bluuebunny/crossref_metadata_2025 huggingface dataset:
Baseline albumin (b-alb) as a potential predictive biomarker for the efficacy of bevacizumab (B) therapy (tx) in patients (pts) with advanced pancreas cancer (APCA): A comparative analysis.
Authors: Martin Ludmila Katherine , Geyer Susan Michelle , Bingman Anissa , Zalupski Mark M. , Bekaii-Saab Tanios S.
Published: March 2020

4039

Background: Phase III studies of B in unselected pts with APCA have demonstrated no improvement in outcome. Recent data suggest certain subsets of APCA patients may benefit from B. Lower b- alb results in a 15-20% increased rate of B clearance that may decrease exposure to B. The resulting clinical implications are not well understood. We evaluated the potential predictive and prognostic role of b-alb in pts with APCA receiving gemcitabine (G)-based tx with or without B. Methods: Relevant data were collected from 3 prospective phase II studies of G-based tx. Pts were grouped according to exposure to B (Gr 1) or no B (Gr 2) and by b-alb < 3.4 g/dL (< LLN) or > 3.4 g/dL (>LLN). Univariate and multivariate analyses of clinical outcome (OS, TTP) were conducted for each group and all pts. Results: 100 pts (46M, 54F) with median age 63 (range 28-82) were included. 94% had stage IV. Median b-alb was similar in both groups. Clinical outcomes by alb are outlined in the table. In Gr 1 but not Gr 2, b-alb > 3.4 g/dL was significantly associated with improved OS and TTP. For pts with b-alb >3.4 g/dL, maintenance of alb >3.4 g/dL throughout tx was significantly associated with improved survival in Gr 1 but not Gr 2. Multivariate analysis revealed significant association between alb > 3.4 and OS regardless of B status (p=0.004) although this was strongly influenced by the survival differential in Gr 1. Conclusions: APCA pts with b-alb > 3.4 g/dL appear to derive significant benefit from B and this benefit is most pronounced in pts who maintain alb > 3.4 g/dL throughout B tx. This finding was not observed in pts treated without B. b-alb > 3.4 g/dL including maintenance of alb > 3.4 g/dL during B tx may predict for improved efficacy of B in APCA. These findings require further investigation in larger prospective trials. [Table: see text]
Development of the SP120 rabbit monoclonal antibody for determining hENT1 status and predicting response to gemcitabine in pancreatic ductal adenocarcinoma.
Authors: Boeck Stefan Hubert , Raponi Mitch , Richardson William , Towne Penny , Isaacson Jeffrey D. , Ranger-Moore Jim , Powell Eric , Clements June , Feng Janine D. , McElhinny Abigail , Ormanns Steffen , Kirchner Thomas , Regine William , Winter Kathryn A. , Ansari Daniel , Rolfe Lindsey , Allen Andrew R. , Andersson Roland , Heinemann Volker , Dicker Adam P.
Published: March 2020

4041

Background: Human equilibrative nucleoside transporter 1 (hENT1) is the primary membrane channel through which gemcitabine (Gem) enters pancreatic tumor cells. Patients whose tumors have low expression of hENT1 may derive little benefit from Gem therapy. Methods: We have developed and analytically validated a rabbit monoclonal antibody, SP120, immunohistochemistry (IHC) in vitro diagnostic (IVD) assay, used on the VENTANA BenchMark ULTRA automated slide staining platform, for assessing hENT1 expression in pancreatic adenocarcinoma. Results: SP120 was shown to be sensitive and specific for membrane expression of hENT1 with variable expression demonstrated across a panel of primary pancreatic adenocarcinoma samples. Using retrospectively collected primary tumor samples (n = 201) from a randomized controlled clinical adjuvant trial (RTOG 97-04), we developed and verified a hENT1 scoring algorithm and cut-off for identifying patients least likely to benefit from Gem (hENT1-low). We confirmed the predictive value of the hENT1 assay by showing there was no association with clinical outcome in the 5FU-treated control group. The distribution of hENT1 expression was similar between these samples and an independent set of 130 pancreatic adenocarcinoma specimens from the AIO-PK0104 study (77 were confirmed metastatic biopsies). Importantly, 100% concordance in hENT1 status (high vs. low) was demonstrated between 16 primary tumors and paired, contemporaneous metastatic lesions. Overall, using this cut-off, approximately two thirds of pancreatic tumors displayed low-hENT1 expression across the different data sets (n = 363). Conclusions: The hENT1 IHC IVD has been developed and is being used in a pivotal trial of a novel lipid-conjugated Gem (CO-101, which enters tumor cells independently of hENT1), vs. Gem in hENT1-low pancreatic cancer patients (NCT01124786). This study is the first prospective test of the hypothesis that gemcitabine is not active in tumors with low hENT1 expression.
Phase I/II study of 90Y-clivatuzumab tetraxetan (90Y-hPAM4) combined with gemcitabine (Gem) in advanced pancreatic cancer (APC): Final results.
Authors: Ocean Allyson J. , Guarino Michael J. , Pennington Kenneth L. , Springett Gregory M. , Gulec Seza A , Bekaii-Saab Tanios S. , Montero Alberto J. , Mitchell Edith P. , Kauh John S. , Sung Max W. , Gold David V. , Horne Heather , Wegener William A. , Goldenberg David M.
Published: March 2020

