bluuebunny/crossref_metadata_2025_split huggingface dataset:
SHR-1210 plus GEMOX as first line treatment in biliary tract cancer: Results from a single-arm exploratory study.
Authors: Chen Xiaofeng , Wu Xiaofeng , Wu Hao , Shao Qianwen , Zhu Feipeng , Qian Xiaofeng , Zhao Fengjiao , Sun Jing , Wang Jian , Han Gaohua , Zhu Dongqin , Zhu Liuqing , Shao Yang , Gu Yanhong , Li Xiangcheng , Shu Yongqian 
Published: May 2019

4092 Background: SHR1210 is a humanized anti-programmed cell death receptor 1 (PD-1) antibody. We conducted a single arm exploratory study to evaluate the efficacy and safety of SHR-1210 plus gemcitabine and oxaliplatin (GEMOX) as first line treatment in patients (pts) with biliary tract cancer (BTC). Methods: Pts received SHR-1210 (3mg/kg, total dose ≤200mg, ivd, D1/2W) combined with gemcitabine (800 mg/m2, ivd, D1/2W) and oxaliplatin (85mg/m2, ivd, D2/2W). Combined chemotherapy lasted for no more than 8-12 cycles. Once chemotherapy intolerance occurred or at end of 12-cycle combined chemotherapy, pts with stable disease or objective response would continue to take SHR-1210 as single agent until disease progression or intolerable toxicity. Response was assessed every 8 weeks. Results: From February 2018 to Dec 15, 2018, 32 eligible pts were recruited, and 27 pts who had been treated for more than 2 months were included in this analysis. Median age was 64 (range 47-75) years. 16 pts were bile duct cancer, while 11 pts were gallbladder cancer. 26 pts can be evaluated for efficacy. Twelve pts achieved partial response (46.15%), 12 pts stable disease (46.15%), and 2 pts progressive disease. Pts with gallbladder cancer had the trend of higher objective response (63.64% vs 33.33%, p = 0.23) than those with cholangiocarcinoma. 19 pts had tissue sample for next generation sequencing. Gallbladder cancer had the tendency of higher median tumor mutation burden (TMB) than cholangiocarcinoma (8.1mut/Mb vs 5.4mut/Mb, p=0.33). Pts with high TMB(>8.6 mut/Mb, based on geenseeq BTC database) had significantly higher objective response than low TMB (100% vs 26%, p=0.0294). The most common grade ≥3 adverse events were nausea (18.52%),increased GGT (gammaglutamyltransferase,18.52%), hypokalemia(18.52%) and fatigue (18.52%). Conclusions: SHR-1210 plus GEMOX showed promising efficacy with tolerable adverse events for BTC pts. Gallbladder cancer pts seem to benefit more from this treatment. Tumor mutation burden may be a predictive factor for immunotherapy. Clinical trial information: NCT03486678.
Randomized, open-label, perioperative phase II study evaluating nivolumab alone or nivolumab plus ipilimumab in patients with resectable HCC.
