bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of benefit from immune checkpoint inhibitors with next gen sequencing (NGS) profiles in esophagogastric cancer (EGC) patients.
Authors: Ku Geoffrey Yuyat , Sanchez-Vega Francisco , Chatila Walid , Margolis Matthew , Fein Carly , Ilson David H. , Hechtman Jaclyn Frances , Tuvy Yaelle , Bouvier Nancy , Kundra Ritika , Shia Jinru , Heins Zachary J. , Middha Sumit , Zehir Ahmet , Ladanyi Marc , Berger Michael F. , Tang Laura H. , Solit David B. , Schultz Nikolaus , Janjigian Yelena Yuriy
Published: September 2018

4025

Background: Immuno-oncology (IO) with anti-PD-1 and –PD-L1 antibodies (Abs) is active in EGC but only benefits a minority of Pts. Biomarkers are needed to identify responders. Methods: We reviewed our experience of Pts treated with anti-PD-1/PD-L1 Abs and correlated their outcomes with PD-L1 and mismatch repair protein (MMR) status by immunohistochemistry (IHC), as well as MSK-IMPACT (≥340-gene) NGS profile. MSIsensor from IMPACT assesses microsatellite instability phenotype, while ≥20 mutations (or 17 mutations/Mb) strongly correlates with MMR-deficiency (dMMR) by IHC (J Clin Oncol 2016;34:2141). Progression-free (PFS) and overall survival (OS) were analyzed from the start of IO. Results: 71 Pts were identified, with 3 Pts receiving 2 IO regimens. 66 had adenoCAs and 5 had squamous CAs. Median age 58, 77% male, 96% had received ≥2 prior chemo regimens. 39 (55%), 18 (25%) and 17 Pts (24%) respectively received anti-PD-1, anti-PD-L1 and anti-CTLA-4 plus anti-PD-1/PD-L1 Abs. 6 Pts (8%) had objective response (2 complete responses or CRs) and the median PFS and OS are 1.6 and 4.7 mos; 2-yr OS is 17%. PD-L1 IHC was performed in 16 Pts (23%; 7 +ve), MMR was tested in 20 Pts (28%; 4 dMMR) and IMPACT was obtained in 44 Pts (62%). All 4 dMMR tumors were also MSI by MSIsensor and had a median of 46 mutations (range, 29-63) or, equivalently, 33 mutations/Mb (range, 21-46); 2 of 2 dMMR tumors tested PD-L1 +ve. 3 of the 4 Pts with dMMR/MSI tumors had a response (including 1 CR) and the median OS of these 4 Pts is not reached with 23+ months of follow-up. Finally, a patient whose tumor is MMR-proficient, not MSI but has 15 mutations (including in POLD1), achieved an ongoing CR at 37+ mos. For the 44 Pts with IMPACT testing, there appeared to be improved OS for tumors with ≥10 vs. <10 mutations/Mb (2-yr OS 80% vs. 12%, p=0.03). Conclusions: Pts with tumors that are MSI or have ≥10 mutations/Mb on MSK-IMPACT appear to derive significant benefit from IO. MSK-IMPACT can offer novel information, identify novel mutations (e.g. POLD1) and may be used to help select Pts for IO. We are seeking to define a mutation no. cut-off that can serve as a biomarker and updated data will be presented.
Three-field versus two-field lymphadenectomy for carcinoma of the middle and lower esophagus: Short-term results of a randomized controlled trial.
Authors: Li Bin , Chen Haiquan
Published: September 2018

4036

Background: The safety and efficacy of esophagectomy with 3-field lymphadenectomy remain controversial. Methods: We did this randomized trial in Fudan University Shanghai Cancer Center in China. Between March 2013 and November 2016, 400 patients with cancer located in the middle and lower esophagus were recruited and randomly assigned to receive 3-field or 2-field lymphadenectomy at a 1:1 ratio. Postoperative complications between the 3-field group (n = 200) and 2-field group (n = 200) were compared on the basis of the intention-to-treatment principle. Results: There was no significant difference between the two arms in terms of gender, age, BMI, FEV1, and tumor location. Median operative time was 183 minutes (range 125 to 331) in 3-field group versus 168 minutes (range 116 to 375) in 2-field group, P< 0.001. Overall morbidity was 28% (56/200) in the 3-field group and 30.5% (61/200) in the 2-field group, P= 0.583. The mortality rate was 0% (0/200) for the 3-field group and 0.5% (1/200) for the 2-field group, P= 1.000. Although more reintubation occurred in the 3-field group than in the 2-field group (3% [6/200] vs. 0% [0/200], P= 0.030), the distribution of severity (stratified according to the Clavien-Dindo classification) and hospital stay were similar between the two groups. A significantly higher number of lymph nodes were retrieved in the 3-field group (median 37, range 3 to 85) compared to those in the 2-field group (median 24, range 7 to 61) ( P< 0.001). 44 patients (22%) had positive cervical nodes in the 3-field group. Conclusions: Morbidity after esophagectomy with 3-field lymphadenectomy is comparable with that after 2-field lymphadenectomy. Cervical lymphatic involvement is common in patients with middle and lower esophageal cancer. 3-field lymphadenectomy may offer more accurate tumor staging related to cervical lymphatic metastasis. TABLE. Regions of lymph nodes metastases Clinical trial information: NCT01807936. [Table: see text]
Early presence of antiangiogenesis-related adverse events as a potential biomarker of antitumor efficacy in patients with metastatic gastric cancer treated with apatinib.
Authors: Liu Xinyang , Qin Shukui , Wang Zhichao , Xu Jianming , Xiong Jianping , Bai Yuxian , Zhe-Hai Wang , Yang Yan , Sun Guo-ping , Wang Liwei , Zheng Leizhen , Xu Nong , Cheng Ying , Guo Weijian , Yu Hao , Liu Tian Shu , Lagiou Pagona , Li Jin
Published: September 2018

