bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multicenter randomized phase II study of nivolumab in combination with gemcitabine/cisplatin or ipilimumab as first-line therapy for patients with advanced unresectable biliary tract cancer (BilT-01).
Authors: Sahai Vaibhav , Griffith Kent A. , Beg Muhammad Shaalan , Shaib Walid Labib , Mahalingam Devalingam , Zhen David Bing , Deming Dustin A. , Dey Sumi , Mendiratta-Lala Mishal , Zalupski Mark 
Published: May 2020

4582 Background: Patients (pts) with advanced biliary tract cancers (BTC) have poor prognosis with a median overall survival (OS) less than 12 months (mos). This randomized phase 2, multi-institutional, study was designed to investigate the role of combinational immunotherapy, using nivolumab (nivo) with gemcitabine (gem)/cisplatin (cis), or nivo with ipilimumab (ipi) in pts with untreated advanced BTC. Methods: Key eligibility criteria include histologically confirmed unresectable or metastatic BTC without prior systemic therapy, measurable disease per RECISTv1.1, ECOG PS 0-1, and absence of autoimmune disease or chronic steroid use. Arm A included gem 1000 mg/m2 and cis 25 mg/m2 d1, 8 Q3w + nivo 360 mg d1 Q3w for 6 mos followed by nivo 240 mg Q2w monotherapy for a total duration of 2 yrs; Arm B included nivo 240 mg Q2w and ipi 1 mg/kg Q6w for 2 yrs, in absence of disease progression. Primary endpoint is progression-free survival (PFS) rate at 6 mos with an alternative hypothesis of 80% (null hypothesis of 59%, one-sided alpha 0.05, power 80%) for each non-comparative arm. Secondary endpoints include overall response rate (ORR) per immune related (ir)RECIST, median PFS and OS and safety. Exploratory objectives include biomarker analysis using include sequential whole exome/transcriptome and immune cell subsets in tissue and blood. Results: 71 eligible pts (49% male, 83% Caucasian) with 35 in Arm and 36 in Arm B with a median age of 62 (range 20-80) yrs, and majority with metastatic disease (90%) were enrolled across 6 US sites. PFS rate at 6 mos was 70% in Arm A and 18.6% in Arm B. The median PFS was 8.8 mos (95% CI, 6.1 to 11.3) in Arm A and 4.1 mos (95% CI, 2.4-5.2) in Arm B. Ten patients on Arm A and 2 on Arm B remain on active treatment; additional 7 are in follow-up for OS. ORR, safety data and median OS evaluation are underway and will be presented at the meeting. Exploratory analyses are pending. Conclusions: The observed PFS rates at 6 mos in either arm are insufficient to reject the null hypothesis of 59% PFS at 6 months. While Arm B is inferior, Arm A appears to be as effective as standard of care although OS estimates are pending maturity. Clinical trial information: NCT03101566 .
Genomics and translational precision oncology for 803 patients with biliary tract cancer.
Authors: Lin Jianzhen , Yang Xu , Cao Yinghao , Li Guangyu , Zhao Songhui , Shi Junping , Pan Jie , Hu Ke , Zhao Lin , Guan Mei , Sang Xinting , Javle Milind M. , Wang Kai , Wang Xiaoyue , Zhao Hai-Tao 
Published: May 2020

4589 Background: Both incidence and mortality of biliary tract cancer (BTC) are increasing, and BTCs are characterized by poor prognosis and limited antitumoral treatments. There is no well-received regimen as the non-first-line treatment in patients with advanced BTCs, leading to the urgency of umbrella-setting personalized therapies according to genomic alterations. Methods: We performed genomic sequencing in a total of 803 BTCs, including 160 patients with whole-exome sequencing and 643 patients with hybrid capture–based comprehensive genomic profiling. Our molecular tumor board developed precise targeted therapies for patients with actionable targets. Results: Overall, the median tumor mutation burden was 3.0 (IQR: 0.8-6.1) Mut/Mb, with 10.5% patients of hypermutated BTCs. The most frequently mutated genes included TP53 (51%), KRAS (23%), ARID1A (16%) and SMAD4 (11%). The most common genes with significantly amplified oncogenes were CCND1 (6.97%), MET (6.72%) and MDM2 (6.6%), while the frequently deleted tumor-suppressor genes are CDKN2A (5.73%) and CDKN2B (5.35%). The mutational map of BTCs highlighted pathways of receptor-tyrosine kinase (RTK)/RAS and p53 signaling were frequently altered. Somatic truncating mutations of mismatch repair genes were identified in 6.1% (49/803) of patients, and germline pathogenic mutations in DNA damage response genes occurred in 8% (64/803) of BTCs. In addition, we demonstrate the amplified chromosomal focal at 7q31.2 was an oncogenic factor and it independently predicts both disease-free survival and overall survival of BTC patients. When molecular screening was linked to targeted therapies, 25.4% (204/803) of patients could match biomarker-assigned drug treatment (BADT). The frequent actionable biomarkers included amplifications of ERBB2 and MET, FGFR2/3 fusions and IDH1 mutations. For 46 patients with refractory BTCs received BADT, the objective response rate was 26.1%, with a median progression-free survival (mPFS) of 5.0 (95%CI: 3.5-6.5) months, and 56.8% patients achieved a ≥1.3 ratio of PFS2/PFS1. 4 of 6 (67%) patients with high microsatellite instability (MSI-H) BTCs had a responsive status after immunotherapy of PD1 inhibitor, confirming that MSI-H status was a robust biomarker of anti-PD1 treatments. Conclusions: Our study established the largest cohort in Chinese BTC patients to investigate the tumor mutational profiling and its translational clinical applications. Clinical trial information: NCT02715089 .
A phase II open-label, single-center, nonrandomized trial of Y90-radioembolization in combination with nivolumab in Asian patients with advanced hepatocellular carcinoma: CA 209-678.
Authors: Tai Wai Meng David , Loke Kelvin Siu Hoong , Gogna Apoorva , Tan Sze Huey , Ng David Chee Eng , Hennedige Tiffany Priyanthi , Irani Farah , Lee Joycelyn Jie Xin , Too Chow Wei , Ng Matthew C.H. , Tham Chee Kian , Lam Justina Yick Ching , Koo Si-Lin , Chung Alexander , Toh Han Chong , Thng Choon Hua , Lim Kiat Hon , Yeong Joe Poh Sheng , Chan Chung Yip , Choo Su Pin 
Published: May 2020

