankar Aditya , Shaw Joanne , Blass Devin , Ballard Brandon , Yi Xiaohui , Anumula Madhavi , Foster Aaron E. , Senesac Joseph , Woodard Paul
Published: January 2019

283

Background: PSCA, a cell surface protein, is upregulated in many solid tumors and correlates with disease stage. BPX601 is an autologous, T-cell product engineered to contain a PSCA-CD3ζ CAR plus the small molecule rimiducid (Rim)-inducible MyD88/CD40 costimulatory domain. BPX601 is optimized for antigen-directed and independent T cell activation, proliferation and persistence, potentially enhancing efficacy in solid tumors versus traditional CARs. This first-in-human study assesses the safety, biological and clinical activity of BPX601 plus Rim in select PSCA-positive cancers. Methods: NCT02744287 is a two-part, open-label trial. Part 1 is an ongoing 3+3 cell dose escalation to identify the recommended BPX601 cell dose (Day 0) given in combination with a fixed, single Rim dose (0.4 mg/kg; Day 7). Eligibility criteria include previously treated metastatic pancreatic cancer (mPDAC) with measurable disease & positive PSCA expression. Results: Patients received only cyclophosphamide (CTX) for lymphodepletion (LD) within three days before BPX601 infusion. Nine adults have been treated across three cell dose levels (cells/kg): 1.25x106 (cells only), 1.25x106+Rim, 2.5x106+Rim. All had mPDAC with ≥ two prior therapies. Common AEs were fatigue and nausea. No DLTs, related SAEs, neurotoxicity or CRS events were reported. Rapid cell engraftment by Day 4 was observed in all patients. No evidence of LD with CTX was seen. Of six patients that received Rim: two had cell expansion 10- to 20-fold within seven days; two had cell persistence > three weeks; all had elevated serum cytokines (IP-10, TNFα) correlated with cell expansion. Best response after ≥ one scan was 4 SD ≥ eight weeks with two minor responses (not confirmed; one patient had matched CA19-9 decrease) and 2 PD. Disease control without new therapy was 16 and > 11 weeks (ongoing) in one and two patients, respectively. Conclusions: BPX601 with single-dose Rim was well-tolerated and resulted in enhanced T cell expansion and prolonged persistence in some patients despite lack of LD. Evidence of clinical benefit in this heavily pretreated mPDAC population was seen. Part 2 is planned to open soon and will include CTX/fludarabine LD to maximize engraftment as well as gastric and prostate cancers. Clinical trial information: NCT02744287.
MAPK pathway proteins expression and correlation with clinicopathological indices and long-term outcome according to the etiology of underlying chronic liver disease in hepatocellular carcinoma.
Authors: Diniz Paulo Henrique Costa , Silva Serena Dafne do Carmo , Sampaio Caio Cesar Lobo , Vidigal Paula Vieira Teixeira , Xavier Marcelo Antonio Pascoal , Faria Luciana Costa , Ferrari Teresa Cristina de Abreu
Published: January 2019

286

Background: Different etiologies of chronic liver disease (CLD) potentially lead to hepatocellular carcinoma (HCC) by multiple mechanisms that can be translated into clinicopathological and prognostic differences. We evaluated the expression of some proteins of MAPK pathway, an important signalling cascade in HCC, and correlated them to clinical and histopathological parameters, and long-term outcome, according to the etiology of the CLD. Methods: 80 patients (pts) who underwent orthotoptic liver transplantation (OLT) for HCC at Universidade Federal de Minas Gerais, a referral center in Brazil, were randomly selected: 41 viral (V) (HBV or HCV infection), 39 nonviral (NV) (alcohol abuse and cryptogenic) etiology. Clinical pre-OLT and histological data were retrospectively collected. Event (E) was defined as death and/or HCC-recurrence since OLT. In explanted liver, tumor and adjacent cirrhosis were subjected to immunohistochemistry, using antibodies against K-RAS, B-RAF and MEK, analysed by two pathologists. Results: V and NV groups were well balanced regarding clinicopathologic indices, but alcohol was the main etiology in men (95%) and HCV in women (38.7%). Median E-free survival (EFS) was 74.5 months (range, 8.5-105), without difference between groups. Microvascular invasion (MIV) (p < 0.01) and age (p = 0.04) were independently associated with E. 11 pts (26.8%) of the V group had strong expression (SE) of K-RAS in tumor comparing to 0 (0%) in cirrhosis (p = 0.008) and to three (7.7%) in NV group HCC (p = 0.024). SE of B-RAF was seen in seven pts (17.0%) in V versus 11 (28.2%) in NV (p = 0.257), without difference from cirrhosis (p = 0.755). SE of MEK was not seen. Weak KRAS expression was more common in older pts (p = 0.04). The proteins expression was not related to E or EFS. Conclusions: SE of K-RAS, but not of BRAF and MEK, were more frequent in V group HCC than in cirrhosis and NV group tumors. It suggests that HBV and HCV can lead to HCC by different mechanisms comparing to NV etiology and KRAS could have a role on carcinogenesis. As there were no differences in clinical outcomes, prognostic, and therapeutic implications need to be stablished.
Clinical trial screening of CDKN2A genomic alterations in patients with pancreatic cancer and hepatobiliary cancers requires greater precision than somatic sequencing alone.
Authors: Vaske Charles Joseph , Garner Chad , Seery Tara Elisabeth , Szeto Christopher , Reddy Sandeep K.
Published: January 2019