4052

Background: Reliable biomarkers of apatinib response in gastric cancer (GC) are lacking. We investigated the association between early presence of common adverse events (AEs) and clinical outcomes in metastatic GC patients. Methods: We conducted a retrospective cohort study using data on 269 apatinib-treated GC patients in two clinical trials. AEs were assessed at baseline until 28 days after the last dose of apatinib. Clinical outcomes were compared between patients with and without hypertension (HTN), proteinuria or hand and foot syndrome (HFS) in the first 4 weeks using Kaplan–Meier methods, Cox proportional hazard regression and logistic regression models. Landmark analyses were performed as sensitivity analyses. Predictive model and risk scores were analyzed to predict overall survival (OS). Results: Presence of AEs in the first 4 weeks was associated with prolonged median OS (169 vs. 103 days, log-rank p=0.0039; adjusted hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.64-0.84, p=0.001), prolonged median progression-free survival (PFS, 87 vs. 62 days, log-rank p=0.0309; adjusted HR 0.69, 95%CI 0.53-0.91, p=0.007), and increased disease control rate (54.67% vs. 32.77%; adjusted odds ratio 2.67, p<0.001). Results remained significant in landmark analyses. An AE-based prediction model and subsequently derived scoring system showed high calibration and discrimination in predicting OS. Conclusions: Presence of HTN, proteinuria or HFS during the first cycle of apatinib treatment was a viable biomarker of antitumor efficacy in metastatic GC patients. [Table: see text]
Safety in numbers? Gastric cancer survival varies with total retrieved lymph nodes.
Authors: Tabatabaie Omidreza , Kasumova Gyulnara G. , van Roessel Stijn , Ukandu Promise , Ng Sing Chau , Schlechter Benjamin L. , Savarese Diane M. F. , Tseng Jennifer F.
Published: September 2018

4058

Background: Recently published AJCC 8thTNM-staging guidelines recommend a minimum of 16 lymph nodes be assessed in gastric cancer surgery with more lymph nodes ( 30) being desirable. However, the independent effects of greater numbers of lymph nodes excised on the overall survival of patients with gastric adenocarcinoma are understudied. Methods: National Cancer Database (NCDB) was reviewed from 2010 to 2014 for patients who underwent potentially curative surgery for gastric adenocarcinoma. Patients with zero or unknown number of harvested lymph nodes were excluded, as were those with metastatic or in-situ disease, or who received neoadjuvant chemo- or radiotherapy. Cox proportional hazards modeling was used for multivariate survival analysis. Results: Of the 12,507 patients who met selection criteria, 4,880 (39.0%) were female. The median age was 69 years [IQR: 59-77]. Median number of lymph nodes examined for each clinical T and N-stage is provided in the table. Overall, 51.0% of patients had < 16 lymph nodes examined. After adjusting for clinical T and N-stages, sex, age, tumor size, grade, facility type, receipt of adjuvant chemotherapy, resection type and race, and compared to patients with < 16 nodes examined, the hazard ratios for death in patients with 16-29, 30-44 and ≥45 examined lymph nodes were 0.87 (95% CI = 0.82-0.93), 0.79 (95% CI = 0.71-0.88) and 0.68 (95% CI = 0.56-0.83), respectively. Conclusions: Total lymph node count is an important independent predictor of overall survival in resectable gastric cancer, with an increased number of excised lymph nodes being associated with progressively decreased risk of death. These findings support the latest AJCC guidelines that higher number of lymph node retrieval is desirable. The recommended oncologic standard for at least 16 nodes to be assessed pathologically is not attained in more than half of upfront gastric resections performed for cancer. [Table: see text]
Treatment patterns for resected gastric cancer using the National Cancer Database.
Authors: Ogunleye Foluso Nelson , Sura Karna Tushar , Blankenship Leann , Ezekwudo Daniel , Gbadamosi Bolanle , Jaiyesimi Ishmael A. , Kabolizadeh Peyman
Published: September 2018

4061

Background: The optimal management of patients with resected gastric cancer remains a therapeutic challenge. Although the benefit of peri-operative chemotherapy or adjuvant concurrent chemoradiotherapy for these patients is clearly established, recurrence and mortality rates remain high despite aggressive treatment. The goal of this study was to characterize the treatment patterns employed for patients with resected gastric cancer using the National Cancer Database (NCDB). Methods: The NCDB was queried between 2004-2013 for patients with invasive resected gastric cancer and negative margins, excluding those with metastatic disease. Results: We identified a total of 21,156 cases. The median age was 67 (range 55-79). A majority of patients were white (74%) followed by black (14%) and other (12%). Most patients had either insurance through the government (58%) or private insurance (37%). 47% of patients had surgery alone with approximately 53% of these patients diagnosed with stage I gastric cancer. The remainder of the patients had radiation alone (1.4%), chemotherapy alone (15.2%), or combined chemotherapy and radiation (36.7%). Table 1 includes the further breakdown of treatment. Conclusions: A majority of patients with resected gastric cancer had treatment with either radiation, chemotherapy, or a combination of both. However, it is interesting to note that in patients receiving adjuvant or neoadjuvant treatment, only a portion of the patients received treatment options with level 1 evidence such as the MAGIC or McDonald regimens. [Table: see text]
A randomized, open-label, multicenter trial of the concurrent chemoradiotherapy of capecitabine with or without oxaliplatin versus cisplatin with 5-FU for Chinese squamous esophageal cancer: An interim report from CRTCOESC.
Authors: Jia Ruinuo , Shan Tanyou , Zhou Fuyou , Zheng Anping , Wan Lixin , Xu Zhiqiao , Zheng Guobao , Luo Xiaoyong , Zheng Yingjuan , Cui Yanhui , Zhang Guifang , Zhou Dan , Sun Jiachun , Kong Guoqiang , Yuan Xiaozhi , Yang Ruina , Ren Jing , Wang Wei , Wang Xinshuai , Gao Shegan
Published: September 2018