Authors: Kaseb Ahmed Omar , Carmagnani Pestana Roberto , Vence Luis M. , Blando Jorge M. , Singh Shalini , Ikoma Naruhiko , Raghav Kanwal Pratap Singh , Sakamuri Divya , Girard Lauren , Tan Dongfeng , Vauthey Jean-Nicolas , Tzeng Ching-Wei David , Aloia Thomas A. , Chun Yun Shin , Yao James C. , Wolff Robert A. , Allison James Patrick , Sharma Padmanee 
Published: May 2019

4098 Background: In HCC, surgical resection is associated with high recurrence rate, and no effective neoadjuvant or adjuvant therapies currently exist. On the basis of of previous reports on the efficacy and safety of anti–PD-1 (nivolumab) and anti–CTLA-4 (ipilimumab) antibodies against HCC, we initiated a randomized pilot trial of perioperative immunotherapy for resectable HCC. Methods: This is a randomized, phase II pilot trial of nivolumab (Arm A) or nivolumab + ipilimumab (Arm B) as pre-operative treatment for patients (pt) with HCC who are eligible for surgical resection. Pt are given nivolumab 240 mg every 2 weeks (wk) for a total of 6 wk. Pt in Arm B are treated concurrently with ipilimumab 1 mg/kg every 6 wk. Surgical resection occurs within 4 weeks after last cycle of therapy. Pt continue adjuvant immunotherapy for up to 2 years after resection. Primary objective is the safety and tolerability of nivolumab +/- ipilimumab. Secondary objectives include overall response rate, complete response rate and time to progression. Exploratory objectives include evaluating the pre- and post-treatment immunological changes in tumor tissues and peripheral blood. Results: 17 pt were enrolled at the time of interim analysis (8 in Arm A, 9 in Arm B) and 14 were evaluable. Most pt (53%) were 60-70yo, and males (70%). 6 pt were HCV-positive and 4 had chronic hepatitis B. 14 pt proceeded with resection as planned; surgery was aborted for 2 pt (1 for frozen abdomen and 1 for development of contralateral liver nodule). One is still receiving preoperative therapy. Pathologic complete response (pCR) was observed in 4/14 evaluable pt – 2 in Arm A and 2 Arm B (29% pCR rate). 4 pt in Arm B and 1 in Arm A experienced grade 3 or higher toxicity prior to surgery. Conclusions: We report a pCR rate of 29% in an interim analysis of a phase II pilot trial of perioperative immunotherapy for resectable HCC. Treatment was safe and surgical resection was not delayed. The study is ongoing and results may contribute to a paradigm shift in the perioperative treatment of HCC. Clinical trial information: NCT03222076.
A phase I study of oncolytic immunotherapy of metastatic neuroendocrine tumors using intralesional rose bengal disodium: Cohort 1 results.
Authors: Price Timothy Jay , Cehic Gabby , Wachter Eric Andrew , Kirkwood Ian , Sebbon Rubin , Leopardi Lisa , Reid Jessic , Alawawdeh Anas , Neuhaus Susan J , Maddern Guy 
Published: May 2019

4102 Background: Metastatic neuroendocrine neoplasms (mNEN’s) originating in the gastrointestinal tract are frequently slow growing yet both symptom and disease control remain important. Treatment options include resection, chemoablation, systemic somatostatin analogues (SSA) or peptide receptor radionuclide therapy (PRRT), but additional options are needed and one such option is hepatic intralesional (IL) rose bengal disodium (PV-10), an oncolytic immunotherapy under development for solid tumours. Methods: This phase 1 study is evaluating the safety, tolerability and reduction of biochemical markers and symptoms resulting from percutaneous administration of PV-10 in 12 subjects with progressive mNEN with hepatic lesions not amenable to resection or other potentially curative therapy. Target lesion(s) must be 1.0 - 3.9 cm in longest diameter. In Cohort 1 (n = 6) subjects receive PV-10 to a single hepatic lesion per treatment cycle, and can receive PV-10 to additional uninjected hepatic lesions ≥6 weeks after prior injection. Cohort 2 (n = 6) subjects may receive injection of multiple lesions per treatment cycle. The primary endpoint is safety. Secondary endpoints include objective response rate (ORR) assessed by contrast enhanced CT and 68Ga-DOTATATE PET, biochemical response (CgA) and patient-reported outcome (EORTC QLQ-C30 and GI.NET21). Results: Cohort 1 has fully enrolled, with 4 of 6 subjects male, median age 65yrs, range 47-72. Primary sites were: small bowel 3, pancreas 2, caecal 1; grade: Gd1 = 5, Gd2 = 1. All patients received prior SSA and PRRT. Median CgA was 645 (range 30-2819). To date 1 subject has received 4 PV-10 treatment cycles, 1 has received 2 cycles, and 4 have received a single cycle. Toxicity has been acceptable, including pain post procedure, carcinoid flare and nausea. LFT’s have remained stable. Overall QOL score was stable for 5 of 6 subjects. ORR in injected lesions is 50% (progression in 1 subject), with overall disease control of 84%. CgA response: 5 stable, 1 progression. One subject with “carcinoid pellagra” had rash resolution. Response follow-up is ongoing and additional efficacy and functional data will be presented. Conclusions: Hepatic IL PV-10 elicited no safety concerns with encouraging evidence of both local and systemic disease control. Enrolment to Cohort 2 is underway. Clinical trial information: NCT02693067.