287

Background: The TAPUR Study is a phase II multi‐basket study that evaluates the anti‐tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations known to be drug targets. Results in two cohorts of PC and GBC pts each with CDKN2A loss or mutation were reported at ASCO 2018. The conclusion was that monotherapy with palbocicilib is not associated with clinical activity in these patients. This may be a false conclusion if the genomic targets were absent in these patients. Methods: A total of 158 GI pts (P = 123, GB = 20, Bile Duct = 15) with deep whole exome sequencing (WES) of tumor and blood samples, and whole transcriptomic sequencing (RNA-Seq) (∼200x106 reads per tumor) were available for this analysis from a commercial database. Variant calling was performed through joint probabilistic analysis of tumor and normal DNA reads, with germline status of variants being determined by heterozygous or homozygous alternate allele fraction in the germline sample. Results: 26 somatic variants and 12 germline variants were detected, with one sample overlapping with a germline and a somatic variant (p.A148T and p.A76Rfs∗44). Counting all 11 discrete germline variants as false positives, a total 37 of 158 samples would be positive for CDKN2A mutant status, a rate of 23% (17%-31% CI). However, if the 8 common germline variants are excluded, the call rate is 29/158 = 18% (12%-25% CI). The false positive rate is 4/158 = 14% (4%-31% CI). By RNAseq, true somatic CDKN2A variants had significantly higher TPM counts than germline variants (T-test p = 0.0002). RB expression was not significantly different between the two groups. Conclusions: The failure of palbociclib to show benefit in CDKN2A mutated PC and GBC patients in the 20 patient cohort of the TAPUR study could possibly be explained by patient selection rather than solely drug failure. It is unlikely related to RB loss.
Single-cell analysis of immune-microenvironment and immune-tumor interaction in human gastric cancers.
Authors: Goh Michele , Lim Ze Ming , Koh Vivien , Lum Josephine , Zhang Xiaomeng , McGovern Naomi , Msallam Rasha , Larbi Anis , Poidinger Michael , Ginhoux Florent , Ng Matthew C.H. , Tan Patrick , Yong Wei Peng , So Jimmy Bok Yan , Chen Jinmiao
Published: January 2019

29

Background: The incidence rates of gastric cancer in Asia are among the highest in the world. Gastric cancer is a heterogeneous disease. The Cancer Genome Atlas and Asian Cancer Research Group provide molecular classification of gastric cancers. Recently, immunotherapy was found to be effective in selected gastric cancer patients. Despite the molecular classification, a classification system based on immune microenvironment is in need to better stratify patients for ideal immunotherapy combinations. Methods: We have performed indexed-sorting single cell RNA-seq to analyze both CD45+ and CD45- cells from biopsy samples of 15 gastric cancer patients (5 Diffuse; 4 Intestinal; 5 Mixed; 1 unknown type). Using our ezsinglecell analytical pipeline, we have built a draft Asian Single-cell Immune Atlas (ASIA) of human gastric cancers. Results: We were able to probe fibroblast, epithelial cells and various subtypes of immune cells. Interestingly, we observed that fibroblast and mast cells were more enriched in diffuse type. In addition, we have profiled single immune cells in tumor and normal adjacent tissues to distinguish tissue-induced versus tumor-driven immune signatures. Comparing tumor and normal tissues, we found that tumor site has less natural killer (NK) and CD8 T cells; more B, myeloid and CD4 T cells. Moreover, CD8 T cells and NK cells showed distinct phenotypes in tumor compared to normal tissues. In particular, inhibitory receptor Tim-3 and CTLA-4 were up-regulated in the tumor. Most interestingly, T Cell Receptor (TCR) reconstruction revealed clonal expansion of CD8 T cells. Conclusions: Both immune (CD45+) and non-immune (CD45-) cell components of human gastric cancers are highly heterogeneous. Diffuse type showed differential tumor microenvironment compared to intestinal and mixed types. Tumor site presented an immune-suppressive phenotype compared to normal adjacent site. The clonal expansion of CD8 T cells suggested the role of adaptive immunity on recognizing tumor antigens. This discovery may determine the clinical applications of immunotherapy for gastric cancer in the future.
Transcript profiling of neuroendocrine tumors (NETs) to identify new targets and mechanism of progression.
Authors: Walzer Emily , Peri Suraj , Devarajan Karthik , Pei Jianming , Cai Kathy Q. , Gong Yulan , Cohen Steven J. , Astsaturov Igor A. , Engstrom Paul F. , Vijayvergia Namrata
Published: January 2019