4043

Background: A Phase I/II trial evaluated single and repeated cycles of fractionated radioimmunotherapy (RAIT) with 90Y-labeled humanized mAb (90Y-hPAM4) plus Gem as first-line therapy in Stage 3-4 APC. Methods: Cycles of Gem once-weekly x 4 with 90Y-hPAM4 on wks 2, 3 and 4 were repeated until progression, withdrawal or unacceptable toxicity. In Part I, 90Y doses were escalated with Gem fixed at 200 mg/m2. In Part II, Gem was increased up to 1000 mg/m2, with 90Y fixed at 12 mCi/m2 for cycle 1 and lowered for retreatment. Results: Of 100 pts entered, 10 withdrew early, while 90 (73 stage IV) received 1-4 cycles. In Part I, 38 pts received 90Y-hPAM4 weekly x 3 at 6.5, 9, 12, or 15 mCi/m2, with the same cycle repeated 1-3 times in 13 pts. By CT-RECIST criteria, 6 pts (16%) had PRs and 16 (42%) had stabilization as best response (58% disease control). After cycle 1, 52% (13/25) with PET-avid images had >25% SUV reduction, and 33% (9/27) with elevated CA19-9 levels decreased by >50%. The median OS was 7.7 mo., but 11.8 mo. for retreated pts [46% (6/13) survived ≥1 yr.], and with improved efficacy at higher 90Y doses. NCI-CTCv3 Grade 3-4 platelets or ANC developed in 20/38 (53%) after cycle 1 (all reversible to Grade 1) and in all retreated pts (irreversible in 4/9 pts at 12 or 15 mCi/m2). In Part II, 52 pts received increased Gem without evidence of improved efficacy, while 13 pts were retreated with more acceptable toxicity at lower 90Y doses of 6.5 or 9 mCi/m2. Treatment was well tolerated with no infusion reactions. Infections requiring IV antibiotics occurred at a low rate and responded to appropriate coverage (bacteremia/sepsis, 7%; febrile neutropenia, 4%; ascending cholangitis, 3%; pneumonia, 2%; others 1%). One case of bleeding occurred, due to rectal tumor invasion. Anecdotal reports of good performance and decreased pain medication requirements require further validation. Conclusions: Fractionated RAIT with 90Y-hPAM4 combined with low-dose 200 mg/m2 GEM appears promising as a treatment regimen for APC. Hematologic toxicity was dose limiting. A 90Y-hPAM4 dose of 12 mCi/m2 for cycle 1 and 6.5 mCi/m2 for cycle 2 have been selected as suitable for further clinical development in the first-line setting.
A phase IB study of erlotinib in combination with gemcitabine and nab-paclitaxel in patients with previously untreated advanced pancreatic cancer: An Academic GI Cancer Consortium (AGICC) study.
Authors: Leichman Lawrence P. , O'Neil Bert H. , Berlin Jordan , Weekes Colin D. , Ames Patricia , McKinley Marti , Davies Angela M. , Cohen Steven J. ,   Academic Gastrointestinal Cancer Consortium (AGICC)
Published: March 2020

4052

Background: The combination of gemcitabine (gem) and nab-paclitaxel (nab) has demonstrated promising activity in advanced pancreatic cancer. Erlotinib (erl) adds modest benefit to gemcitabine. We initiated this phase IB study to evaluate the safety of the three drug combination and obtain preliminary evidence of efficacy. Methods: Patients (pts) with previously untreated locally advanced (la) or metastatic (met) pancreatic cancer with ECOG PS 0-1 were treated with gem and nab IV days 1,8,15 and once daily erl days 1-28 Q28 days. Standard 3+3 design was used with dose levels (DL) (gem,nab,erl): 1(1,000, 125, 100), -1 (1,000, 100, 100), -2 (1,000, 75, 100), -3 (1,000,75,75). CT scans were obtained Q 2 cycles. DLT was defined as ≥grade (gr) 3 non-hematologic, febrile neutropenia, ≥gr 3 thrombocytopenia, or missing ≥2 doses gem, nab or >5 doses erl within first cycle (C). Results: Nineteen pts were enrolled and completed a total of 62 cycles (range 0-11). Pt characteristics: M/F (9/10), White/Hispanic/AA (15/2/2), median age 63 (range 54-78), ECOG PS 1=11, met/la (12/7). In DL1, 1/3 pts had gr3 dehydration in C 2 and 1/3 had gr 4 neutropenia/sepsis in C 4. Although not formally DLT, 3 more pts were enrolled. Of the next 3 pts, 1 DLT of gr 3 diarrhea/gr 4 neutropenia in C 1 was noted and 1 other pt DC’d therapy for neutropenia after 2 cycles. Of 3 pts in DL -1, 2 DLTs (gr 3 optic neuropathy, too many missed doses) were observed. Of 3 pts in DL -2, 2/3 had DLT (gr 3 esophagitis/fatigue and gr 3 transaminitis). Of 6 evaluable pts in DL -3, no DLTs were observed. Most common gr 3/4 toxicities were neutropenia (9), dehydration, thrombocytopenia (3 each), and hypotension (2). Of 13 pts evaluable for response, 6 had partial response (46%), 5 stable disease (38%), and 2 progressive disease (15%) as best response. Median PFS and OS of entire cohort were 5.3 and 9.3 months respectively. Conclusions: The combination of erlotinib with gemcitabine and nab-paclitaxel is not tolerable at standard single agent dosing of all drugs. However, significant clinical activity was noted, even at DL -3. Further study of the combination will need to incorporate reduced dosing.
M402, a heparan sulfate mimetic and novel candidate for the treatment of pancreatic cancer.
Authors: Schultes Birgit Corinna , Lolkema Martijn P.J.K. , Chu Chia Lin , Zhou He , Long Alison , Lockley Michelle , Avery William , Kurtagic Elma , Galcheva-Gargova Zoya , Miller Paul , Duffner Jay , Maschek Birgit J , Jarlenski Donna , Tuveson David A. , Roach Jim , Venkataraman Ganesh , Kishimoto Takashi K , Flaherty Keith T.
Published: March 2020