4063

Background: CRT with 5- FU and cisplatin (PF) has shown greater clinical efficacy for local advanced esophageal cancer (EC) but with high rate of acute toxicities (ATs). CRTCOESC is a randomized, open-label, multicenter trial designed to evaluate the effect and safety of capecitabine with or without oxaliplatin versus PF with CRT in Chinese EC. Methods: Pts with biopsy-proven squamous EC (T2-4N0-2M0) were randomized to single capecitabine (Arm1), capecitabine plus oxaliplatin (Arm2), or PF (Arm3), while daily radiation 50Gy/2Gy for all. Pts were stratified by different regimens cycles. Both grade3-5 ATs and 2-year OS were the primary endpoint, with a planned accrual of 249 pts to detect a decrease in Grade3-5 ATs from 40% to 20%. The secondary endpoint included objective response rate (ORR) and 2-year progression free survival (PFS). Interim analysis of ATs and ORR was planned for the first 120 pts. Results: The study accrued 128 pts from 2014.10-2016.12, 118 were eligible. 86 patients were finished 16-weeks follow-up at least and analyzed in the interim report (Arm1: Arm2: Arm3 = 24: 37: 25). There was no difference between three arms on pts pretreatment characters (age, gender, weight, performance status, clinical stage, lymphonodus status, and pathology grade). Incidence of grade3-5 ATs in Arm1/2/3 were 25%: 32.4%: 64% ( p = 0.03); it was significantly lower in Arm1/2 than Arm3 (Arm1 vs Arm3, p = 0.041; Arm2 vs Arm3, p = 0.022); and there no meaningful different between Arm1 and Arm2 ( p = 0.738). The pCR rate and ORR were 50%: 48.6%: 48% and 87.5%: 83.8%: 100% in Arm1/2/3 ( p = 0.99; p = 0.133). 56 patients had been finished 1 year follow-up (Arm1: Arm2: Arm3 = 12: 26: 18). The 1-year OS and PFS were 75%: 91.9%: 76% and 66.7%: 62.2%: 60% in Arm1/2/3 ( p = 0.166; p= 0.926). Conclusions: Compared with PF, CRT with single capecitabine with or without oxaliplatin shown lower incidence of ATs and similar ORR and 1-year OS. The single capecitabine seemly carried out a benefit of lower ATs than it plus oxaliplatin; there was no meaningful difference for them on ORR and 1-year OS. Ruinuo Jia and Tanyou Shan did equal work. Clinical trial information: NCT02025036.
Results of a phase II randomized study evaluating the potential benefit of a postoperative intraperitoneal immunotherapy after resection of peritoneal metastases from gastric carcinoma metastases (IIPOP- NCT01784900).
Authors: Goere Diane , Glehen Olivier , Mariette Christophe , Auperin Anne , Elias Dominique
Published: September 2018

4064

Background: Prognosis of patients with peritoneal extension from gastric carcinoma remains poor. The aim of this multicentre, open-label, phase 2 randomized study was to analyze the potential survival benefit of an immediate postoperative intraperitoneal immunotherapy using a bi-specific (anti-EpCAM, anti-CD3), trifonctional agent named catumaxomab. Methods: Patients with limited synchronous carcinomatosis from gastric carcinoma (Peritoneal cancer index (PCI) ≤ 12), were treated after complete resection (gastrectomy plus all peritoneal deposits), by an intraperitoneal infusion of catumaxomab during 5 days. Patients were randomized between 2 arms according to the total doses administered of catumaxomab (100µg vs 140µg). The first end-point was the 2-year overall survival (OS). Forty randomized patients were required (20 in each arm), considering that a 2-year OS rate ≤ 30% would be considered as unacceptable, and ≥ 55%, a promising survival rate. The study was stopped prematurely due to the manufacturing stop of the catumaxomab. Results: Between March 2013 and September 2014, 26 patients were included in the study; among them, 11 were randomized, with a median PCI of 9 [1-12]. Seven patients received the whole planned treatment of catumaxomab; in the remaining 4 patients, interruptions were related to postoperative complications. One patient died postoperatively of multiorgan failure and grade 3-5 complications occurred in all the patients, without difference between the 2 groups. At the end of the follow-up, 3 were alive (25, 30, 36 months). The median OS was 19 months, and the 1 and 2- year OS rates were 63.6% and 36.4% respectively. Conclusions: This study has to be stopped prematurely; however, encouraging results regarding overall survival were observed. Intraperitoneal immunotherapy represents an innovative and promising treatment in patients with peritoneal metastases, considering the poor response to systemic chemotherapy and the “immunocompetence” of the peritoneum. The evaluation of a potential benefit of a local immunotherapy has to be pursued. Clinical trial information: NCT01784900.
Updated antitumor activity and safety of FPA144, an ADCC-enhanced, FGFR2b isoform-specific monoclonal antibody, in patients with FGFR2b+ gastric cancer.
Authors: Catenacci Daniel V.T. , Rha Sun Young , Bang Yung-Jue , Wainberg Zev A. , Chao Joseph , Lee Keun Wook , Korn Wolfgang Michael , Kim Yeul Hong , Song Eun-Kee , Chiu Chang-Fang , Yen Chia-Jui , Berlin Jordan , Kim Jin-Soo , Sikorski Robert S. , Collins Helen , Clark Lee , Inamdar Sandeep P. , Zhang Charlie , Lee Jeeyun
Published: September 2018