292

Background: Few studies have characterized the molecular drivers of NET growth and mechanisms differentiating poorly differentiated (PD) and well differentiated (WD) NETs. We explored the role of dysregulated transcriptome as the principal molecular mechanism of NETs with the goal to identify novel targets and biomarkers of differentiation. Methods: With IRB approval, de-identified, formalin fixed NET samples were used to extract total RNA for transcriptome analysis. All pathology specimens were centrally reviewed. Gene expression profiles of 774 genes were obtained using nCounter platform (PanCancer pathway panel, Nanostring TechnologiesTM). The resulting count data was voom normalized and differentially expressed genes between PD and WD NETs were identified using linear modeling methods available in R-Bioconductor LIMMA package. Candidate genes with potential therapeutic implications were validated in tissue microarrays by immunohistochemistry (IHC). Results: Analysis of gene count data between 16 PD and 23 WD NETs resulted in 154 differentially expressed genes on the 774 gene panel (FDR < 10% and 2 fold change (FC) up- or down-regulated), some of which may be potential drug targets (Figure 1). E.g. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for transcriptional repression, and CHK1, a G2/M cell cycle regulator, were upregulated in PD compared to WD NETs (2.7 and 3.1 FC, respectively) and serine/threonine-protein kinase PAK 3, involved in cytoskeleton reorganization, was upregulated in WD NETs (3.4 FC). IHC staining also suggested overexpression of EZH2 and its enzymatic substrate H3K27me in PD NETs (p < 0.001). PAK 3, another novel therapeutic candidate overexpressed in WD NETs (p < 0.001) was confirmed using IHC, validating the transcriptome analysis at protein level. Conclusions: These findings, combined with previously reported pathway analysis (Vijayvergia et.al 2017)], highlight biological differences between PD and WD NETs and serve as a platform for future research. They also support investigation of novel drugs that inhibit activity of EZH2 (e.g. EPZ6438) in PD NETs and PAK3 (e.g FRAX597) in WD NETs.
Association between overall survival and adverse events with lenvatinib treatment in patients with hepatocellular carcinoma (REFLECT).
Authors: Sung Max W. , Finn Richard S. , Qin Shukui , Han Kwang-Hyub , Ikeda Kenji , Cheng Ann-Lii , Kudo Masatoshi , Tateishi Ryosuke , Ikeda Masafumi , Breder Valery , Rau Kun-Ming , Ma Yuk Ting , Alsina Angel , Ryoo Baek-Yeol , Ren Zhenggang , Mody Kalgi , Dutcus Corina E. , Tamai Toshiyuki , Saito Kenichi , Piscaglia Fabio
Published: January 2019

317

Background: In the phase 3 REFLECT study, lenvatinib (LEN) demonstrated a treatment effect on overall survival (OS) by statistical confirmation of non-inferiority to sorafenib (SOR) in patients (pts) with unresectable hepatocellular carcinoma (uHCC), who had not received prior treatment for advanced disease (Kudo M et al, Lancet 2018). Lenvatinib is approved in several major markets for the first line systemic treatment of uHCC. The most common adverse events (AEs) in pts treated with LEN were hypertension and diarrhea. In addition, LEN showed a different AE profile from that of SOR. Pts who received LEN experienced more instances of hypertension, proteinuria, dysphonia, and hypothyroidism than patients who received SOR. Recently, hypertension in LEN-treated pts with differentiated thyroid cancer was shown to be correlated with improved efficacy. Here we report the post hoc analysis exploring whether AEs associated with LEN were correlated with longer OS in REFLECT. Methods: 478 Pts were randomized to receive LEN (12 mg/d for actual body weight ≥ 60 kg or 8 mg/d for actual body weight < 60 kg). Subgroup analyses were conducted based on whether pts treated with LEN experienced any-grade AEs of interest (AEIs). OS was estimated by the Kaplan-Meier method. Results: The AEIs in pts treated with LEN were hypertension (42%), diarrhea (38%), proteinuria (24%), dysphonia (24%), and hypothyroidism (16%). OS was longer in pts who had several AEs of interest than in those who did not (table). Conclusions: In pts treated with LEN, the occurrence of hypertension, diarrhea, proteinuria, or hypothyroidism was generally associated with longer OS in pts with uHCC in this post hoc exploratory analysis. The potential confounding factors at baseline should be further investigated. Clinical trial information: NCT01761266. [Table: see text]
Surveillance for locally advanced esophageal and gastroesophageal junction (GEJ) cancers: Patterns of recurrence and methods of detection.
Authors: Matloubieh Jubin Eghbali , Licona-Freudensten Alexandra Pilar , Baran Andrea M , Lada Michal J , Jones Carolyn E , Peyre Christian G , Hezel Aram F , Noel Marcus Smith , Dunne Richard Francis , Tejani Mohamedtaki Abdulaziz
Published: January 2019