4056

Background: Recent advances in pancreatic cancer research implicate the involvement of several heparin-binding growth factors (such as HGF, HB-EGF, PDGF, hedgehogs, and TGFs) that control tumor-stroma interactions. We have rationally designed a heparan sulfate mimetic, M402, which has been previously shown to affect tumor progression and metastasis through disruption of multiple pathways. We hypothesized that M402 could modulate tumor-stroma interactions and enhance the efficacy of gemcitabine, and evaluated its efficacy in two preclinical models. Methods: A genetically engineered mouse model (GEMM; KrasLSLG12D p53LSLR172H) featuring spontaneous pancreatic tumor formation and metastasis assessed M402’s effect on tumorigenesis and metastasis. The orthotopic Capan-2 model in nude mice evaluated the effect of M402 on desmoplasia, a fibrotic response that hinders effective delivery of chemotherapeutics, via inhibition of sonic hedgehog (SHH) signaling in fibroblasts and stellate cells. In both models, M402 was studied as monotherapy and with gemcitabine. Results: In the GEMM, M402 significantly prolonged survival in combination with gemcitabine while each monotherapy showed modest efficacy. M402, alone and in combination, also reduced metastases and local invasion and inhibited epithelial-to-mesenchymal transition. In the Capan-2 model, gemcitabine was increasingly less effective as desmoplasia progressed over time. The addition of M402 to gemcitabine increased its efficacy with respect to primary tumor burden. Metastasis, invasion, and surrounding fibrotic lesions appeared particularly impacted by the combination treatment. M402 was also effective as monotherapy with dose-dependency, which correlated with reduced SHH signaling. Conclusions: M402 can modulate tumor-stroma interactions involved in the metastatic and desmoplastic pathways in two pancreatic cancer models supporting the translation of these findings into a clinical study. A first-in-human study is planned that will evaluate the safety, pharmacokinetics, efficacy, and biomarker profiles of escalating M402 doses in combination with gemcitabine in patients with metastatic pancreatic cancer.
Activity of front-line FOLFIRINOX (FFX) in stage III/IV pancreatic adenocarcinoma (PC) at Memorial Sloan-Kettering Cancer Center (MSKCC).
Authors: Lowery Maeve A , Yu Kenneth H. , Adel Nelly G. , Apollo Arlyn J. , Boyar Michelle S. , Caron Philip , Ilson David , Segal Neil Howard , Janjigian Yelena Yuriy , Reidy Diane Lauren , Abou-Alfa Ghassan K. , O'Reilly Eileen Mary
Published: March 2020

4057

Background: The PRODIGE/ACCORD trial recently established FFX as a treatment option for good performance status (PS) pts with stage IV PC (Conroy et al, NEJM 2011). We evaluated the activity and toxicity associated with FFX therapy in pts with advanced PC treated at MSKCC outside of a clinical trial. Methods: 80patients (pts) treated withFFX as 1st-line therapyat MSKCC between 07/1/10 and 12/30/11, were identified from an institutional database (prior IRB approval). Records were reviewed for demographic, treatment, toxcity, and response data. Results: 61 and 19 pts received FFX for stage IV and III PAC respectively. Demographics and outcomes are summarized in the table. Median starting dose of FFX was 80% of that used in the PRODIGE/ACCORD trial. Median overall survival (OS) was 12.5 months (mo) (95% CI 9.5–15.5) in pts treated with 1st line FFX for stage IV PAC and 13.7 mo (95% CI 11.3–15.8) in pts with stage III PAC. 68% of pts with stage IV PAC who discontinued FFX for disease progression (PD) or toxicity received 2nd-line gemcitabine-based therapy. Conclusions: We observed activity and acceptable toxicity in carefully selected patients treated with FFX at 80% dose intensity and routine use of growth factor support. Treatment with FFX resulted in median OS of > 1 year in pts with stage IV PAC and is an active front-line regimen. [Table: see text]
Benefits of platinum-based chemotherapy (Pt-chemo) in pancreatic adenocarcinoma (PC) associated with BRCA mutations: A translational case series.
Authors: Faluyi Olusola Olusesan , Tran Ben , Kanji Zaheer , Moore Sara , Zogopoulos George , Borgida Ayelet , Holter Spring , Gallinger Steven , Moore Malcolm J.
Published: March 2020

4058

Background: The prognosis of PC is poor with limited response to standard chemotherapy. Prior randomized studies of cisplatin and gemcitabine in PC demonstrated no additional benefit over gemcitabine alone. Preclinical data and case reports suggest that BRCA mutant PC may have increased sensitivity to Pt-chemo. Our case series characterizes the benefits of Pt-chemo in germline BRCA mutant PC. Methods: Patients with PC and germline BRCA mutations were identified using the Ontario Pancreatic Cancer Study and Pharmacy databases. Review of clinical records provided demographic, treatment and survival data. Radiology review assessed responses to chemotherapy. RNA was extracted from tumor samples for gene expression studies using a panel of DNA repair genes and Nanostring technology. BRCA loss of heterozygosity (LOH) was also investigated. Results: We identified 14 PC patients with BRCA mutations (8 BRCA2, 6 BRCA1). 11 of these had metastatic disease of which 5 received Pt-chemo. Of the 5 treated with Pt-chemo, there were 3 partial responses (PR) and 2 complete responses (CR) using Recist criteria. For the remaining 6 not treated with Pt-chemo, there was 1 PR with gemcitabine. Additionally, two patients with locally advanced disease at diagnosis became resectable following Pt-chemo. Overall survival was superior for patients receiving Pt-chemo (33.0±25.6 vs 7.3±4.5 months; p=0.04). Gene expression and LOH results will be presented. Conclusions: Responses and survival associated with Pt-chemo observed in our case series of BRCA mutant PC adds to existing data supporting the use of Pt-chemo in this subgroup. Despite the low (2 to 5%) prevalence of BRCA mutations in PC, the benefits gained from personalizing treatment using Pt-chemo supports BRCA testing in selected patients.
Choice of chemotherapy in the treatment of metastatic squamous cell carcinoma of the anal canal.
Authors: Eng Cathy , Rogers Jane , Chang George J. , You Y. Nancy , Das Prajnan , Rodriguez-Bigas Miguel A. , Ohinata Aki , Phillips Jonathan , Abbruzzese James L. , Wolff Robert A.
Published: March 2020

