bluuebunny/crossref_metadata_2025_split huggingface dataset:
The association of objective response and overall survival in patients with inoperable or metastatic gastric and esophagogastric junction (EGJ) cancer: A pooled analysis of individual patient data from first-line clinical trials.
Authors: Bolt Toki Anna , Pauligk Claudia , Werner Dominique , Mayer Frank , Hofheinz Ralf Dieter , Homann Nils , Luley Kim , Al-Batran Salah-Eddin 
Published: March 2020

4095 Background: The aim of the study is to determine whether the achievement of an objective response to first-line chemotherapy is prognostic of patient’s outcome in gastric/EGJ adenocarcinoma. Methods: Individual patient (pts) data from prospective first-line trials conducted by a single study group were used. Patients received platin/5-FU based chemotherapy with or without docetaxel. Responses were evaluated according to WHO criteria in all trials. Response data, patients’ characteristics (age, sex, entity, histological type, primary location, ECOG PS, and type and number of metastatic sites), type of chemotherapy, and overall survival data were analyzed. Results: 612 pts were included. Median age was 66 yrs; 31.5% had ECOG status 0, 58.3% ECOG 1, and 9.8% ECOG 2 & 3. Gastric primaries were found in 44.4% and EGJ in 35.8% of pts (19.7% were overlapping/not evaluable). According to Lauren classification, 36.8% had intestinal, 32.4% diffuse, and 8.5% mixed types (22.4% were not classifiable). 64.5% had positive non-regional lymph nodes (LN) involvement, 14.1% LN involvement without other metastases, 33.3% had peritoneal carcinomatosis, 44.0% liver and 16.7% lung metastases. Response rates were complete (CR) in 3.1%, partial (PR) in 36.4%, stable disease (SD) in 34.5%, and progressive disease (PD) in 15.0% pts (10.9% were not evaluable). Overall response rate (OR; CR + PR) was 39.5%. Median overall survival times in pts with CR vs PR vs SD vs PD were 37.9 vs 14.7 vs 10.9 vs 5.2 months, respectively; p=1.26 x 10-33). OR (CR or PR) also strongly predicted OS (16.7 vs 8.1 months in pts with vs no OR, p=1.08 x 10-17). OR remained the strongest predictor of OS in the multivariate analysis (p=6.55 x 10-7) including all baseline criteria mentioned above followed by ECOG PS (p=0.048) and the presence of non-regional LN as the only site of metastasis (p=0.034). Conclusions: The achievement of an objective response is the strongest predictor of survival in pts with gastric and EGJ cancer and could serve as a surrogate marker if validated.
Concurrent chemoradiotherapy with cetuximab plus twice-weekly paclitaxel and cisplatin followed by esophagectomy for locally advanced esophageal squamous cell carcinoma.