4067

Background: FGFR2b-overexpressing gastric cancer is characterized by poor prognosis. FPA144, a humanized monoclonal IgG1 antibody that specifically binds to and blocks FGFR2b, has been engineered for enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). FPA144-001 is a two-part Phase 1 study of FPA144 monotherapy in patients with advanced solid tumors, including gastric and gastroesophageal cancers (GEJ cancers). Methods: Part 1A was a 3+3 design to assess safety and PK and to establish a recommended dose (RD) of FPA144. Patients with gastric cancer were enrolled in Part 1B to assess PK in gastric cancer. Part 2 includes 4 cohorts of gastric cancer patients with either high, moderate, low or no FGFR2b overexpression based on a centralized immunohistochemistry (IHC) assay. Here, we describe results of gastric cancer patients that highly overexpress FGFR2b (FGFR2b+ High) enrolled in Parts 1 and 2 of the study. Results: As of October 28, 2016, 18 FGFR2b+ High (IHC 3+ ≥10% tumor membrane staining) patients were enrolled in the study. 12 of these patients received the RD of 15 mg/kg every 2 weeks. Enrolled patients received a median of 3 prior treatment regimens. Fatigue (22.2%, none ≥ gr 3) and infusion reaction (16.7%, 5.6% gr 3) were the most common treatment-related AEs. Treatment-related SAEs were reported in 2 patients: Grade 2 ulcerative keratitis and Grade 3 infusion reaction. There were 5 PRs, 4 confirmed and 1 unconfirmed. Disease control (PR+SD) was 55.6%, including a confirmed ORR of 22% with median DOR of 15.4 weeks. ctDNA analysis of a responding patient revealed baseline elevated FGFR2 gene copy (165 copies in the blood, mutation allele burden 66%) that decreased after monotherapy (nadir 75 copies, mutation allele burden 38.5%) corresponding with clinical response, serum tumor markers and near complete response on PET imaging. Conclusions: The demonstration of activity and an acceptable safety profile supports further development of FPA144 in patients with FGFR2b+ tumors. FGFR2 gene amplification detected in ctDNA may provide a non-invasive diagnostic test for patient selection. Updated data will be presented. Clinical trial information: NCT02318329.
Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC).
Authors: Wainberg Zev A. , Segal Neil Howard , Jaeger Dirk , Lee Kyung-Hun , Marshall John , Antonia Scott Joseph , Butler Marcus , Sanborn Rachel E. , Nemunaitis John J. , Carlson Cheryl Ann , Finn Richard S. , Jin Xiaoping , Antal Joyce , Gupta Ashok Kumar , Massard Christophe
Published: September 2018

4071

Background: Durvalumab, an anti-PD-L1 mAb, has shown early and durable clinical activity with manageable safety in an ongoing Phase 1/2, multicenter, open-label study in pts with advanced solid tumors. Interim analyses from the HCC cohort in the dose-expansion part of this study are reported here. Methods: Patients with HCC (Child-Pugh class A) received durvalumab 10 mg/kg i.v. q2w for 12 months or until confirmed progressive disease, whichever occurred first. The primary objective was to evaluate the safety profile; secondary objective was to assess the antitumor activity (investigator-assessed RECIST v1.1). Clinical activity was evaluated for the total HCC population and by viral status. Results: As of Oct 24 2016, 40 HCC pts with median 23.9 (range 2.4–34.7) weeks follow-up received durvalumab. 93% had prior sorafenib. Treatment-related AEs occurred in 80.0% of pts, most commonly fatigue (27.5%), pruritus (25.0%) and elevated aspartate aminotransferase (AST) (22.5%). Grade 3–4 treatment-related AEs were reported in 20.0% of pts, most commonly elevated AST (7.5%) and elevated alanine aminotransferase (5.0%). 7 (17.5%) pts completed the initial 12-month treatment and 7 (17.5%) pts discontinued treatment because of an AE (none related to treatment). There were no deaths due to treatment-related AEs. Clinical activity is presented in the table. 4 pts achieved a PR; 2 were ongoing at data cut-off. Conclusions: Durvalumab had an acceptable safety profile and showed promising antitumor activity and OS in pts with HCC, particularly HCV+ pts. Clinical trial information: NCT01693562. [Table: see text]
Theranostic trial of well differentiated neuroendocrine tumors (NETs) with somatostatin antagonists 68Ga-OPS202 and 177Lu-OPS201.
Authors: Reidy Diane Lauren , Pandit-Taskar Neeta , Krebs Simone , O' Donoghue Joseph A. , Raj Nitya Prabhakar , Cruz Elizabeth , Pham Hanh , Lashley Alicia , Bodei Lisa , Weber Wolfgang
Published: September 2018

4094

Background: Radiolabeled somatostatin receptor 2 (sstr2) antagonists have shown higher tumor uptake and tumor-to-organ ratios than agonists in preclinical models. We performed a phase I study to evaluate the safety and radiation dosimetry of the sstr2 antagonists 68Ga-OPS202 and 177Lu-OPS201 (68Ga/177Lu-DOTA-JR11) in patients (pts) with metastatic well differentiated NETs (NCT02609737). Efficacy data after 177Lu-OPS201were recorded. Methods: Pts with RECIST disease progression underwent a 68Ga-OPS202 PET/CT to confirm in-vivo binding of the sstr2 antagonists and if positive, underwent treatment with 3 doses of 177Lu-OPS201. The first dose of 50 mCi 177Lu-OPS201was used to calculate tumor and normal organ radiation doses. Dosimetry was then calculated to administer 177Lu-OPS201in divided doses for the 2nd and 3rdfractions, 8-10 weeks apart. Results: 19 pts enrolled (primary tumors: 1 lung, 7 small bowel, 8 pancreatic NETs, 1 gastric NET, 1 rectal NET, 1 kidney). Average age was 55 y (22-73 y), 52% female; mean number of prior treatments was 3. All pts received 1 therapeutic dose of 177Lu-OPS201, 7 pts received 2 doses. All tumors were visualized by 68Ga-OPS202 PET/CT. With the exception of the kidneys and bladder, no organ demonstrated uptake of 68Ga-OPS202 above background. Tumor radiation doses ranged from 0.15 Gy/mCi to 0.48 Gy/mCi. Subacute hematologic toxicity after cycle 1 was mild-moderate (G3 2/19 leukopenia that reversed before cycle 2). 4/7 (57%) pts that received the second dose of 177Lu-OPS201had G4 hematological toxicities, which occurred 4-6 weeks after administration. G 3/4 toxicities in the four pts have resolved to G2 or lower; none of these pts demonstrated fever, infection, bleeding, or renal toxicity. Substantial efficacy was observed: 1 patient achieved a CR (1/19, 5%), 32% PR (6/19), 47% SD (9/19) and 16% POD (3/19). Median PFS has not yet been reached. Conclusions: In this trial of heavily treated NETs, preliminary data are promising for the use of 68Ga-OPS202/177Lu-OPS201 as a theranostic combination for imaging and therapy. Additional studies are planned to determine an optimal therapeutic dose and schedule. Clinical trial information: NCT02609737.
Use of antiresorptive therapy (ART) and skeletal-related events (SREs) in patients with bone metastases of neuroendocrine neoplasms (NEN).
Authors: Apostolidis Leonidas , Jaeger Dirk , Winkler Eva Caroline
Published: September 2018