32

Background: Trimodality treatment with neoadjuvant chemoradiation (CRT) followed by surgery is a standard treatment for esophageal/GEJ (E/GJ) cancers. Following esophagectomy, there is no strong consensus about optimal surveillance and routine imaging. At our institution, patients have surveillance CT scans every 4-6 months for the first 2 years post-surgery and every 6-12 months for the next 3 years. Methods: An IRB-approved chart review was performed identifying patients who underwent surgical resection for locally advanced E/GJ cancer between January 2011 and December 2015 at the University of Rochester. Study objectives were to describe timing of and methods used to detect recurrence as well as their impact on patient outcomes. Recurrence-free (RFS) and overall survival (OS) were graphed via the Kaplan-Meier method. Results: 138 patients underwent surgical resection for E/GJ cancer during the study period: 107 (77.5%) were male, median age was 64, and 116 patients (84.1%) had adenocarcinoma. 111 patients (80.4%) received neoadjuvant CRT. Median OS for entire cohort was 43.4 months. 65 patients (47.1%) relapsed with a median RFS of 19.8 months. Recurrence was detected by routine imaging in 34 patients (52.3%), imaging triggered by symptoms in 25 patients (38.5%), and symptoms alone in 6 patients (9.2%). Median OS post-relapse was 1.5 months when detected based on symptoms alone, 5.0 months when detected by imaging triggered by symptoms, and 13.5 months when detected by routine scans (Log-rank p = 0.046). There were no significant associations between baseline patient /tumor characteristics and subsequent method of recurrence detection. Conclusions: 47.1% of patients suffered relapse after trimodality therapy for E/GJ cancer, consistent with published literature. Almost half of these were detected based on symptoms despite routine imaging. Increased OS for patients with relapse detected by routine scans is likely related to lead time bias, but may be related to increased treatment intensity, or due to less aggressive tumors. Prospective randomized trials are needed to determine the true benefit of regular surveillance scans among esophageal cancer survivors.
Temozolomide in grade III neuroendocrine neoplasms (G3 NENs): A multicenter retrospective review.
Authors: Chan David , Bergsland Emily K. , Chan Jennifer A. , Gadgil Rujuta , Halfdanarson Thorvardur Ragnar , Hornbacker Kathleen , Kelly Virginia , Kunz Pamela L. , McGarrah Patrick Walsh , Raj Nitya Prabhakar , Reidy Diane Lauren , Thawer Alia , Whitman Julia , Wu Linda , Singh Simron
Published: January 2019

321

Background: G3 NENs are aggressive, and optimal systemic treatment is unclear. Temozolomide (TEM)-based regimens have been used to treat grade 1-2 NETs, but their efficacy in G3 NENs (Ki-67 > 20%) remains undetermined. Aims: To assess the clinical efficacy of TEM-containing regimens in advanced grade III gastroenteropancreatic NENs (GEPNENs). Methods: A multicentre retrospective review (2008-2017) of patients with metastatic/unresectable G3 GEPNENs who received a TEM-containing regimen. The primary endpoint was time to treatment failure (TTF). Radiologic response was extracted from local reports without formal RECIST criteria. Results: 118 patients in six centers were included (median age 55, 65% male, 15% functional, 75% pancreatic NEN). 57% were well-differentiated, 35% poorly-differentiated, and 18% unknown based on local pathology reports. The regimen used was CAPTEM in 93% and TEM in 7%. Best radiological responses were: complete response (1%), partial response (39%), stable disease (22%), progressive disease (31%), unknown (7%) not by RECIST. Median TTF was 150 days and median overall survival (OS) 18.0 months. Fifteen patients (14%) required dose reductions/discontinuation due to adverse events. TTF was shorter for patients on TEM alone (p = 0.02, Table 1). Well-differentiated NENs had better response rate (52% vs 26%, p = 0.02) and overall survival (30.1 vs 12.0 mo, p = 0.008) compared to poorly-differentiated NEN. Conclusions: This is the largest TEM treatment series in G3 NEN, involving collaboration of several major North American NET centers. 40% of patients showed some degree of response, and treatment was generally well-tolerated. TEM-based regimens should be considered a viable treatment option in this setting. Prospective confirmatory trials (such as EA2142) may face difficulties in accrual due to disease rarity. [Table: see text]
A phase Ib study evaluating olaratumab in combination with nab-paclitaxel and gemcitabine in first-line treatment of metastatic pancreatic cancer.
Authors: Pelzer Uwe , Bendell Johanna C. , Womack Mark S. , Bahary Nathan , Macarulla Teresa , Borazanci Erkut Hasan , Levy Donna Elise , Mo Gary , Ramage Samuel Cowan , Garrido-Laguna Ignacio
Published: January 2019