Final results of the TALENT trial (GETNE1509): a prospective multicohort phase II study of lenvatinib in patients (pts) with G1/G2 advanced pancreatic (panNETs) and gastrointestinal (giNETs) neuroendocrine tumors (NETs).
Authors: Capdevila Jaume , Fazio Nicola , Lopez Lopez Carlos , Teule Alex , Valle Juan W. , Tafuto Salvatore , Custodio Ana B. , Reed Nicholas , Raderer Markus , Grande Enrique , Garcia-Carbonero Rocio , Jiménez-Fonseca Paula , Alonso Vicente , Antonuzzo Lorenzo , Spallanzani Andrea , Berruti Alfredo , Sevilla Isabel , La Casta Munoa Adelaida , Hernando-Cubero Jorge , Ibrahim Toni 
Published: May 2019

4106 Background: Approved systemic therapies for advanced NETs have showed limited tumor shrinkage and no data of activity after progression to prior targeted agents (TA) is available. Lenvatinib, a potent VEGFR1-3 & FGFR1-4 inhibitor may increase efficacy and revert primary and acquired resistance to TA. We report the final results of the TALENT trial. Methods: Two independent cohorts were included: panNETs and giNETs. All pts had baseline documented progression disease (PD) by RECIST. For panNETs, PD to TA was mandatory, regardless of prior therapy with somatostatin analogs (SSAs) or chemotherapy (CHT); and for giNETs, PD on SSAs. Pts were treated with lenvatinib at 24 mg qd until PD or intolerable toxicity. The primary endpoint was overall response rate (ORR) by central radiology review. Progression-free (PFS) and overall survival (OS) were assessed by investigator. With 55 pts per arm, our study was powered to identify an ORR ≥25% (90% power, 5% α-error). Results: We recruited 111 pts: 55 panNETs and 56 giNETs (78% from small intestine). Prior therapies were CHT 32%, SSAs 87%, everolimus 70% and sunitinib 30% for panNETs. ORR was 29%, 42.3% for panNETs and 16.3% for giNETs. With a median follow-up of 19 m, PFS and OS for panNETs were 15.5 m (95% CI 11.3-not reached (NR)) and 29.2 m (95% CI 23.2-NR); and 15.4 m (95% CI 11.5-19.4) and NR for giNETs, respectively. Pts who obtained a response by RECIST had a significantly better PFS compared with non-responders (NR vs 11.2 m in panNETs (p=0.004); 37.2 m vs 14.9 m in giNETs (p=0.005). In the subgroup analyses, all pts obtained the same benefit in PFS and ORR, including tumor grade, prior therapies, hormone release, primary location and tumor burden. The most frequent G3/4 adverse events were hypertension (22%), fatigue (11%) and diarrhea (11%). Dose reductions/interruptions were needed in 91.8% with a median dose of 20 mg qd. Conclusions: To our knowledge, we report the highest ORR by central radiology assessment with a TA in this setting. Lenvatinib showed a promising PFS and OS in a pretreated population with benefit across subgroups. Further development in advanced NETs is warranted. Clinical trial information: NCT02678780.
Molecular characterization of the tumour microenvironment in neuroendocrine malignancy.