4060

Background: Metastatic squamous cell carcinoma (SCCA) of the anal canal is an uncommon malignancy with no standard approach. The reported median overall survival (OS) is 9-12 months (M) following 5-FU + cisplatin (FC)-based therapy. The aim of this study is to evaluate first-line chemotherapy approaches in this patient (pt) population. Methods: A retrospective analysis was conducted of 428 pts with metastatic SCCA of the anal canal identified from the MDACC tumor registry between 1/1/2000 - 5/31/2011. Electronic medical records were reviewed for histology, date of diagnosis and/or recurrence, site of metastasis, type of therapy provided, response rate (RR), progression-free survival (PFS), OS, and lines of salvage therapy. All eligible pts were required to be treatment-naïve for metastatic disease and have radiographic imaging at MDACC. Waiver of informed consent was obtained. Results: 99 pts fulfilled all criteria; 10 were lost to follow-up; 12 did not initiate chemotherapy. 77 pts were evaluable; M: F = 20:57; median age = 55 years (range: 37 - 82); HIV(+) = 5% (4/77); prior chemoXRT with curative intent: 70% (54/77), complete response (CR): 87% (47/54), median time to development of metastatic disease =17M. 29% (22/77) presented with metastatic disease. Sites of disease included distant lymph nodes (41%); liver (45 %); lung (25%); bone (15%); and brain (8%). The median follow up was 37M. 73% (56/77) of patients were treated with platinum-based therapy; 51% (n=39) received FC and 22% (n= 17) received carboplatin + paclitaxel (CP). The median PFS was 6M; FC trended better than CP for PFS (7M vs. 5M, p<0.067). The overall median OS = 29M. 40% (31/77) of pts received neoadjuvant first-line therapy followed by metastasectomy (68%), XRT (26%), or both (6%); resulting in a median OS = 35M. Conclusions: Metastatic SCCA of the anal canal is a malignancy in which 5-FU+cisplatin is a commonly used regimen. Our analysis suggests FC results in improved PFS over CP but is underpowered supporting further analysis. The short median PFS with front-line chemotherapy, and yet longer OS reflects the challenges in treating this patient population and the importance of multidisciplinary management in select cases.
Trastuzumab (TRA) in combination with different first-line chemotherapies for treatment of HER2-positive metastatic gastric or gastroesophageal junction cancer (MGC): Findings from the German noninterventional observational study HerMES.
Authors: Hegewisch-Becker Susanna , Moorahrend Enno , Kröning Hendrik , Petersen Volker , Hannig Carla , Pott Dirk , Tirier Christian , Lerchenmuller Christian A. , Schlag Rudolf , Schneider-Kappus Wolfgang , Kaechele Volker , Al-Batran Salah-Eddin
Published: March 2020

4065

Background: The international phase III study ToGA has recently shown that TRA is effective in prolonging survival in HER2-positive MGC. However, few data are available for TRA as part of routine clinical practice. Methods: This non-interventional observational study was conducted to evaluate the efficacy, safety and feasibility of TRA in previously untreated pts with HER2-positive MGC. Results: Between Apr 2010 and Jan 2012, data from 110 pts were collected. All pts were evaluable for safety. Baseline pt characteristics were as follows: median age 63 yrs (range 29–88); gender (male 70%; female 29%); ECOG PS (0: 25%; 1: 50%; 2: 15%; 3: 5%); distant mets (91%); liver mets (54%), lymph node mets (35%); peritoneal carcinomatosis (23%). The median duration of TRA treatment was 4.4 months (0–17.1). According to the schedule of chemotherapy TRA was administered every 2–3 wks in a median dose of 4–6 mg/kg BW. Only 28% of pts received TRA according to the label in combination with cisplatin and 5-FU or capecitabine. The remainder received: cisplatin, 5-FU and leucovorin (17%); 5-FU, leucovorin, oxaliplatin and docetaxel (8%); 5-FU, leucovorin and oxaliplatin (7%); capecitabine (6%); other combinations (25%); TRA monotherapy (7%). Although most pts didn’t receive cisplatin-based therapy, preliminary median progression-free survival was 6.8 months, thus comparable to the ToGA data. Most common adverse events (AEs, all grades) were diarrhoea (7%), vomiting (5%) and nausea (5%). Most common grade 3/4 AEs were vomiting (3%), nausea (2%) and fatigue (2%). Health-related quality of life as assessed by EORTC QLQ-C30 and QLQ-STO22 remained stable during observation time. An updated analysis of approx. 200 pts will be presented at the meeting. Conclusions: TRA combined with diverse chemotherapies is safe and effective in the routine treatment of MGC. Cisplatin-free less toxic regimens are feasible and equally effective. The results are in line with those from the ToGA trial and suggest that treatment with TRA should be regarded as standard of care for pts with HER2-positive MGC.
Measuring transcripts of components of the BRCA1 DNA repair pathway, components of the hippo-YAP pathway, β-TrCP, HER2, AEG-1, EZH2 and other genes in advanced gastric cancer.
Authors: Wei Jia , Costa Carlota , Liu Baorui , Sanchez Jose Javier , Gimenez Capitan Ana , Yu Lixia , Zou Zhengyun , Qian Xiaoping , Sun Xia , Shen Jie , Mayo Clara , Molina-Vila Miguel Angel , Benlloch Susana , Taron Miquel , Rosell Rafael
Published: March 2020