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Background: Increased platelet-derived growth factor receptor alpha (PDGFRα) expression is linked to epithelial-mesenchymal transition in pancreatic cancer. Olaratumab (O) is a fully human monoclonal antibody against PDGFRα previously approved for the treatment of advanced soft tissue sarcoma. Here, we report the initial safety and antitumor activity data of O in combination with nab-paclitaxel + gemcitabine (nPG) in first-line metastatic pancreatic cancer patients (pts). Methods: In this 3+3 dose escalation study, pts with stage IV pancreatic cancer received intravenous 15 mg/kg (cohort 1) or 20 mg/kg (cohort 2) O + nPG (125 mg/m2/1000 mg/m2) on D1, 8, and 15 of a 28-day cycle. Following dose escalation, additional pts were enrolled in an expansion phase to confirm safety. Primary objective was to determine a dose of O that can be safely combined with nPG. Results: As of September 2018, 10 pts were treated in dose escalation (cohort 1: 3 pts; cohort 2: 7 pts) with no dose-limiting toxicities (DLTs) observed. Safety of 20 mg/kg O + nPG was confirmed in the expansion cohort; 1 of 12 pts (8.3%) experienced a DLT of grade 4 neutropenia. Most frequent adverse events (AEs) (≥ 25%) reported across all cohorts included fatigue (50%); neutropenia (50%); nausea (46%); thrombocytopenia (41%); and constipation (32%). Related grade ≥ 3 AEs reported in > 2 pts were neutropenia (N = 7; 32%), infusion-related reaction, and neuropathy (both N = 3; 14%). There were no deaths related to study drugs. Among pts evaluable for response, 2 of 15 pts had a partial response and 11 pts had stable disease as best response for an objective response rate of 13%. Notably, 2 of 3 pts in cohort 1 continue on treatment for more than 12 months as of the data cut-off. Updated data will be presented at the meeting. Conclusions: Both dose levels were tolerated. Safety profile was similar to nPG chemotherapy with most toxicity manageable through dose adjustments of nPG. Clinical trial information: NCT03086369.
Efficacy and safety of varlitinib, a reversible pan-HER tyrosine kinase inhibitor, in combination with platinum-based regimens in biliary tract cancers: A pooled analysis from three phase I studies.
Authors: Tan Aaron C. , Oh Do-Youn , Chao Yee , Hsieh Chih-Yi , Chang Wei-Ling , Isanto Fenny , Chen Ying-Chen , McHale Mark , Lindmark Bertil , Ng Matthew C.H.
Published: January 2019

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Background: Varlitinib is a nanomolar inhibitor of EGFR, HER2, and HER4 and has shown potent anti-tumor activity as monotherapy in preclinical BTC models. During Phase (Ph) 1 development, significant tumor shrinkage was observed in biliary tract cancer (BTC) patients (pts). Tissue microarray analysis has revealed that ~70% of BTC pts exhibit HER overexpression, suggesting varlitinib could be beneficial in BTC. Methods: Data from BTC pts were pooled from 3 Ph1 trials of varlitinib (dosed 200-500 mg BID) in combination with cisplatin and 5-FU/capecitabine (cape) (Study 002); oxaliplatin and 5-FU/cape (Study 002SG); cisplatin and gemcitabine (Study 007). The depth of tumor response, disease control rate (DCR), and treatment-related adverse events (TRAEs) were analysed. Results: As of 12 June 2018, 43 pts were recruited: 12 (27.9%); 10 (23.3%) and 21 (48.8%) from study 002; 002SG and 007 respectively. 002SG and 007 were still ongoing at data cut-off. 20 (46.5%) pts were male and the median age was 62 years (range 42-82). Most tumors were cholangiocarcinoma (74.4%), followed by gallbladder cancer (16.3%) and carcinoma of the Ampulla of Vater (9.3%). 14 (32.6%) pts had received ≥ 1 prior lines of treatment. Of the 37 pts evaluable for efficacy (those with measurable disease and received ≥ 1 dose of treatment), partial responses were observed in 10 (27.0%) pts and stable disease in 16 (43.2%) pts, with a DCR of 70.3%. The median depth of tumor response was -10.8% (range 49.5% to -87.1%). Of 43 pts, the most frequent (≥ 30%) TRAE (any grade) were fatigue (37%), decreased appetite (34%), and nausea (32%) and the most common Grade ≥ 3 TRAE were hyperbilirubinemia (12%), increased AST (9%), and neutropenia (9%). The median PFS data is not matured and will be provided if evaluable at the time of presentation. Conclusions: Varlitinib with platinum-based chemotherapy has a promising efficacy and safety profile in BTC. A Ph2/3 randomised study of varlitinib and cape in 2nd line BTC and a Ph1b/2 study of varlitinib with platinum-based chemotherapy in 1st line BTC are ongoing. Clinical trial information: NCT02648425, NCT02435927, and NCT02992340.
Progression-free survival (PFS) and subgroups analyses of lenvatinib in patients (pts) with G1/G2 advanced pancreatic (panNETs) and gastrointestinal (giNETs) neuroendocrine tumors (NETs): Updated results from the phase II TALENT trial (GETNE 1509).
Authors: Capdevila Jaume , Fazio Nicola , López-López Carlos , Teule Alexandre , Valle Juan W. , Tafuto Salvatore , Custodio Ana B. , Reed Nicholas , Raderer Markus , Grande Enrique , Garcia-Carbonero Rocio , Jiménez-Fonseca Paula , Alonso Vicente , Antonuzzo Lorenzo , Spallanzani Andrea , Berruti Alfredo , Sevilla Isabel , La Casta Munoa Adelaida , Hernando Jorge , Ibrahim Toni
Published: January 2019