Authors: Pinato David James , Vallipuram Anu , Evans Joanne , Wong Clement , Zhang Hua , Brown Matthew , Dina Roberto , Trivedi Pritesh , Akarca Ayse , Marafioti Teresa , Mauri Francesco A , Sharma Rohini 
Published: May 2019

4107 Background: A comprehensive characterization of the tumour microenvironment is lacking in neuroendocrine tumors (NETs), where immunotherapy is undergoing efficacy testing. We investigated drivers of cancer-related immunosuppression across NETs of various sites and grade using multi-parameter immunohistochemistry and targeted transcriptomics. Methods: Tissue microarrays (n = 102) were stained for PD-L1 & 2, Indoleamine-deoxygenase-1 (IDO-1) and evaluated in relationship to functional characteristics of tumor-infiltrating T-lymphocytes (TILs) and biomarkers of hypoxia/angiogenesis including VEGF-A, Hif-1α and Carbonic Anhydrase-IX. PD-L1 expression was tested in circulating tumour cell (CTCs, n = 12) to evaluate its relationship with metastatic dissemination. Results: PD-L1 expression was highest in lung NETs (n = 30, p = 0.007), whereas PD-L2 was highest in pNETs (n = 53, p < 0.001) with no correlation with grade, stage or biomarkers of hypoxia. Incubation of QGP-1 and BON-1 NET cells in 1% O2 did not induce PD-L1 expression confirming transcriptional independence from hypoxia. PD-L1+ NETs (n = 26, 25%) had frequent IDO-1 co-expression (p = 0.03), greater CD4+/FOXP3+ and CD8+/PD1+ TILs (p < 0.001) and necrosis (p = 0.02). CD4+/FOXP3+ infiltrate was highest PD-L1/IDO-1 co-expressing tumours (p = 0.006). Survival was predicted by tumour grade (p < 0.001) and necrosis (p < 0.001) but not PD-L1, PD-L2 nor IDO-1. High-grade NETs had lower CD4+/FOXP3+ and CD8+/PD1+ TILs density (p < 0.001) and Nanostring immune-profiling revealed enrichment of macrophage-related transcripts in cases with poorer prognosis. We identified PD-L1(+) CTC subpopulations in 75% of evaluated patients (n = 12). Conclusions: PD-L1 expression correlates with T-cell exhaustion independent of tumour hypoxia and is enhanced in a subpopulation of CTCs, suggesting its relevance to the progression of NETs. These findings support a potential therapeutic role for PD-L1/IDO-1 inhibitors in a subset of NETs.
Long-term survival and safety from a multi-center, open-label, pivotal phase 2 study of iobenguane I 131 in patients (Pts) with unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma (PPGL).
Authors: Noto Richard B. , Jimenez Camilo , Chin Bennett B. , Dillon Joseph S. , Solnes Lilja , DiPippo Vincent A. , Mahmood Syed , Stambler Nancy , Lin Tess , Jensen Jessica Donato , Wong Vivien , Pryma Daniel A. 
Published: May 2019

4108 Background: PPGL, rare neuroendocrine tumors with a 5-yr survival rate as low as 12%, have a high unmet need for effective treatment options. AZEDRA, a high-specific-activity iodine-131 meta-iodobenzylguanidine (HSA I-131-MIBG), is the first and only FDA- approved therapeutic radiopharmaceutical agent indicated for the treatment of adult and pediatric pts with iobenguane scan positive, unresectable, locally advanced or metastatic PPGL who require systemic anticancer therapy. Methods: Pts with advanced disease who were heavily pre-treated and were ineligible for curative surgery or chemotherapy received a dosimetric dose followed by up to two therapeutic doses (each at 296 MBq/kg to a max of 18.5 GBq). The primary endpoint, defined as the proportion of pts with at least 50% reduction of all antihypertensive medication(s) lasting ≥6 months, was met and previously reported. Updated secondary endpoints including overall survival (OS) and safety are reported. Results: A dosimetric dose of HSA I-131-MIBG was administered to 74 pts. Of those, 68 pts received one therapeutic dose and 50 received two doses of HSA I-131-MIBG. Clinical benefit rates (objective tumor responses defined by RECIST 1.0 and stable disease) were observed in 71.4% and 98.0% of pts receiving one and two therapeutic doses, respectively. As of Jan 25, 2019, median OS for all pts was 41.1 months (95% CI 31.1, 91.2). Median OS was 17.5 months (95% CI 4.0, 31.5) and 48.7 months (95% CI 33.2, 91.2) in pts receiving one and two doses, respectively. A tail of survival was observed, with OS of 73.1% at 2 yrs and 44.2% at 4 yrs. The most common (≥50%) adverse events were nausea, fatigue, and myelosuppression. Myelosuppressive events resolved within 4-8 wks without requiring stem cell transplantation. Late radiation toxicity included 8 pts with secondary malignancies (myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), colon cancer, and lung carcinoma) of which MDS, ALL and AML were considered related to I-131 radiotherapy. Conclusions: Updated results from this pivotal phase 2 study suggest that HSA I-131-MIBG is an efficacious and safe treatment for advanced PPGL. Clinical trial information: NCT00874614.