4068

Background: The primary goal of this study was to classify gastric cancer in two different sub-groups. We speculated that HER2-positive gastric cancers could be regulated by β-TrCP, while tumors unaffected by β-TrCP activation could be more dependent on the Hippo-YAP signaling pathway, in which TAZ increases the expression of AXL. Gastric cancer can overexpress AEG-1 and EZH2. The relationship between EZH2 and the Hippo-YAP pathway was explored in this study. We also explored BRCA1 complexes, including upstream components, such as 53BP1 and MMSET. Methods: Paraffin-embedded samples were collected from 132 advanced gastric cancer patients (p) treated with first-line FOLFOX, 58 of whom received second-line docetaxel-based treatment. Gene expression levels of HER2, β-TrCP, TAZ, AXL, EZH2, AEG-1, BRCA1, and genes involved in DNA repair pathways (RAP80, PIAS1, PIAS4, MDC1, 53BP1, MMSET, and UBC9) were quantified by real-time PCR. BIM, IDO, and SPINK1 were also examined. Results: A close correlation was found for the majority of the genes, for example, BRCA1-MMSET (rho=0.28; P=0.002) and AXL-TAZ (rho=0.58; P>0.001). Median overall survival (OS) was 12.5 months (m). Among the 58 p receiving second-line docetaxel, in p with high levels of BRCA1, OS was 24.9 m, while it was 19.1 m in p with intermediate levels and 9.5 m in p with low levels (P=0.009). OS was 28.6 in p with high levels of MMSET, 13.8 in p with intermediate levels and 12.3 in p with low levels (P=0.001). In the multivariate analysis, only BRCA1 was a significant marker for OS (Table). Conclusions: The study showed the predictive value of BRCA1, which could be useful for customizing chemotherapy with or without docetaxel. In addition, MMSET requires further study since it is involved in DNA repair upstream of BRCA1. [Table: see text]
Cetuximab, paclitaxel, cisplatin and concurrent radiation in Chinese patients with locally advanced esophageal squamous cell carcinoma: An open-label, multicenter, phase II study.
Authors: Yu Jinming , Meng Xue , Wang Jian hua , Sun Xindong , Wang Lv hua , Ye Ming , Feng Ping bo , Zhu Guang ying , Lu You , Han Chun , Zhu Shu chai , Liao Zhongxing X.
Published: March 2020

4073

Background: In China more than 90% of esophageal malignancies are of squamous cell carcinoma (SCC). We conducted this Chinese multicenter trial to determine the efficacy and safety of the addition of cetuximab with paclitaxel, cisplatin, and concurrent radiation for patients with esophageal SCC and to determine whether KRAS status predicts response. Methods: Patients with unresectable locally advanced cervical, upper or mid-esophageal SCC without distant metastasis were eligible for this open-label phase II trial. All patients received cetuximab (400 mg/m2 day 1 before chemoradiotherapy and 250 mg/m2 q1w × 7 weeks), paclitaxel (45 mg/m2 q1w × 7 weeks) and cisplatin (20 mg/m2 q1w × 7 weeks) with 59.4 Gy of radiation. The primary end point was response rate. Second end points included toxicity, overall survival (OS), progression-free survival (PFS), and KRAS mutation status. Results: Fifty-five patients were enrolled and evaluable to safety. Non-hematological adverse events were generally grade 1 or 2, and were most often rash (94.5%), mucositis (58.2%), fatigue (45.5%), nausea (41.8%) and hepatic dyfunction (40%). Hematologic adverse events included grade 3 neutropenia (32.7%) and grade 3 anemia (1.82%). Ten patients did not complete the protocol therapy (6 for chemotherapy dose delays, 1 for paciltaxel hypersensitivity, 1 by the treating physicians for unstated reasons, 1 for concurrent unrelated infection, and 1 for tracheo-esophageal fistula). The response rate was 97.7%. The 1-year OS and median OS was 87.3% and 16.8 months, the 1-year PFS and median PFS was 30.4% and 13.9 months, respectively. No mutations were detected at KRAS codons 12 or 13 in the 52 available specimens. Conclusions: Cetuximab can be safely administered with chemoradiation for Chinese patients with esophageal cancer and may improve the clinical response rate. KRAS mutations were too rare to be analyzed as a predictor of response.
Prognostic impact of FHIT, APC, and HER2 status in resected gastric cancer: A clinical-biological risk stratification model.
Authors: Bria Emilio , Barbi Stefano , De Manzoni Giovanni , Beghelli Stefania , Tomezzoli Anna , Frizziero Melissa , Sperduti Isabella , Bersani Samantha , Tortora Giampaolo , Scarpa Aldo
Published: March 2020

4076

Background: The dismal prognosis of gastric cancer prompts for the identification of factors predictive of survival/response to treatment. The potential prognostic value of 11 molecular markers was investigated in a retrospective series of 208 resected gastric cancers. Methods: Molecular/clinicopathological data were correlated to cancer-specific/overall survival (CSS/OS) using a Cox model. Molecular data were: microsatellite instability, CDX2, APC, ß-catenin, E-Cadherin, FHIT, P53, p21, HER-2 (IHC/FISH), TOPO2A amplification (FISH) e PIK3CA mutation (exons 9/20). ROC analysis provided optimal cut-offs and model validation. A logistic equation with regression analysis coefficients was constructed to estimate individual patients’ probability (IPP) of death. Internal cross-validation (100 simulations, 80% of the dataset) was accomplished. Multivariate model Ratios served to derive a prognostic continuous score to identify risk classes. Results: 208 patients were studied (median follow-up 16 months, range 1-155). Multivariate analysis selected 8 independent CSS predictors: sex (HR 1.53, p=0.04), stage (HR 5.40, p<0.0001), R (HR 2.69, p<0.0001), localization (HR 1.64, p=0.008), LN (HR 1.55, p=0.02), APC (HR 1.91, p=0.001), FHIT (HR 1.54, p=0.05) and HER-2 (HR 1.92, p=0.08). Independent OS predictors were: sex, age, stage, R, localization, LN, APC and HER-2. Cross-validation analysis confirmed APC, FHIT and HER-2 as the biological variables displaying significant correlation with CSS (replication: 98%, 51%, 31%). The multivariate model predicted a 2-yr IPP of cancer-death/death with a prognostic accuracy of 0.87 (SE 0.02)/0.91 (SE 0.02). A 2-class risk stratification model was developed with the ROC generated cut-off prognostic score (AUC 0.87, SE 0.03; Sensitivity 85.3%, Specificity 78.9%); see table below. This 2-class model has a prognostic performance for CSS/OS of 0.82 (SE 0.03)/0.81 (SE 0.02). Conclusions: FHIT, APC and HER-2 represent powerful prognostic factors for resected GC and may complement clinical parameters to accurately predict individual patient risk. [Table: see text]
Phase II trial of tesetaxel, an oral taxane, as second-line therapy for patients with advanced gastroesophageal cancer.
Authors: Mulcahy Mary Frances , Baker Jackie S. , Sun Weijing , Rha Sun Young , Danesi Hassan , Itri Loretta , Ajani Jaffer A.
Published: March 2020

4077

Background: Tesetaxel is a novel, orally administered taxane. It is not a substrate for P-glycoprotein, and preclinical data suggest tesetaxel has potent antitumor activity that exceeds standard taxanes in human tumor xenografts while causing substantially less neuropathy. Tesetaxel is not associated with hypersensitivity, thus eliminating the need for premedication and extended observation. A prior study showed an overall major response rate (ORR) of 20% with tesetaxel used as 2nd-line therapy in patients (pts) with advanced gastric cancer. We previously showed that “flat” (i.e., non weight-based) dosing with tesetaxel was associated with excessive variability; therefore, we amended the final trial design to evaluate whether we could extend the prior observations in a confirmatory Phase 2 trial using the MTD. Methods: Eligibility included: adenocarcinoma of stomach/GE junction; 1 prior fluoropyrimidine-platinum regimen; ECOG PS 0-1; and adequate organ function. Tesetaxel was administered orally once every 3 weeks starting at 27 mg/m2 escalated to 35 mg mg/m2 pending tolerance. ORR was the primary endpoint; estimated overall survival (OS) was secondary. Results: To date, 24 pts -- from a final target of 27 – have been enrolled (10 men, 14 women; median age, 58 yrs [range, 26-81]). Preliminary ORR in 15 evaluable cases to date are shown in the table below. At this time, only 4 pts have died and median survival is too early to estimate. Grade 3-4 adverse events have included neutropenia (27%), anemia, fatigue (13% each), and anorexia (7%). One pt (7%) experienced Grade 3 peripheral neuropathy. There have been no episodes of febrile neutropenia. Conclusions: Oral tesetaxel administered once every 3 weeks is active against gastric cancer in the 2nd-line setting. The observed 20% ORR confirms earlier data and appears at least equivalent to docetaxel (ORR= 5%-19%), as reported in 4 prior studies in this population. Tesetaxel was well tolerated and was not been associated with hypersensitivity. We expect to present final ORR and estimated OS from this trial. [Table: see text]
A phase II study of tivantinib monotherapy in patients with previously treated advanced or recurrent gastric cancer.
Authors: Muro Kei , Ryu Min-Hee , Yasui Hirofumi , Nishina Tomohiro , Ryoo Baek-Yeol , Boku Narikazu , Kang Yoon-Koo
Published: March 2020

4082

Background: Tivantinib is a selective, non-ATP competitive, small-molecule inhibitor of c-MET and is under development in several cancers such as NSCLC and HCC. Elevated expressions of c-MET and its ligand, hepatocyte growth factor, have been frequently found in gastric cancer, and are associated with a more aggressive phenotype. In this single-arm phase II study, we evaluated the efficacy of tivantinib monotherapy in Asian patients (pts) with previously treated metastatic gastric cancer (MGC). This is the first clinical trial evaluating the efficacy of a selective c-MET inhibitor for MGC. Methods: Eligibility criteria included MGC with at least 1 measurable lesion per RECIST; 1 or 2 prior chemotherapy regimens; ECOG PS 0 or 1; and normal CYP2C19 metabolism. Tivantinib was daily administered 360 mg bid orally. The primary endpoint was disease control rate (DCR) defined as CR, PR or SD after 8 weeks administration. Pretreatment tumor tissue collection was required to evaluate the relationship between biomarkers and efficacy. Pharmacokinetic (PK) evaluation was also conducted. Results: Thirty patients received tivantinib and were eligible for analysis: median age 62.5 (41-70) years; ECOG PS 0/1 (8/22); 1/2 prior regimen (16/14); 12 pts (40%) with prior gastrectomy. No objective response was observed, and DCR was 36.7% (11/30 pts). Median progression-free survival was 43 (95% CI: 29.0-92.0) days. Grade 3 or 4 adverse events (AEs) occurred in 13 pts (43.3%), in which neutropenia (n = 4) and anemia (n = 4) were recognized as drug-related. Only 2 pts discontinued due to AEs. There is no treatment-related death and novel safety concern. c-MET gene amplification (≥ 5 copies/cell) was observed in 4 pts (13.3%). No obvious relationship of treatment outcome with biomarkers including c-MET gene amplification, c-MET, p-c-MET and HGF expression in tumor and serum HGF was identified. Gastrectomy and/or ethnicity (Korean or Japanese) did not affect PK parameters. Conclusions: Tivantinib as a monotherapy showed only a modest efficacy in previously treated MGC, and further trial testing in combination would be warranted in MGC. It would be an important finding that gastrectomy do not affect PK profile of tivantinib.
Assessment of HER2 status from an epidemiology study in tumor tissue samples of gastric and gastro-esophageal junction cancer: Spanish results of the HER-EAGLE study.
Authors: Gomez Lourdes , Concha Angel , Garcia-Caballero Tomas , Busteros Jose Ignacio , Burgos Emilio , Company Maria , Landolfi Stefania , Ruiz Irune , Gonzalez-Carrero Joaquin , Ortiz Duran Rosa Maria , Ibanez Martinez Jose , Martinez Carmen , Iglesias Mar , Florez Maria del Pino , Peligros Isabel , Rodriguez Rufo , Musulen Eva , Leon Paola Beatriz , Parra Juan Francisco , Vilardell Felip
Published: March 2020