Authors: Lin Chia-Chi J. , Hsu Chih-Hung , Cheng Jason C. , Yen Chueh-Chuan , Shiah Her-Shyong , Huang Ta-Chen , Chen Wei-Wu , Wang Hsiu-Po , Yeh Kun-Huei , Lee Jang-Ming , Cheng Ann-Lii 
Published: March 2020

4099 Background: We investigated the efficacy and safety of adding cetuximab to twice-weekly paclitaxel/cisplatin-based concurrent chemoradiotherapy (CCRT), followed by surgery, for patients with locally advanced esophageal squamous cell carcinoma (ESCC). Methods: Patients with locally advanced ESCC (T3N0-1M0 or T1-3N1M0 or M1a by AJCC 2002) were treated with paclitaxel (35 mg/m2 1 h D1, 4/wk), cisplatin (15 mg/m2 1 h D2, 5/wk), cetuximab (400 mg/m2 2 h D-5, then 250 mg/m21 h D3/wk) and radiotherapy (2 Gy D1-5/wk). The feasibility of esophagectomy was evaluated for all patients at the accumulated radiation dose of 40 Gy. If esophagectomy was not feasible, CCRT was continued to a radiation dose of 60-66 Gy. Results: 66 patients were enrolled between Oct 2008 and Jun 2010, and 61 (94%) of them had T3N1M0 or M1a tumors by endoscopic ultrasonographic staging. All patients received CCRT to 40 Gy. Forty-three patients underwent surgery, and 17 patients continued definitive CCRT to 60-66 Gy. Of the scheduled doses of paclitaxel, cisplatin, and cetuximab, 80%, 79%, and 99% were given, respectively. The most common grade 3/4 toxic effects were leukopenia (51%), neutropenia (15%), esophagitis (19%), and infection (12%). The pathological complete response rate was 24% (intent-to-treat, 16/66) (95% confidence interval: 13-35%) and 37% (who underwent resection, 16/43). At the median follow-up of 34.6 months, the median progression-free (PFS) and overall survivals were 21.6 and 33.9 months, respectively. No KRAS codon 12/13 mutations were identified in 47 tumor samples. The median PFS for patients with two, one, and no adverse tumor biomarkers (Tau+, ERCC1+, pEGFR-) (n = 40) was 12.3 months, 27.6 months, and greater than 33.6 months, respectively (p = .087). Conclusions: Adding cetuximab to twice-weekly paclitaxel/cisplatin-based CCRT prior to esophagectomy is an active and tolerable treatment for locally advanced ESCC. Clinical trial information: NCT01034189. [Table: see text]
Concordance of HER2 and its related molecules between primary and paired liver metastatic sites in gastric cancer.
Authors: Shinozaki Eiji , Yamamoto Noriko , Saiura Akio , Sano Takeshi , Chin Keisho , Ogura Mariko , Matsusaka Satoshi , Suenaga Mitsukuni , Ozaka Masato , Mizunuma Nobuyuki 
Published: March 2020

4108 Background: Trastuzumab is the 1st molecular targeting drug in HER2-positive advanced gastric cancer that has been shown to confer overall survival benefit adding to chemotherapy. In breast cancer it has been already used long time, it is known that there are the discordance of its target; HER2 between primary and metastatic site. Although molecular targeting drugs as Trastuzumab are expected to control the metastatic disease, molecular status is usually evaluated in the primary site because metastatic sites are difficult to biopsy. In this study we attempted to compare HER2 and its related molecular status, which have interaction each together, between primary and paired liver metastatic sites in gastric cancer. Methods: Total 58 consecutive cases with gastric cancer who underwent surgical resection of primary site and synchronous or metachronous liver metastasis were examined. HER2, EGFR, c-MET and IGF-1R status were evaluated by immunohistochemistry(IHC) in primary and paired liver metastasis. HER2 expression by IHC using HercepTest (DAKO) were assessed according to Gastric Cancer Scoring System. On the other molecular expression by IHC, positive expression was defined as 25% or more staining with intensity 2 or 3+. We analyzed the concordance of their expression in both sites. Results: The patient cohort consists predominantly of male (78%), with Lauren’s diffuse (37%) and intestinal tumors (62%). Fifty three percent of cases were synchronous liver metastasis. The positive rate of primary and paired liver metastatic sites were 10.3%, 8.6% in HER2, 1.7%, 5.1% in EGFR, 44.8%, 31.0% in c-MET and 31.0%, 29.3% in IGF-1R. The concordance between primary and paired liver metastatic sites were 91.3%, 93.1%, 75.8%, and 70.6%, respectively. Conclusions: Our data suggested that in HER2 and EGFR the concordance between primary and metastatic site were high, other hands the concordance of c-MET and IGF-1R were relatively low. It might be necessary to rebiopsy to estimate the expression of c-MET and IGF-1R in gastric cancer.
A phase II study of perioperative S-1 combined with weekly docetaxel in patients with locally advanced gastric cancer: Clinical and pharmacogenetic results.