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Background: Pts with advanced G1/G2 NETs have limited treatment options with overall response rates (ORR) with targeted agents (TA) < 10%. Benefit on PFS after TA therapy has not been demonstrated. The mechanism of action of lenvatinib (VEGFR1-3 & FGFR1-4 inhibitor) may increase efficacy and revert primary and acquired resistance to TA. We report the updated results on PFS, safety and subgroups. Methods: This prospective phase II study had two cohorts: G1/G2 panNETs and giNETs. All pts had baseline documented disease progression (PD) by RECIST. For panNETs, PD to TA was mandatory, regardless prior therapy with somatostatin analogs (SSAs) or chemotherapy (CHT), and for giNETs, PD on SSAs. Pts were treated with lenvatinib at 24 mg qd until PD or intolerable toxicity. The primary endpoint was ORR by central radiology review. PFS was calculated by investigator assessment. Biochemical responses were defined as reduction from baseline > 50%. With 55 pts per arm our study was powered to identify an ORR ≥ 25% (90% power, 5% α-error). Results: We recruited 111 pts (55 panNETs/56 giNETs). Prior therapies were CHT 32%, SSAs 87%, everolimus (E) 70% and sunitinib (S) 30% for panNETs. ORR was 29%, 40% for panNETs and 18.5% for giNETs. With a median follow-up of 17 months (m), PFS for panNETs was 15.8 m (95% CI 11.4-NR) and 15.4 m (95% CI 11.5-19.5) for giNETs. Dose reductions/interruptions were needed in 91.8% with a median dose of 20 mg qd. In the subgroups analyses, all pts obtained the same benefit in PFS and ORR, including grade and prior therapy with S (PFS: 16.4 m, ORR: 43.7%) or E (PFS: 15 m, ORR: 37.1%) (p = ns). A significant correlation of chromogranin A decrease and prolonged PFS in giNETs (17.6 m vs NR, p = 0.032) was observed. The most frequent G3-4 adverse events were hypertension (20.7%), asthenia (13.5%), diarrhea (7.2%) and abdominal pain (5.4%). Conclusions: Lenvatinib showed the highest reported ORR with a TA by central radiology assessment in panNETs and giNETs with promising PFS in a pretreated population. The benefit was observed across subgroups analyses, including pretreated pts with TA. Clinical trial information: NCT02678780.
Survival outcomes between surgery with adjuvant therapy compared to neoadjuvant therapy with surgery in stage I pancreatic adenocarcinoma: Results from a large national cancer database.
Authors: Datta Samit Kumar , Belini Geoffrey , Singh Maharaj , Papenfuss Wesley Allan , Sanchez Federico Augusto , Guda Nalini , Weese James L. , Chevinsky Aaron
Published: January 2019

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Background: There has been a paradigm shift in the treatment of stage 1 pancreatic adenocarcinoma (PAC) from surgery first followed by adjuvant therapy (AT) to Neoadjuvant therapy (NAT) first followed by surgery and this is reflected in the current NCCN guidelines as well. Data comparing these two modalities are limited. AIM: To compare long time survival between surgery vs Surgery + AT and NAT + Surgery in a large National Cancer Database. Methods: We identified patients with surgically resected AJCC clinical stage 1, 1A, and 1B PAC between 2004-2014. Patients were stratified into 3 groups to assess outcomes. Exclusion criteria: those with incomplete survival and sequence of therapy data. Hazard ratios (HR) were calculated for evaluation of survival, as well as for 30-Day and 90-Day Mortality between the 3 groups. Results were adjusted for age and Deyo-Charlson comorbidity index. Results: A total of 9684 pts with Clincal stage 1, 1A, 1B PAC between 2004-2014 were identified. Of these 2266 pts underwent surgery alone; 6222 had surgery followed by AT; and 1196 pts had neoadjuvant therapy followed by surgery. There was a HR of 0.995 (95% CI 0.935-1.058 p = 0.864) and 0.984 (95% CI 0.924-1.048, p = 0.617) for 30- and 90-Day mortality comparing upfront surgery to NAT, respectively. With AT as the reference group for survival, there was a HR of 1.362 (95% CI 1.286-1.443, p < 0.001) for surgery only and HR of 0.929 (95% CI 0.859-1.004, p = 0.064) for NAT. Conclusions: 1. Surgery alone had worse overall survival. 2. There was no significant difference in overall survival when comparing AT and NAT 3. A prospective randomized trial evaluating the differences in survival is needed.
Phase II trial of preoperative modified FOLFIRINOX (mFOLFIRINOX) followed by postoperative gemcitabine (GEM) in patients (pts) with borderline resectable pancreatic ductal adenocarcinomas (BR-PDAC).
Authors: Yoo Changhoon , Kim Kyu-Pyo , Song Ki Byung , Lee Sang Soo , Park Do Hyun , Song Tae Jun , Lee Seung Soo , Park Jin-hong , Hwang Dae Wook , Lee Jae Hoon , Shin Sang Hyun , Shin Eunseon , Ryoo Baek-Yeol , Kim Song Cheol
Published: January 2019