4096

Background: Antiresorptive therapy (ART) with bisphosphonates or denosumab is effective in preventing skeletal-related events (SREs) in patients with bone metastases (BM). In neuroendocrine neoplasms (NEN), BM are a negative prognostic factor, however tend to be asymptomatic and SREs are considered a rare event. The role of ART in preventing SREs in NEN has not been investigated so far. Methods: Retrospective analysis of all patients with bone metastases in the NEN database of the National Center for Tumor Diseases who presented at our center between 12/2012 and 01/2017. Overall survival (OS) from diagnosis of BM as well as time to SRE (TTSRE) were calculated. In patients experiencing an SRE within 1 month after diagnosis (i.e. before efficacy of ART could be assessed), TTSRE was defined as the time to a subsequent SRE. Results: In a total of 513 patients in the database, 108 patients with BM could be identified. Median OS was not reached in a median follow-up of 15.2 months. ART was applied to 42.6 % of patients. OS with or without ART did not differ significantly (p = 0.2538). 28.7 % of patients experienced at least 1 SRE, 20.4 % after more than 1 month. Median TTSRE was 63.8 months with ART and 127.0 months without ART (p = 0.1751). TTSRE was shortened in grade 3 vs. grade 1+2 NEN (172 months vs. not reached, HR 4.058, p = 0.0032), as well as in lytic vs. non-lytic metastases (24.5 vs. not reached, HR 7.319, p < 0.0001), however not significantly different in oligometastatic vs. disseminated bone disease (not reached vs. 63,8 months, HR 1.415, p = 0.4287). Application of ART did not significantly change TTSRE in either of these subgroups. Significant toxicity attributable to ART was observed in 15.2 % of ART patients. Conclusions: SREs in NEN patients with BM were not uncommon, especially in patients with grade 3 NEN and osteolytic metastases. Application of ART did not significantly alter median OS or TTSRE, no subgroup with a benefit of ART could be identified. The use of ART in NEN should be questioned and evaluated prospectively.
TAS-118 (S-1 plus leucovorin) versus S-1 in gemcitabine-refractory advanced pancreatic cancer: A randomized, open-label, phase III trial (GRAPE trial).
Authors: Ueno Makoto , Ioka Tatsuya , Ueno Hideki , Park Joon Oh , Chang Heung-Moon , Sasahira Naoki , Kanai Masashi , Chung Ik-Joo , Ikeda Masafumi , Nakamori Shoji , Mizuno Nobumasa , Omuro Yasushi , Yamaguchi Taketo , Hara Hiroki , Sugimori Kazuya , Furuse Junji , Takeuchi Masahiro , Okusaka Takuji , Boku Narikazu , Hyodo Ichinosuke
Published: September 2018

4099

Background: Addition of oral leucovorin (LV) to S-1 significantly improved progression-free survival (PFS) in a previous randomized phase II trial in Japanese patients (pts) with gemcitabine (GEM)-refractory advanced pancreatic cancer (PC). TAS-118 is an oral drug containing S-1 and LV. This phase III trial conducted in Japan and Korea compared overall survival (OS) between GEM-refractory advanced PC pts treated with TAS-118 and S-1. Methods: GEM-refractory PC pts were randomized in a 1:1 ratio to receive TAS-118 (S-1; 40-60 mg and LV; 25 mg bid for 1w, q2w) or S-1 (S-1; 40-60 mg bid for 4w, q6w). The primary endpoint was OS. The secondary endpoints included PFS, overall response rate, disease control rate, duration of response, and safety. Results: Five hundred and eighty-six pts were eligible for efficacy assessment (TAS-118: n=296 and S-1: n=290). Baseline characteristics were well balanced between the treatment arms. TAS-118 did not result in a statistically significant improvement in OS compared with that achieved with S-1 (median OS, 7.6 months vs. 7.9 months; hazard ratio [HR], 0.98; 95% CI, 0.82 to 1.16; P=0.756). However, it significantly improved PFS compared to that achieved with S-1 (median PFS, 3.9 months vs. 2.8 months; HR, 0.80; 95% CI, 0.67 to 0.95; P=0.009). Pre-planned subgroup analysis of OS showed significant interactions between the treatment effects and pancreatic resection (P=0.025), and between the treatment effects and country (P=0.004). Grade 3/4 drug-related adverse events (≥5% incidences) in TAS-118 and S-1 arms included diarrhea (7.0% vs. 7.3%), anorexia (6.7% vs. 5.0%), stomatitis (6.7% vs. 0.7%), and anemia (3.3% vs. 5.0%). Conclusions: The primary endpoint was not met. Further, the interactions between the treatment effects and pancreatic resection, and between the treatment effects and country, might affect the results. Clinical trial information: 132172. [Table: see text]
A randomized phase II trial comparing different schedules of nab-paclitaxel (nabP) combined with gemcitabine (GEM) as first line treatment for metastatic pancreatic adenocarcinoma (mPDAC).
Authors: Corrie Philippa , Qian Wendi , Basu Bristi , Valle Juan W. , Falk Stephen , Iwuji Chinenyu , Wasan Harpreet Singh , Palmer Daniel H. , Scott-Brown Martin , Wadsley Jonathan , Arif Seema Safia , Bridgewater John A. , Propper David , Gillmore Roopinder , Gopinathan Aarthi , Bax Lisa , Machin Andrea , Neesse Albrecht , Tuveson David A. , Jodrell Duncan Ian
Published: September 2018