Authors: Park Sook Ryun , Kim Young Woo , Ryu Keun Won , Lim Hyeong-Seok , Lee Jun Ho , Kong Sun-Young , Kim Mi-Jung , Choi Mihee , Park Young Iee 
Published: March 2020

4114 Background: We conducted a phase II study to evaluate the efficacy and safety of perioperative S-1 + docetaxel (DS) in locally advanced gastric cancer (LAGC), and to investigate the association between CYP2A6 genotypes and treatment outcomes. Methods: Eligibility criteria included 18-70 yrs, PS 0-1, measurable lesion(s), and LAGC (clinical stage III-IV (M0) by Japanese staging system). Pts were given each 3 cycles of pre- and post-operative chemotherapy (S-1 40 mg/m2 bid on D1-14, docetaxel 35 mg/m2iv on D1, 8 q 3 wks), and underwent surgery (≥D2). Results: From Oct 2006 to June 2008, 44 pts entered into the study, and 43 pts were eligible. Median age=53 yrs (range, 33-69); PS 0/1=2/41; M/F=29/14; and stage IIIA/IIIB/IV (M0)=20/18/5. All 43 eligible pts completed preoperative DS and 40 pts (93%) completed postoperative DS. The most common G3/4 toxicities during pre- and post-operative DS were neutropenia (28% vs. 65%), stomatitis (19% vs. 5%), and abdominal pain (5% vs. 18%). The clinical response rate was 74.4% (95% CI, 61.4-87.4%) with 1 CR (2.3%) and 31 (72.1%) PRs. R0 resection rate was 97.7%, major pathologic response rate was 48.8% with 1 CR, and pathologic stage was 0/1/2/3/4 (%) = 2.3/44.2/20.9/20.9/11.6. With a median follow-up of 66.6 months, 3-yr PFS and 5-yr OS was 62.8% and 69.6%, respectively. Survival differed according to clinical response, clinical downstaging, and CYP2A6 genotypes (Table). Pts with two CYP2A6 variant alleles (V/V) had higher Cmax (27.7±4.6 vs. 20.3±1.2; p=0.045) and AUCinf (220.4±43.1 vs. 172.5±12.5; p=0.187) of tegafur, and lower Cmax (1.4±0.2 vs. 1.8±0.1; p=0.178) and AUCinf (8.4±1.2 vs. 9.7±0.5; p=0.308) of 5-FU than those with no or one variant allele (W/W or W/V). Conclusions: DS is active with a manageable toxicity profile in the perioperative setting in pts with LAGC. CYP2A6 genotype may be predictive of efficacy (S-1 and docetaxel was provided by JEIL Pharm. Co., Ltd. and sanofi-aventis Korea Co., Ltd., respectively). Clinical trial information: NCT00587145. [Table: see text]
A multitranscript blood neuroendocrine tumor molecular signature to identify treatment efficacy and disease progress.
Authors: Modlin Irvin M. , Drozdov Ignat , Kidd Mark S. 