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Background: mFOLFIRINOX and GEM are standard chemotherapy for metastatic and resected PDAC, respectively. This phase 2 trial assessed the efficacy and safety of perioperative chemotherapy consisted of preoperative mFOLFIRINOX and postoperative GEM in pts with BR-PDAC. Methods: Pts with histologically proven and radiologically confirmed BR-PDAC as defined by NCCN criteria were eligible. Pts received 8 cycles of preoperative mFOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, 5-FU 2,400 mg/m2 over 46 hours, and leucovorin 400 mg/m2), every 2 weeks. For pts who underwent surgery, postoperative GEM (1,000 mg/m2 D1, 8, 15, every 4 weeks) was given for 6 cycles. Primary endpoint was 1-year progression-free survival (PFS) rate and secondary endpoints were PFS, overall survival (OS) and curative surgery rate. A total of 44 pts were required to show the improvement in 1-year PFS rates from 30% to 50% with a two-sided alpha of 0.05, beta of 0.8 and drop-out rates of 10%. Results: Between May/2016 and Mar/2018, 44 patients were enrolled. Median age was 60 years (range, 35-76) and 26 pts (59%) were male. Pancreas head was most common site (n = 26, 59%). With mFOLFIRINOX, response rate was 34% and surgery was done in 27 patients (61%); 22 and 5 patients achieved R0 and R1 resection, respectively, and postoperative GEM was given in 24 patients (89%). With median follow-up of 16.6 months (95% CI, 10.9-22.2), 1-year PFS rate was 51.7% (95% CI, 35.2-68.2), and median PFS and OS was 13.0 months (95% CI, 7.7-18.4), and 14.3 months (95% CI, not available), respectively. PFS and OS were significantly differed according to the surgery (p < 0.001 for both) and response to mFOLFIRINOX (p < 0.001 and p = 0.03, respectively). Relative dose intensities of irinotecan, oxaliplatin and 5-FU were > 77% during mFOLFIRINOX. Grade 3-4 neutropenia (55%), anemia (14%), nausea (11%), and diarrhea (7%) were most common severe toxicities and 3 pts (7%) discontinued mFOLFIRINOX due to the toxicities. Conclusions: Perioperative chemotherapy using mFOLFIRINOX and GEM were feasible and effective for pts with BR-PDAC. Future randomized trial is warranted. Clinical trial information: NCT02749136.
Effect of neoadjuvant chemoradiotherapy on prognosis in resectable and borderline resectable pancreatic cancer with venous involvement.
Authors: Nagai Minako , Sho Masayuki , Akahori Takahiro , Nakagawa Kenji , Nakamura Kota , Takagi Tadataka , Tanaka Toshihiro , Nishiofuku Hideyuki , Kichikawa Kimihiko , Ikeda Naoya
Published: January 2019

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Background: The efficacy of neoadjuvant treatment for pancreatic cancer (PC) remains to be established. In this study, we have retrospectively evaluated the impact of neoadjuvant chemoradiothrapy (NACRT) on perioperative and long-term clinical outcome in PC. Methods: One hundred eighty one patients who preoperatively received full-dose gemcitabine (1000mg/m2) with concurrent radiation of 54 Gy between 2006 and 2017 were analyzed. One hundred forty nine patients who proposed upfront surgery were served as control. Results: Among the 181 patients treated with NACRT, 23 (13%) couldn’t undergo pancreatic resection after NACRT because of distant metastasis in 10, tumor progression in 7 and poor PS in 6. While among the 149 patients who proposed upfront surgery, 10 (7%) couldn’t undergo pancreatic resection at laparotomy, because of distant metastasis in 8 and tumor progression in 2. In overall survival analysis of all patients with resected and unresected tumor, patients treated with NACRT had a better prognosis than those without (median survival time: 37.0 vs. 27.1M, P = 0.049). According to tumor resectability status including R (resectable), BR-P (borderline resectable with venous involvement) and BR-A (borderline resectable with arterial involvement) PC, in the R and BR-P group, overall survival was significantly better in the patients with NACRT (45.7 vs. 33.8M, P = 0.049, 61.7 vs. 14.6M, P = 0.002). Also only for resected tumors, patients treated with NACRT had a better prognosis than those without in the R and BR-P group (53 vs. 36.5M, P = 0.033, 61.7 vs. 14.6M, P = 0.002), while NACRT had no significant impact on prognosis in the BR-A group. The rate of pancreatic fistula, delayed gastric emptying and abdominal abscess were lower in the NACRT group than the control group. Furthermore, the lymph node metastasis rate, R0 resection rate and pathological stage were favorable in the NACRT group (P < 0.001, P = 0.005, P < 0.001). The completion rate of adjuvant chemotherapy was also higher in the NACRT group (P = 0.001). Conclusions: NACRT had a variety of favorable impact in PC treatment. In particular, it significantly improved the prognosis in the R and BR-P, but not BR-A.
Changes in alpha-fetoprotein (AFP) and systemic therapy outcomes in advanced hepatocellular carcinoma (HCC): A multicenter retrospective analysis.
Authors: Bocobo Andrea Grace , Bracci Paige M. , Parks Anna , Hannan Lindsay Marie , Bauer Kelly , Goyal Lipika , Gordan John Dozier , Venook Alan P. , Harris William Proctor , Kelley Robin Kate
Published: January 2019