4100

Background: NabP+GEM chemotherapy improves survival compared with GEM monotherapy as treatment for mPDAC. A PDAC mouse model suggested that nabP potentiates GEM activity by reducing cytidine deaminase levels and scheduling may be critical to optimise clinical benefit. Methods: Patients (pts) were randomised to receive standard concomitant (CON) nabP+GEM or sequential (SEQ) administration, with nabP given 24 hours before GEM. After 6 cycles, pts benefiting from treatment could continue the same regimen until disease progression. The primary endpoint was progression-free survival (PFS) by RECIST v1.1; secondary endpoints included safety, objective response rate (ORR), overall survival (OS) and quality of life (QoL). Serial blood and baseline tumour samples were collected for exploratory biomarkers. Results: Between March 2014 and 2016, 146 pts (71 SEQ, 75 CON) were recruited. Median age (range) was 66 (45-82) years; Karnofsky performance status was 70 (in 12% pts), 80 (27%), 90 (38%) or 100 (24%); 47% had pancreatic head primaries; 84% had liver metastases. Median no. cycles received was 4 SEQ, 3 CON; 51 pts (35%) received ≥6 cycles of treatment (42% SEQ, 28% CON). A 24+2hr interval was achieved in > 90% SEQ admin. Grade ≥3 adverse events experienced by ≥10% pts (SEQ, CON) were neutropaenia (54%, 30%; p = 0.003), febrile neutropaenia (12%, 12%), fatigue (22%, 15%), vomiting (7%, 11%) and anaemia (10%, 5%). G-CSF was administered at local investigator's discretion to 35 pts (23 SEQ, 12 CON; p = 0.015). To date, 112 pts have died. 6 month (m) PFS by SEQ and CON arms were 47% and 33%; median PFS were 5.8 and 4.0m; hazard ratio (HR) = 0.66, 95% CI = 0.46-0.95; 12m OS by SEQ and CON arms were 29% and 26%; median OS were 10.1 and 7.9m; HR = 0.88, 95% CI = 0.61-1.29. ORR was 50% SEQ and 33% CON (p = 0.065). Mean baseline QoL Global health status score was 60.6 SEQ and 63.4 CON. The mean change in QoL score from baseline at 24 weeks was -2.1 SEQ and -12.1 CON. Conclusions: Sequential delivery of nabP combined with GEM trended towards improving all clinically relevant efficacy end points: PFS, OS, and ORR. Translational correlates will be reported in due course. Clinical trial information: ISRCTN71070888.
Prospective assessment for pathogenic germline alterations (PGA) in pancreas cancer (PAC).
Authors: Jordan Emmet , Lowery Maeve Aine , Wong Winston , Kemel Yelena , Mukherjee Semanti , Ravichandran Vignesh , Basturk Olca , Yu Kenneth H. , Iacobuzio-Donahue Christine , Lincoln Anne , Varghese Anna M. , Abou-Alfa Ghassan K. , Leach Steven D , Klimstra David S. , Allen Peter J. , Robson Mark E. , Stadler Zsofia Kinga , Vijai Joseph , Offit Kenneth , O'Reilly Eileen Mary
Published: September 2018

4102

Background: Cancer predisposition syndromes are identified in a subset of PAC. Identifying PGA has implications for therapy as well as for cancer predisposition in blood relatives. Germline testing (GT) in the US is currently performed in a small subset of PAC patients according to NCCN/other guidelines. At MSKCC, we have implemented an ‘opt in’ strategy to perform germline testing in all patients evaluated in PAC clinics at MSKCC. Methods: PAC pts consented prospectively for GT had samples analyzed for pathogenic or likely pathogenic variants using the MSK-IMPACT germline platform (NCT01775072). All pts first had somatic profiling of tumor samples for > 340 genes by MSK-IMPACT. Clinicopathological features, time to progression on platinum (TTPP) and overall survival (OS) were collated. Results: N = 305 PAC pts consented for GT between 9/2015-11/2016.164/305 (54%) were male, 70/305 (23%) were Ashkenazi Jewish. 242 pts (79%) had a family hx of cancer. 67/305 (22%) had a GA identified, 45/67 (67%) were stage III/IV at dx. Median age at PAC dx for all GA carriers was 60 years (y) (range 29-81) compared to 66 y (18-69) without GA. Median age at dx was 54 y (32-68) for BRCA1 and 61 y (37-77) for BRCA2 GA. 3/9 and 3/20 pts with BRCA1/2 GA had a PAC dx < 50 y. 2/63 pts (3%) with no family hx had a GA (CDKN2A, PMS2). N = 5/22 pts (23%) with a 1st degree relative (DR) with PAC had a GA. N = 13/45 pts (29%) had a GA with either a 1st or 2nd DR with PAC. 19/84 pts (23%) with ≥2 1stDR with cancer had a GA detected. For median OS and TTP on platinum therapy, see Table. Pts with BRCA1/2, ATM and those with coexisting GA tended to have a better median OS as well as longer TTP on platinum therapy (Table). Conclusions: GA’s are significantly under identified in PAC using current practices with a high, frequency (22%) observed in this relatively unselected cohort. BRCA mutations are the most frequent GA noted. There are significant implications of these observations for therapy and for blood relatives. [Table: see text]
Defining DDR defectiveness in pancreatic cancer.
Authors: Dreyer Stephan , Paulus-Hock Viola , Lampraki Eirini-Maria , Bailey Peter , Chang David Kuang-Fu , Biankin Andrew
Published: September 2018