Analysis of patient diaries in the NETTER-1 Study of 177Lu-DOTATATE versus high-dose octreotide in progressive midgut neuroendocrine tumors.
Authors: Strosberg Jonathan R. , Wolin Edward M. , Chasen Beth A. , Kulke Matthew H. , Bushnell David L , Caplin Martyn , Baum Richard P. , Hobday Timothy J. , Hendifar Andrew Eugene , Santoro Paola , Broberg Per , Demange Arnaud , Oberg Kjell E. , Ruszniewski Philippe B. , Ravasi Laura , Krenning Eric 
Published: May 2019

4111 Background: The primary statistical analysis for the NETTER-1 trial showed a clinically and statistically significant PFS benefit with 177Lu-DOTATATE vs. high-dose octreotide. 177Lu-DOTATATE treatment was also correlated with a significant delay in time to deterioration in HRQoL. In addition to HRQoL questionnaires, patients were asked to record presence or absence of a range of symptoms in a daily diary. Methods: A Mixed Model Repeated Measures (MMRM) was used to analyze the change, compared to baseline, of the occurrence of abdominal Pain, diarrhea and cutaneous flushing as these symptoms were regarded as the most relevant to judge the overall disease status. For each visit (week = 0, 4, 8, etc.) the number of days with symptoms during the previous period was calculated. At baseline, the number of days with symptoms was counted over the previous 6 weeks, whereas the time frame between visits lasted 4 weeks. Results: The estimated number of days with symptoms declined significantly more in the 177Lu-dotatate arm compared to the octreotide arm. The difference in change and the confidence intervals for the symptoms abdominal pain, diarrhea and flushing of skin are, respectively: -3.11 [-4.88; -1.34], -3.11 [-5.04; -1.18] and -1.98 [-3.88; -0.08]. Conclusions: Analysis of symptom diaries confirms that 177Lu-Dotatate can palliate clinically relevant symptoms when compared to high-dose octreotide.
Immune checkpoint inhibitors (ICIs) in gastrointestinal (GI) cancer: Immune-related adverse events (IRAEs) and efficacy.
Authors: Das Satya , Ciombor Kristen Keon , Haraldsdottir Sigurdis , Pumpalova Yoanna S , Sahin Ibrahim Halil , Shyr Yu , Chu Shih-Kai , Lin Emily Pei-Ying , Hsu Chih-Yuan , Goff Laura Williams , Cardin Dana Backlund , Bilen Mehmet Asim , Berlin Jordan , Wu Christina 
Published: May 2019

4116 Background: Despite the therapeutic promise of ICIs for patients (pts) with some advanced malignancies, they are FDA-approved for only a few GI cancer pts. In NSCLC, melanoma and urothelial carcinoma, there is emerging data that pts who experience IRAEs while on ICIs have improved outcomes compared with pts who do not. This association in GI cancer pts has not been reported. Methods: We retrospectively analyzed outcomes for metastatic GI cancer pts receiving ICIs for FDA-approved indications (later-line MSI-H tumors, 2nd line hepatocellular carcinoma (HCC), 3rd line PD-L1+ gastric (GA)/gastroesophageal junction (GEJ) adenocarcinoma), at Vanderbilt Ingram Cancer Center, Winship Cancer Institute and Stanford Cancer Institute. Our primary aim was to compare progression-free survival (PFS) and overall survival (OS) between pts who did and did not experience IRAEs. Secondary aims were comparison of these outcomes within pts who experienced IRAEs, by initial IRAE severity (Grade (G)3/G4 vs G1/G2) (CTCAE v5.0), time-to-onset (TTO) (≤ 6 weeks (w) vs > 6 w) and management (steroids vs drug cessation vs observation). PFS and OS were determined by Kaplan-Meier (KM) analysis; KM comparisons were done by the logrank test. Results: Between 1/2015-12/2018 61 GI cancer pts with HCC (28), colorectal cancer (27) and GA/GEJ cancer (6) were treated with ICIs; median age was 63 years. The majority (59) received single-agent nivolumab or pembrolizumab while minority (2) received nivolumab and ipilimumab; median time on ICIs was 5.9 months (mos). Twenty-four pts experienced initial IRAEs (6 G3/G4, 18 G1/G2); median TTO was 3.8 mos. Pts who experienced any IRAE had improvements in PFS and OS compared to those who did not (PFS: 32.4 mos (95% confidence interval (CI), 32.4-not reached (NR)) vs 4.8 mos (95% CI, 2.9-8.7), p = 0.0001; OS: 32.4 mos (95% CI, 32.4-NR) vs 8.5 mos (95% CI, 6-NR), p = 0.0036). Among pts who experienced IRAEs, PFS and OS differences between above-specified subgroups did not meet statistical significance. Conclusions: GI cancer pts who experienced IRAEs while on ICIs had marked improvements in PFS and OS compared to those who did not, suggesting the predictive potential for IRAEs as a clinical biomarker in this population.
Efficacy and safety of lanreotide 120 mg in the treatment of clinical symptoms associated with inoperable malignant intestinal obstruction (IMIO): Results from a phase II multicenter study.
Authors: Duck Lionel , Demolin Gauthier , D'Hondt Lionel A. , Dopchie Catherine , Hendrickx Koenraad , Lannoye Beatrice , Bastin Fabienne , Lossignol Dominique , Hamdan Oussama Ibrahim , Lybaert Willem , Vandenhaute Vincent , Grira Torkia , De Ruyter Vincent , Geboes Karen Paula 
Published: May 2019

4118 Background: Intestinal obstruction is a severe complication in patients (pts) with digestive or gynecological cancers. For inoperable pts, there is a need to relieve symptoms and limit nasogastric tube (NGT) use. Previous studies have suggested the efficacy of somatostatin analogues in relieving obstruction-related symptoms such as nausea, vomiting and pain. Methods: This was a single arm, prospective study (NCT02275338). Pts with IMIO received one deep subcutaneous injection of LAN 120mg at day 0 (D0). Evaluations were performed on D7, 14 and 28. The primary endpoint was the proportion of responders before or at D7. Response was defined as ≤2 vomiting episodes/day (for pts without NGT at baseline) or no vomiting recurrence (after NGT removal), during at least 3 consecutive days at any time point between the D0 and D7. In line with the literature, a proportion of 30% responders was used as reference for defining statistical significance. Responders at D28 were offered a second LAN 120 mg injection. Results: 52 pts with advanced GI or ovarian malignancies were included in 15 Belgian sites. 17 pts without NGT and 35 with NGT. 21 pts received a second dose of LAN. Median age was 68.0 (59.5; 76.0) years. On D7 the proportion of responders in the ITT population was 24/52 (46.2%), significantly greater than the reference proportion of 30% (one-sided binomial test: p = 0.006). Pts without NGT responded better (15/17, 88.2%) than pts with NGT (9/35, 25.7%). Pts without ascites responded better (57.7% vs 34.6%). Pts with NGT showed a steady trend for clinical improvement leading to sustainable responses of 45.7% on D14. Median time to response was 9 days for the overall population; 3 days for patients without NGT vs 14 days for patients with NGT (p < 0.001). The most frequently reported AEs were GI disorders (in 34 pts). The most common events were diarrhoea and abdominal pain. Conclusions: Our study is the first using long acting LAN 120mg in patients with IMIO and suggests an effect in controlling clinical symptoms in pts with and without NGT at baseline. LAN 120 mg safety profile was similar to that reported for the other indications. Clinical trial information: NCT02275338.