4089

Background: Overexpression of HER2 is an important biomarker in gastroesophageal junction (GEJ) and gastric cancer (GC) and a predictive factor for trastuzumab (T, Herceptin). The ToGA phase III trial showed the benefit in overall survival of adding trastuzumab to chemotherapy inHER2-positive advanced GEJ/GC patients, following validated scoring criteria by a central laboratory. This study examines the incidence of HER2 positivity (local laboratories) in GEJ/GC according to EMA Herceptin label. Methods: HER-EAGLE was an epidemiological, non–interventional, international study assessing HER2 status by IHC/ISH in tumor samples from any stage GEJ/GC patients. Neutral buffered 10% formalin embedded tissues (surgical excision specimens or minimum 6-8 biopsies) analyzed via validated Ventana and Dako methods and scoring criteria used in ToGA: HER2-positive if IHC 3+ or IHC 2+ (FISH/SISH confirmed; HER2/CEP17 ratio ≥ 2.0); HER2-negative if IHC 0 or IHC 1+. Overall and subgroup estimates calculated with 95%CI. Data from the Spanish cohort are presented. Results: The Spanish cohort of HER-EAGLE included 1,954 participants (63.7% males) from 33 hospitals (Dec2010 to Aug2011), with 469 biopsies (24.0%) and 1,479 excisions (75.7%). Samples were 13.7% GEJ and 86.3% GC, and the adenocarcinomas were 1,137 intestinal (58.2%), 510 diffused (26.1%), 163 mixed (8.3%; Laureen classification), and 144 not available (7.3%). Median time from sampling to HER2 analysis of 5.1 years (range from days to 12 years). Total of 210 cases tested IHC 3+ (10.7%), 215 IHC 2+ (11.0%), 308 IHC 1+ (15.8%), and 1,221 IHC 0 (62.5%). Overall, HER2 positivity (IHC 3+ or IHC2+/ISH+) was 14.1% (95%CI 12.61 – 15.75). HER2 positivity by histological type was higher in intestinal adenocarcinomas (19.5%) compared to diffused (4.5%) or in mixed (9.2%). Conclusions: HER-EAGLE confirmed the feasibility of community based HER2 testing in GC as the first study with a high number of samples analyzed by local laboratories. The incidence of HER2-positivity (EMA label definition) was similar to the ToGA screening population, and it was again higher in adenocarcinomas of intestinal type (19.5%).
Positive association of gastric cancer surgery outcome with surgeon specialization in a Shanghai high-volume general hospital.
Authors: Shen Zhenbin , Sun Yihong , Wang Cong , Zhao Naiqing , Chen Weidong , Wang Xuefei , Wang Hongshan , Fang Yong , Liu Fenlin , Tang Zhaoqing , Wang Yanna , Li Haojie , Piao Yongzhe , Chu Laura , Wang Lisa , Dong Wei , Qin Xinyu
Published: March 2020

4092

Background: Numerous studies suggest positive relationship between hospital volume and cancer treatment outcomes, the surgeon’s experience and specialty training may also be important. This was examined in a high volume hospital in Shanghai among patients who underwent gastric cancer (GC) surgery. Methods: Data on consecutive patients (pts) undergoing R0 or R1 GC resection in Zhongshan hospital between January 2003 and June 2010 were collected and analyzed. Follow-up on pts who were non-Shanghai residents were less complete therefore excluded. Post-operative mortality, pathologic results and survival outcome for pts treated by surgical training, i.e., sub-specialized vs., non-specialized, were obtained. Survival was calculated by the Kaplan-Meier method and Log-rank test was used to determine statistical significance. To determine whether sub-specialty surgical training was an independent factor for overall survival (OS), univariate and multivariate analyses were performed using Cox proportional hazards regression. Results: Total 5,046 pts underwent R0 or R1 GC resection were identified.1594 pts had complete covariate data, survival information and were included in the study. Of them, the sub-specialized group included 217 cases treated by 3 surgeons, while the non-specialized group included 1377 cases treated by 52 surgeons. 5-year cumulative OS was higher in the sub-specialized group (62.9% vs. 54.6%, p=0.032). Multivariate analysis showed that tumor stage(p<0.001), location of tumor (p=0.003), vascular invasion (p<0.001) and surgeon (HR=1.54, p=0.001) were all associated with OS. The incidence of positive margin was higher in non-specialized group (2.0% vs. 2.7%, p<0.001) and the probability of retrieved lymph nodes less than 15 was more in non-specialized group (25.9% vs. 7.3%, p<0.001). Postoperative mortality was also higher in non-specialized group than in specialized group(1.5% vs. 0.9%, p<0.001). Conclusions: In high volume general hospital, sub-specialty training is desirable in gastric cancer surgery, the quality of gastric cancer surgery can be further improved by sub-specialty training leading to better treatment outcome.
A phase I/II study of AZD6244 in combination with sorafenib in advanced hepatocellular carcinoma.
Authors: Choo Su Pin , Ng Quan Sing , Chen Wallace Jian Jun , Tham Chee Kian , Yong Wei-Peng , Wang Ling Zhi , Koh Tong San , Goh Boon C. , Thng Choon Hua , Huynh Hung The , Zee Ying Kiat , Low Li shan , Toh Han Chong
Published: March 2020

4100^

Background: Preclinical studies have shown that pharmacological inhibition of the MEK/ERK pathway by AZD6244 enhanced the anti-tumor effect of sorafenib in both orthotopic and ectopic models of HCC. We conducted this study to determine tolerability, pharmacokinetics, and pharmacodynamics of AZD6244 when combined with sorafenib in advanced HCC. Methods: Patients with biopsy-proven unresectable BCLC B/C hepatocellular carcinoma were recruited. Only those with Childs-Pugh A or B (7) liver cirrhosis and without prior systemic therapy were included. Sorafenib at 400mg bd was given 1 week before initiation of AZD6244 which was escalated in subsequent cohorts from 75mg om based on 3+3 design. PK and PD studies and QOL assessments were performed. DCE-MRI imaging was performed to assess tumor vascularity in response to treatment. Results: Fourteen patients were recruited (including 2 replaced). 11 had evaluable disease. Characteristics: all male, all Chinese, 12 were BCLC C stage. Two DLTs were seen out of 6 patients at dose level 1 (AZD6244 at 50mg bd) which were grade 3 fatigue and grade 3 abdominal pain with elevated transaminases. When an additional dose level 1A was added (ADZ6244 at 100mg om), 2 out of 3 patients had DLTs of grade 3 raised aspartate transaminase and grade 3 diarrhea. Thus, the MTD was determined to be AZD6244 at 75mg om when combined with sorafenib 400mg bd. Common toxicities were diarrhea (83%), rash (58%), fatigue (50%), hypertension (42%), anorexia/vomiting/thrombocytopenia (25%). Two patients had reversible LVEF dysfunction and there were no eye toxicities. PK of AZD6244 showed oral clearance of 11.2 + 6.8 L/h and terminal half-life of 6.0 +2.0 h.Objective responses were 3 PR, 6 SD and 2 PD.DCE-MRI measurements demonstrated significant reductions in permeability surface area product (PS, ml/100ml/min) and fractional intravascular blood volume (v1, ml/100ml) seven days after starting sorafenib. No additional antivascular activity was observed when AZD6244 was added to sorafenib. Conclusions: The recommended phase II dose for AZD6244 is 75mg om when combined with sorafenib 400mg bd for advanced HCC patients. This combination is feasible, shows activity and warrants further investigation.
A phase I/II study of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGFR in advanced hepatocellular carcinoma (HCC).
Authors: Yau Thomas Cheung , Sukeepaisarnjaroen Wattana , Chao Yee , Yen Chia-Jui , Lausoontornsiri Wirote , Chen Pei-Jer , Sanpajit Theeranun , Lencioni Riccardo , Camp Aaron C , Cox Donna S , Kallender Howard , Ottesen Lone Harild , Poon Ronnie Tung-Ping
Published: March 2020