Published: March 2020

4137 Background: Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) or NETs (also called “carcinoids”) are problematic since they present with advanced disease and have limited treatment options. Imaging has proved to be insensitive in identifying treatment effect. Similarly, the currently used biomarker, a neurosectory peptide, Chromogranin A (CgA) is of limited value as a predictor of treatment efficacy. We have developed a multi-transcript (n=51 genes) molecular signature for PCR-based blood analysis which exhibits a high sensitivity (85-98%), specificity (93-97%), positive predictive value (95-96%) and negative predictive value (87-98%) for the identification of GEP-NENs. This test significantly outperforms (p<0005) plasma CgA (measured by ELISA). Methods: The candidate gene signature was examined by a 2-step PCR method in a training set of 130 blood samples (GEP-NENs: n=63, treatment-naïve (n=28)) and validated in an independent set ([n=182, GEP-NENs: n=133, including complete remission (n=4), clinically stable disease (n=82) and non-responders/clinically progressive disease (n=47). Results: The PCR score was significantly elevated (p<0.0001) in the treatment-naïve group compared to treated GEP-NENs, while levels were significantly reduced (p<0.004) in 11 matched samples (pre- and post-treatment – surgical removal (n=10), RFA (n=1)). In the independent set, the scores for complete remission were not different to controls (0.5±0.25 vs. 0.4±0.16), while scores for stable disease (0.63±0.12) were significantly lower than for non-responders (5.85±0.34, p<0.002). Stable disease could be differentiated from clinically progressive disease since the latter exhibited a high score (85% vs. 10%, p<0.0001). The performance metrics for differentiation were: sensitivity (91%), specificity (91%), PPV (86%), NPV (95%). Conclusions: This study demonstrated that the multi-transcript molecular signature is both sensitive and specific for the detection of neuroendocrine tumor disease and is capable of differentiating clinically stable from progressive disease. It therefore has potential utility as a measure for monitoring treatment efficacy for GEP-NENs.
Open-label, phase IIIb, multicenter, expanded access study of everolimus in patients with advanced neuroendocrine tumors (NET).
Authors: Bechter Oliver Edgar , Unger Nicole , Borbath Ivan , Ricci Sergio , Hwang Tsann-Long , Park Young Suk , Tomasek Jiri , Raef Hussein , Laohavinij Sudsawat , JeanLouis Lisa , Panneerselvam Ashok , Saletan Stephen , Stergiopoulos Sotirios G. , Pavel Marianne E. 
Published: March 2020

4138 Background: Everolimus (EVE) antitumor efficacy in patients (pts) with advanced NET was demonstrated in 2 double-blind, placebo (P)–controlled, phase III trials (RADIANT-2 and RADIANT-3). Median PFS in pancreatic (pNET) pts was 11.0 months (EVE) vs. 4.6 months (P) (HR 0.35, 95% CI 0.27-0.45, P <0.001) in RADIANT-3. Median EVE exposure in RADIANT-3 was 38 wks. EVE was approved for advanced pNET in the US and Europe in 2011. An expanded access protocol was launched to gather additional safety data and provide access to EVE for pts with advanced NET while awaiting regulatory approval. Methods: Pts aged ≥18 years with biopsy-proven NET; WHO performance status 0-2; and adequate bone, hepatic, and renal function were enrolled. Main exclusion criteria were poorly differentiated NET and cytotoxic therapy within 4 wks of enrollment. EVE (10 mg/d) was administered until disease progression, unacceptable toxicity, discontinuation, death, commercial availability of EVE, or until May 30, 2012. Pts were enrolled from April 21, 2011 to April 20, 2012. Primary objective was grade 3/4 and serious adverse events (AEs). Secondary objectives included investigator-assessed best overall response rate and PFS. Results: The full analysis set included 246 pts (pNET, n=126; non-pNET, n=120); the safety set included 240 pts (pNET, n=123; non-pNET, n=117). Median age was 61 and 66 years; 54% and 49% were male. Main primary tumor sites in non-pNET pts included small intestine (40%) and lung (22%). Median duration of EVE exposure was 12.1 wks and 24 wks in pNET and non-pNET. At data cutoff, there were 21 and 32 PFS events; 105 and 88 pts were censored. Grade 3/4 AEs were reported in 42.3% and 69.2% of pNET and non-pNET; those reported in ≥10% of pts in pNET and non-pNET included hyperglycemia (12.2% and 5.1%), diarrhea (10.6% and 31.6%), stomatitis (9.8% and 11.1%), nausea (8.1% and 10.3%), and anemia (5.7% and 11.1%). Median investigator-assessed PFS was 7.6 (95% CI 5.52-7.62) months and 10.8 (8.77-Not Estimable) months in pNET and non-pNET. Conclusions: EVE was well tolerated in pts with advanced NET. AEs were similar to those previously reported. Protocol-specified early termination of pts limits the interpretation of PFS medians. Clinical trial information: EudraCT Number: 2010-023032-17.
Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with metastatic renal cell carcinoma (mRCC).
Authors: Cho Daniel C. , Sosman Jeffrey Alan , Sznol Mario , Gordon Michael S. , Hollebecque Antoine , Hamid Omid , McDermott David F. , Delord Jean-Pierre , Rhee Ina Park , Mokatrin Ahmad , Kowanetz Marcin , Funke Roel Peter , Fine Gregg Daniel , Powles Thomas 
Published: March 2020

4505 Background: Human RCC expresses PD-L1 and has been shown to respond to immune-based therapy. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Methods: Pts with mRCC received MPDL3280A administered IV q3w at doses between 3-20 mg/kg in a Phase I expansion study. Pts were treated for up to 1 y. Response was assessed by RECIST v1.1. Results: As of Jan 10, 2013, 53 RCC pts were evaluable for safety and treated at doses of 3 (n=2), 10 (n=12), 15 (n=18) and 20 mg/kg (n=21). These pts had a median age of 62 y (range 33-79 y), 100% were PS 0-1 and all had had prior surgery. 83% of pts had received prior systemic therapy; 38% received immunotherapy, 57% received TKIs and 36% received anti-angiogenic therapy. Pts received treatment with MPDL3280A for a median duration of 190 days (range 21-317). The incidence of G3/4 AEs in RCC pts was 43%, regardless of attribution, with hypophosphatemia, fatigue, dyspnea and hyperglycemia (all 4%) being the most common. 13% of G3/4 AEs were attributable to study drug. 1 case of myasthenia gravis was observed in a pt who was retrospectively found to have anti-acetylcholine receptor antibodies prior to starting therapy. No G3-5 pneumonitis or diarrhea was reported. No treatment-related deaths occurred. 39 RCC pts enrolled prior to Jul 1, 2012, were evaluable for efficacy. RECIST responses, including CR, were observed across dose levels, with all responses ongoing at the time of data cutoff. Some RCC pts experienced prolonged SD prior to experiencing RECIST response. The 24-week PFS was 50%. Analysis of biomarker data from mandatory archival tumors demonstrated a correlation between PD-L1 status and efficacy. In addition, response correlated with low IL-17 expression in tumor tissue. Updated data will be presented. Conclusions: MPDL3280A was well tolerated, with no pneumonitis-related deaths. PD-L1–positive status correlates with response to MPDL3280A. Durable responses have been observed in RCC pts treated with MPDL3280A and further study is warranted. Clinical trial information: NCT01375842.
Phase II efficacy and safety study of nintedanib versus sunitinib in previously untreated renal cell carcinoma (RCC) patients.