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Background: AFP is elevated in 70% of HCC and is associated with poor prognosis. The role of AFP as a biomarker of response to systemic treatments has not been established, though small, retrospective studies show association between AFP decline and survival on sorafenib. The relationship between AFP changes and response to immune checkpoint inhibitors (CPI) has not been reported. This study examines AFP changes on treatment for association with outcomes on first-line (1L) SOR and any subsequent CPI in a contemporary, multicenter U.S. population. Methods: Design: Multicenter retrospective case series. Key eligibility: Received 1L SOR or SOR-based combination for advanced HCC; ≥ 1 post-treatment AFP value available; enrolled on IRB-approved registry. Objectives: associate AFP changes within 3 months of start of treatment with overall survival (OS) and time on treatment (TOT) on 1L SOR and any subsequent CPI; associate baseline AFP with OS and TOT for SOR and CPI; relate baseline AFP and changes on treatment to clinical covariates. Results: 152 patients were identified from two centers. Baseline characteristics: M/F 132/20; HBV/HCV/nonviral 40/71/41; Child Pugh A/B 128/23; BCLC A/B/C: 4/15/133. Baseline AFP < 20/ ≥ 400: 43/59. 43 received CPI after SOR. See Table. Baseline AFP was not related to TOT or OS for SOR or CPI. Multivariable analyses for AFP with clinical covariates will be presented. Conclusions: This series is the largest multicenter analysis of AFP response to systemic therapy with SOR and CPI. AFP decrease and increase within the first 3 months of treatment with SOR and CPI were inversely and significantly associated with median OS. AFP warrants further study in randomized cohorts as a biomarker of response to systemic therapy in HCC, now with multiple treatment options available at progression.[Table: see text]
Real world usage of gemcitabine and nabpaclitaxel in older adults with metastatic pancreatic cancer: A single institution experience.
Authors: Winer Arthur , Handorf Elizabeth A. , Nagappan Lavanya , Blumenreich Aryeh , Chowdhury Farhana , Vijayvergia Namrata , Dotan Efrat
Published: January 2019

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Background: The median age at diagnosis for metastatic pancreatic cancer (mPC) is 72. Gemcitabine and Nab-Paclitaxel (GA) is often the preferred chemo regimen in this population due to presumed reduced toxicity compared with FOLFIRINOX. While the traditional GA schedule (TDS) includes treatment on days 1, 8, and 15 of a 28-day cycle, it can cause side effects and patients often require dose reductions. There is data for a modified dosing schedule (MDS) treating only on day 1 and 15. Therefore, we retrospectively analyzed our older adults treated with GA using the TDS versus the MDS and compared tolerability and outcomes between the two groups. Methods: We identified pts with mPC >64 y/o treated with GA at Fox Chase Cancer Center between 1/2010 - 7/2018 and collected their demographic, disease and treatment information. We analyzed discrete variables using Fisher’s exact test and continuous variables using Wilcoxon tests. Overall survival (OS) was analyzed by the Kaplan-Meier method and Cox proportional hazards regression. Results: Fifty-six pts were identified with a median age at diagnosis of 71 (range: 64-90) and 67.8% with metastatic disease at presentation. 57% received GA in the first line. 44% were treated with TDS while 56% received a MDS; an older median age was seen in the MDS group (73 vs 69 y/o, p<0.001). Up front dose reductions of GA were seen in 24% in the TDS vs 48% in MDS, and they were more common with nab-paclitaxel (26% in MDS vs 10% in TDS) than with gemcitabine (two pts in TDS vs one pt in MDS). Of pts who began with TDS only 11 (19% of all pts) were able to tolerate it without adjustment throughout treatment; 14 (25%) transitioned to the MDS. More pts suffered grade ≥3 toxicity with the TDS vs. MDS (68% vs. 51%; p=0.27) and more required a dose reduction (TDS 72% vs. MDS 48%; p=0.1). 58% required an additional GA dose reduction over the course of treatment. Median OS among GA treated pts in the front line (n=32) was not significantly different (MDS: 11.7 mo vs. TDS: 13 mo; p=0.1). Conclusions: These results demonstrate tolerability and similar efficacy of the GA MDS among older adults with mPC. Given the limited sample size, further studies are required to help establish the appropriate therapy for older patients.