4108

Background: Hepatocyte growth factor (HGF)/MET signalling plays a pivotal role in tumor cell proliferation, migration and invasion in HCC and circulating levels of HGF correlate with poor prognosis. This phase I/II trial (MET111645) evaluated foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2 and VEGFR, as first-line therapy in Asian advanced-HCC patients. Methods: Asian patients with measurable, unresectable/metastatic HCC, no prior sorafenib or other multi-kinase inhibitors, ECOG PS 0-1, adequate organ function and Child-Pugh grade A were recruited. The phase I was a standard 3+3 dose escalation design with a phase II cohort expansion. The primary endpoint was safety and tolerability at the maximum tolerated dose (MTD) and the secondary endpoints included antitumor activity (objective response rate [ORR], disease stabilization rate [DSR; confirmed CR/PR or SD for at least 12 weeks], and time to progression [TTP] evaluated by central review according to modified RECIST), and overall survival (OS) at the MTD, plus pharmacokinetics (PK). Results: Thirteen patients were enrolled in phase I. Two dose-limiting toxicities (DLT) (renal failure, proteinuria) were observed at 45 mg once daily (QD) but no DLTs were observed at 30 mg QD. Thus, the MTD was determined to be 30 mg QD. A further 32 patients were enrolled at the MTD, for a study total of 39 patients treated at 30 mg QD. The most common AEs, independent of causality,were hypertension (36%), decreased appetite (23%), and pyrexia (21%). The most common SAEs were hepatic encephalopathy (10%) and ascites (8%). Two patients discontinued foretinib due to AEs. No dose reductions were reported. Thirty-eight patients were evaluable for efficacy. The ORR was 24% (95% CI 11-40), DSR 79% (95% CI; 63-90), and the median TTP was 4.2 months (95% CI 2.7-7.5). Mature OS data will be presented. Mean steady-state exposures (AUC/Cmax) were comparable after administration of foretinib at 30 and 45 mg. Conclusions: Foretinib has an acceptable safety, tolerability, and PK profile in an Asian HCC population. It has demonstrated promising antitumor activity that warrants further testing in a randomized setting.
Updated results from a phase III trial of sunitinib versus placebo in patients with progressive, unresectable, well-differentiated pancreatic neuroendocrine tumor (NET).
Authors: Vinik Aaron , Van Cutsem Eric , Niccoli Patricia , Raoul Jean-Luc , Bang Yung-Jue , Borbath Ivan , Valle Juan W. , Metrakos Peter , Smith Denis , Chen Jen-Shi , Hoersch Dieter , Castellano Daniel E. , Kennecke Hagen F. , Picus Joel , Van Hazel Guy , Patyna Shem , Lu Dongrui (Ray) , Chao Richard C. , Raymond Eric
Published: March 2020

4118

Background: In a double-blind phase III trial, sunitinib (Sutent; SU) improved progression-free survival (PFS) vs placebo (PBO; 11.4 vs 5.5 mos; HR: 0.42, 95% CI: 0.26–0.66; P=0.0001) and was well tolerated in patients (pts) with unresectable, well-differentiated pancreatic NET that had progressed ≤12 mos before baseline. Initial overall survival (OS) revealed a benefit for SU vs PBO, although median OS had not been reached. We now report PFS assessed by blinded independent central review (BICR) and updated OS. Methods: Pts were randomized 1:1 to SU 37.5 mg or PBO on a continuous daily dosing schedule, each with best supportive care. The primary endpoint was investigator-assessed PFS; OS was a secondary endpoint to be evaluated every 2 yrs for 5 yrs, or until 95% of pts had died. Additionally, BICR was performed retrospectively; baseline and on-study CT/MRI scans were evaluated by a 2-reader, 2-time-point lock, followed by a sequential locked-read, batch-mode paradigm by blinded, third-party radiologists. Results: 171 pts were randomized (SU, n=86; PBO, n=85) from Jun 2007 to Apr 2009. The trial ended when an independent data monitoring committee noted efficacy favoring SU and more serious AEs and deaths with PBO. The study was unblinded at closure; pts were offered open-label SU and followed for survival. Median PFS by BICR was 12.6 mos (SU) vs 5.8 mos (PBO) (HR: 0.32, 95% CI: 0.18–0.55; P=0.00001). At study closure, there were 9 and 21 deaths in the SU and PBO arms (HR: 0.41, 95% CI: 0.19–0.89; P=0.02). By Apr 2011 (2 yrs additional follow-up) a total of 87 deaths occurred (51%), median OS was estimated at 33.0 mos in the SU arm, and 26.7 mos in the PBO arm (HR: 0.71, 95% CI: 0.47–1.09; P=0.11 [Table]). 69% of pts crossed over to SU on progression. Conclusions: BICR confirmed investigator assessment of PFS and demonstrated a 6.8-mo improvement in median PFS with SU. Updated OS favors SU, although this result is non-significant for reasons that may include crossover of treatment and limited statistical power. [Table: see text]