4115

Background: Recent whole genome sequencing analysis of Pancreatic Cancer (PC) revealed that up to 24% of PC may harbor defects in DNA damage response (DDR). There is increasing evidence that DDR defective tumors preferentially respond to DNA damaging agents, representing novel therapeutic strategy for PC using a synthetic lethality approach. The aim of this study is to define and refine DDR defective phenotypes in PC using next-generation preclinical model systems. Methods: From a panel of 40 patient-derived cell lines (PDCL) and 64 patient-derived xenografts (PDX), generated and extensively characterized as part of the International Cancer Genome Initiative (ICGC), we identified DDR defective models using recently described putative biomarkers of DDR defectiveness. Cytotoxic viability assays were performed using a panel of DNA damaging agents and inhibitors of key molecules in DDR pathway, including Cisplatin, PARP inhibitors, ATR inhibitor (AZD6738); and ATM inhibitor (AZD0156). Appropriate subcutaneous PDX models were also generated to test the hypothesis using various therapeutic regimens. Results: DDR defective PDCLs were selected based on a combination of an unstable genome, and/or a high BRCA mutational signature, and/or deleterious mutations in BRCA1/2, PALB2 or ARID1A. DDR defective PDCLs were significantly more sensitive to Cisplatin, PARP and ATR inhibitors. The ATR inhibitor AZD6738, and ATM inhibitor AZD0156 sensitized PDCLs with no putative biomarkers of DDR defectiveness to Cisplatin, demonstrating a ‘fabricated’ synthetic lethality. A BRCA1 mutant PDX model responded exceptionally to Cisplatin and the PARP inhibitor Olaparib monotherapy. Conclusions: This study provides proof of concept data that DDR deficiency represents an attractive segment to target in PC using a variety of DNA damaging agents and novel agents targeting key molecules of the DDR pathway in PC. In addition, the DDR defective segment may be significantly larger than just germline BRCA1/2 mutants, which is current clinical trial recruitment criteria. Robust molecular assays with clinical utility to define DDR defectiveness is urgently needed.
Cancer predisposing germline mutations in patients (pts) with urothelial cancer (UC) of the renal pelvis (R-P), ureter (U) and bladder (B).
Authors: Carlo Maria Isabel , Zhang Liying , Mandelker Diana , Vijai Joseph , Cipolla Catharine Kline , Robson Mark E. , Funt Samuel , Hakimi A. Ari , Iyer Gopa , Rosenberg Jonathan E. , Coleman Jonathan , Solit David B. , Offit Kenneth , Bajorin Dean F.
Published: September 2018

4510

Background: Urothelial cancers (UC) are suspected to have a substantial hereditary component, but other than highly penetrant genes such as those in mismatch-repair pathway (e.g. MSH2) typically associated with R-P/U primaries, heritable gene mutations have not been systematically studied. We sought to investigate the prevalence of known cancer pre-disposing germline mutations in pts with UC originating from all sites within the urinary tract. Methods: Pts with R-P, U and B primaries, unselected for suspicion of inherited cancer syndrome, were prospectively enrolled from medical oncology and urology clinics to a germline sequencing protocol from June 2016 to January 2017. Germline gene analysis was performed in a CLIA-certified lab using a next generation sequencing (NGS) platform (MSK-IMPACT) that analyzes tumor-normal DNA pairs. The germline gene panel consisted of 76 genes associated with hereditary cancer predisposition. Results: As of January 24, 2017, 101 pts have NGS results available, with median age 63 (31-87), 76% male, 24% female. Primary sites were B (67%), R-P/U (31%), or both (3%). 73% had organ-confined disease and 27% had metastases. 8% had early onset (≤45 yrs at diagnosis), 10% had a family history of UC, 25% had documented non-UC cancers. 25 pathogenic or likely pathogenic (P-LP) mutations were identified in 22 patients. P-LP mutations were present in 29% of pts with R-P/U primaries and 18% of pts with B primaries. 12 DNA damage response gene alterations were found (4 CHEK2, 3 BRCA1, 2 BRCA2, 1 ATM, 1 BRIP1, 1 NBN) and 8 in Lynch syndrome associated genes (5 MSH2, 2 MSH6, 1 MLH1). Other mutations include 2 APC, 1 TP53, and 1 FH. Notably 3 pts had 2 alterations each ( MSH6/ APC, BRCA2/ APC, BRCA1/ CHEK2). 9/22 pts with P-LP mutations did not meet American College of Medical Genetics criteria for genetic screening. Conclusions: 22% of UC pts had a germline mutation in a cancer-associated gene. There was an unexpectedly high frequency of pts with DNA-repair pathway mutations. Active accrual is ongoing to define the full spectrum of alterations. These results have profound implications for genetic counseling and screening and further studies are warranted.
Health-related quality of life as a marker of treatment benefit with nivolumab in platinum-refractory patients with metastatic or unresectable urothelial carcinoma from CheckMate 275.
Authors: Necchi Andrea , Grimm Marc-Oliver , Retz Margitta , Arranz Arija Jose Angel , Bracarda Sergio , Bedke Jens , Baron Ari David , Sharma Padmanee , Galsky Matt D. , Vaena Daniel A. , Kalinka-Warzocha Ewa , Cwikiel Magdalena , Pal Sumanta K. , Morales Rafael , Taylor Fiona , Gooden Kyna McCullough , Plimack Elizabeth R.
Published: September 2018