Authors: Eisen Tim , Shparyk Yaroslav , Jones Robert , MacLeod Nicholas James , Temple Graham , Finnigan Helen , Kaiser Rolf , Studeny Matus , Loembe Arsene Bienvenu , Bondarenko Igor 
Published: March 2020

4506 Background: Sunitinib (S) is established as a standard first-line therapy for patients (pts) with advanced RCC. However, treatment can be limited by the occurrence of drug-related adverse events (AEs). This Phase II study assessed the efficacy and safety of nintedanib (N) – a potent, triple angiokinase inhibitor of VEGFR-1–3, PDGFR-α/β, and FGFR-1–3, as well as RET and Flt3 – vs S in previously untreated pts with RCC. Methods: Ninety-nine eligible pts (96 of whom were treated) with advanced, unresectable/recurrent clear cell RCC, an ECOG performance status of 0–1, and no prior systemic therapy were randomized 2:1 to receive N 200 mg twice daily (n=64; given in 4-week cycles) or S 50 mg once daily (n=32; 4 weeks on, 2 weeks off schedule). Treatment continued until disease progression or unacceptable drug-related AEs. Primary endpoints were progression-free survival at 9 months (PFS-9) and, in N-treated pts only, QTc interval change (baseline to day 15). Secondary endpoints included PFS, objective response rate (ORR; RECIST 1.1), overall survival (OS), time to progression (TTP), time to treatment failure (TTF), and AEs. Results: Baseline characteristics were balanced between the arms. PFS-9 was not statistically significantly different between N- and S-treated pts (43 vs 45%; p=0.85). There were also no statistically significant differences between N and S with regard to PFS (median: 8.44 vs 8.38 mo; hazard ratio: 1.16; 95% CI: 0.71–1.89; p=0.56), confirmed ORR (18.8 vs 31.3%; p=0.19), OS (median: 20.37 vs 21.22 mo; p=0.63), TTP (median: 8.48 vs 8.54 mo; p=0.52), and TTF (median: 8.41 vs 8.36 mo; p=0.46). Grade ≥3 AEs occurred in 47% of N-treated pts and 56% of S-treated pts. Common AEs (all grades; N vs S) included diarrhea (61 vs 50%), nausea (38 vs 34%), fatigue (both 25%), and vomiting (16 vs 22%). Dermatologic AEs (8 vs 47%) were less frequent with N than S. There was no increase from baseline in QTc >60 ms on days 1 or 15 in N-treated pts, and there was no relationship between N exposure and QT interval change. Conclusions: N demonstrated similar efficacy to S and had a manageable safety profile, including a lower incidence of dermatologic AEs vs S. In addition, N was not associated with QT prolongation. Clinical trial information: NCT01024920.
Survival, safety, and response duration results of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in a phase I trial in patients with previously treated metastatic renal cell carcinoma (mRCC): Long-term patient follow-up.
Authors: Drake Charles G. , McDermott David F. , Sznol Mario , Choueiri Toni K. , Kluger Harriet M. , Powderly John D. , Smith David C. , Sankar Vindira , Gutierrez Andres A. , Wigginton Jon M. , Kollia Georgia , Gupta Ashok Kumar , Atkins Michael B. 
Published: March 2020

4514 Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that negatively regulates T-cell activation. PD-L1, a PD-1 ligand, has been associated with poor prognosis in mRCC pts. In a phase I study of nivolumab, a PD-1 receptor blocking antibody, in pts with previously treated mRCC and other solid tumors, an MTD was not reached at 10 mg/kg IV Q2WK. Cohorts of mRCC pts were expanded at the 1 and 10 mg/kg dose levels. Methods: Pts received nivolumab for ≤12 cycles (4 doses/cycle) until unacceptable toxicity, progression, or complete response. We report overall survival (OS), updated response data, and long-term safety for the mRCC cohorts from a data analysis in July 2012. Results: 34 pts with mRCC were treated at 1 mg/kg (n=18) or 10 mg/kg (n=16). 44% of pts had received ≥3 prior therapies (74% prior antiangiogenic therapy; 59% prior immunotherapy). Median OS across doses has not yet been reached. Median duration of response was 12.9 months for both doses with 5 of the 10 responses lasting ≥1 year. The incidence of grade 3-4 related adverse events for the RCC cohort was 21% and included hypophosphatemia (6%) and respiratory disorders (6%), with no confirmed-drug related deaths or grade 3 pneumonitis. Treatment discontinuation due to drug-related AEs occurred in 18/304 (6%) of patients in the overall treated population. Conclusions: Nivolumab produced durable survival and responses in a subset of heavily pretreated mRCC pts, with an acceptable safety profile, even after long term continuous dosing. Overall survival appears promising for this population of pts. These findings provide the basis for an ongoing randomized phase III trial of nivolumab in mRCC (NCT01668784). Follow-up data through a February 2013 cutoff is being collected. Clinical trial information: NCT00730639. [Table: see text]