4526

Background: CheckMate 275 (NCT02387996), a phase II, single-arm study of nivolumab (3 mg/kg every 2 weeks) treatment in platinum-refractory patients (pts) with metastatic urothelial carcinoma, showed an objective response rate of 19.6% (95% CI, 15.0%–24.9%) with manageable toxicity. The objective of this analysis was to examine the impact of nivolumab on health-related quality of life (HRQoL) in the study. Methods: HRQoL was measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and three-level EQ-5D (EQ-5D-3L) and visual analog scale (VAS). Questionnaires were completed at baseline and every 8 weeks thereafter for the first 48 weeks. The analysis cohort included pts with scores recorded at baseline and ≥1 postbaseline assessments while on treatment. Data were analyzed using mixed models, adjusting for baseline score. Results: Of the 270 patients treated with nivolumab, 168 (62%) had an assessment at baseline and ≥1 postbaseline assessment and were included in HRQoL analyses. Completion rates at baseline were 97% for both questionnaires. Statistically significant ( P< 0.05) improvements in mean scores for the EORTC QLQ-C30 subscales measuring role, emotional, and social functioning; global health status/quality of life; nausea/vomiting; pain; dyspnea; insomnia; appetite loss; constipation; and diarrhea were observed at ≥1 time points. With the exception of cognitive functioning, no significant worsening in subscale scores was observed in the EORTC QLQ-C30. Statistically significant and clinically meaningful improvement (based on a minimally important difference of 7) in EQ-5D VAS was noted between weeks 17 and 41. EQ-5D-3L utility index scores based on the UK tariff remained stable during treatment. Conclusions: Results of CheckMate 275 indicate that pts with metastatic or unresectable urothelial carcinoma whose disease progressed or recurred after treatment with a platinum agent exhibited stable, or in some cases statistically significantly improved, HRQoL while being treated with nivolumab, as measured by EORTC QLQ-C30 and EQ-5D-3L. Clinical trial information: NCT02387996.
Survival outcomes in elderly patients with muscle invasive bladder cancer: An analysis of the National Cancer Database.
Authors: Fischer-Valuck Benjamin Walker , Rao Yuan , Rudra Soumon , Hui Caressa , Baumann Brian , Gay Hiram Alberto , Michalski Jeff M.
Published: September 2018

4538

Background: Many elderly patients are precluded from radical cystectomy (RC) due to existing comorbidities or morbidities associated with RC. Chemoradiation therapy (CRT) is an alternative treatment in this population, but remains widely under-utilized with many receiving chemotherapy (CT) or radiation therapy (RT) alone. This population-based analysis sought to determine if CMT has similar overall survival (OS) to RC, and if CRT is associated with improved OS compared to monotherapy in these patients. Methods: We queried the National Cancer Database (NCDB) for all newly diagnosed MIBC (cT2-T4a N0 M0) cases in patients aged 80 years or older from 2004 to 2013. All included patients underwent TURBT followed by RC, RT alone, CT alone, CRT, or no further treatment. Only patients with radiation doses ( > = 50Gy) were included as receiving RT. Kaplan-Meier, log-rank, and multivariate Cox proportional hazards regression was performed with OS as the primary outcome. Results: 10,055 patients aged > = 80 years were identified. 1,588 underwent RC, 839 received RT, 1,013 received CT, 1,035 had CRT, and 5580 had no further treatment. Mean age was 85.1 years (range, 80-90). 82.1% of patients had Stage II disease. Mean follow-up was 27.6 months (range, 0-137.8). Mean survival of the entire cohort was 28.0 months (95% CI, 27.2-28.8). Mean survival was 43.8 months (95% CI, 41.2-46.3) for patients with RC and 40.8 months (95% CI, 38.2-43.3) for CRT (P = 0.85). Mean survival was 29.1 months (95% CI, 26.8-31.4) and 30.7 months (95% CI, 28.2-33.2) for RT alone vs. CT alone, respectively (P < 0.0001 for both RC and CRT comparisons). 5-year OS for CT alone, RT alone, CRT, and RC was 15.7%, 15.1%, 24.0% and 29.6%, respectively. Multivariate analysis adjusting for age, year of diagnosis, gender, race, treatment location, treatment facility, insurance status, Charlson/Deyo Score, grade, and stage demonstrated an OS benefit in favor of CRT (HR 0.70; 95% CI, 0.63-0.77; P < 0.0001) and RC (HR 0.69; 95% CI, 0.63-0.76; P < 0.0001). Conclusions: For elderly patients with MIBC, both RC and CRT were associated with improved OS compared to CT or RT alone. CRT has similar OS compared to RC, and could be considered standard treatment in this population.
Thromboembolic events after high-intensity training during cisplatin-based chemotherapy for testicular cancer.
Authors: Thorsen Lene , Fossa Sophie D. , Haugnes Hege Sagstuen , Tandstad Torgrim , Brydoy Marianne , Wisloff Torbjorn , Edvardsen Elisabeth , Gjerset Gunhild Maria , Larsen Karl-Otto , Sandset Per Morten , Henriksson Carola , Negaard Helene FS
Published: September 2018

4551

Background: Physical activity (PA) is believed to reduce acute side-effects as deconditioning, fatigue and nausea during chemotherapy and enhance post-treatment physical and psychosocial recovery. The national multicenter randomized TAST-trial (clinicaltrial.gov: NCT02577172) aimed to determine the effect of high-intensity training (HIT) during chemotherapy for testicular cancer (TC) on acute and post-treatment physical- and psychosocial outcomes. Methods: Patients aged 18 – 60 years with newly diagnosed metastatic TC, planned for 3 or 4 cisplatin-based chemotherapy cycles in combination with etoposide (EP) or etoposide plus bleomycin (BEP), were randomized to HIT during 9 or 12 weeks of chemotherapy or to one lifestyle counseling session (LCS) during first cycle. The HIT included two supervised endurance interval sessions per week, of which 10-15 minutes per session at 85 – 95 % of peak heart rate. The intensity, duration and number of the intervals were predetermined, but adjusted in accordance to the patients’ daily condition. Thromboembolic (TE) complications were registered consecutively. Results: Among the first 9 patients randomized to HIT, 33% (3 patients aged 22, 30 and 44 years) developed severe TE complications; 2 cases of pulmonary embolism (respectively at day 9 and 7 of BEP cycle 2) and 1 myocardial infarction (at day 7 of BEP cycle 3). Common for these patients were non-seminoma TC, clinical stage IIA, good prognosis group and no known risk factors for TE events. TE complications were not observed among the 10 patients randomized to the LCS. Conclusions: Since TC patients within good prognosis group are expected to have about 5 % risk of TE complications during or shortly after cisplatin-based chemotherapy, we cannot exclude that the HIT may have contributed to the unexpected high number of TE events. Until possible mechanisms explaining our observations have been explored, we discourage high-intensity endurance training during cisplatin-based chemotherapy for TC. These observations led to closure of the TAST-trial after inclusion of 19 of 94 planned patients. Clinical trial information: NCT02577172.