4590 Background: Nivolumab (N) and Y90-radioembolization (RE) are both therapeutic options in advanced hepatocellular carcinoma (aHCC). Increasing evidence suggests that radiotherapy synergizes with immune checkpoint inhibitors to augment anti-tumour effects. Methods: Eligible Child-Pugh A aHCC patients (pts) were treated with Y90-RE followed by N 240mg, 21 days after Y90-RE and every 2 weeks thereafter. Pre- and on-treatment tumor biopsies together with circulating biomarkers were obtained. Primary end-point was overall response rate (ORR) (per RECIST v 1.1). Overall response was defined as the composite overall response observed for the lesions within Y90-RE field and outside Y90-RE field. Key secondary end points included disease control rate (DCR), progression free survival (PFS), overall survival (OS), and safety. 36 evaluable pts were needed to assess whether the addition of N improved the ORR of Y90-RE from 21% to 41% as determined by Simon two-stage optimal design with 80% power and one sided significance level of 0.05. Results: Forty pts were enrolled of which 36 were evaluable. At baseline: 63.9% were HepB in aetiology; 63.9% BCLC stage C; 47.2% had AFP > 400ng/mL; number of liver lesions – median 5 (range 1- 20); size of largest liver lesion – median 80mm (range 14-177mm); 27.8% had prior TACE; and 13.9% had prior systemic therapy. ORR was 31% (95% CI 16.4 - 48.1%). Eight out of 11 responders had not progressed at study cut-off. DCR was 58.3%. 81% of target lesions within Y90-RE field regressed. With a median follow up of 16.4 months, median PFS and OS were 4.6 months (95% CI 2.3m - 8.4m) and 15.1 months (95% CI 7.8m - NE) respectively. Six- and 12-month PFS rates were 44.2% (95% CI 27.3% - 59.9%) and 26.1% (95% CI 11.2% - 43.8%) respectively. Overall, N+ Y90-RE was well tolerated and safe; only 11% had grade 3/4 treatment related adverse events (AEs). Responders demonstrated significant alterations of LIF, MIG and Eotaxin3 levels in the pre-treatment cytokine analyses. Conclusions: Combination N+Y90-RE resulted in an encouraging ORR of 31% (95% CI 16.4 - 48.1%) in aHCC. 81% of target lesions within Y90-RE field regressed suggesting synergy in combining Y90-RE with nivolumab. This combination is safe and tolerable with low G3/4 treatment related AEs of 11%. Further biomarker analyses will be presented at the meeting. Clinical trial information: NCT03033446 .
Perioperative circulating tumor DNA analysis to predict patient prognosis in liver cancer.
Authors: Zhou Ledu , Xu Ying , Wang Dong , Ye Ke , Xiao Liang , Long Guo , Chen Rongrong , Xia Xuefeng 
Published: May 2020

4593 Background: Resection is a major method for early-stage liver cancer patients. Unfortunately, there still a few patients with post-operation recurrences. Circulating tumor DNA (ctDNA) had been reported as a biomarker in reflecting tumor load and treatment efficacy in some cancer species. Here, we report an application of ctDNA in the perioperative period of liver cancer using targeted sequencing with a 1021-gene panel. Methods: 97 patients diagnosed with liver cancer were enrolled in this study. Postoperative peripheral blood samples were collected within 7 days after surgery and analyzed using hybridization capture based NGS ERSeq method from all patients. Whether a mutant gene was detected in the peripheral blood was defined as ctDNA(+) and ctDNA(-), respectively. Results: Multivariate Cox analysis showed that the post-operation ctDNA was an independent poor prognostic predictor (AFP, RR: 1.0002, 95% Cl: 1.0001-1.0002; ctDNA, RR: 3.738, Cl: 1.872-7.691). 21 patients were ctDNA(+), and all of them had recurrenced (21/21, 100%), while 76 patients were ctDNA(-), and only 12 (12/76, 15.8%) patients had recurrenced. The median disease-free survival time was 5.0 months in ctDNA(+) group and the ctDNA(-) group had not reach the median time (Log-rank test, P < 0.0001). ctDNA combined with AFP would effectively predict the prognosis of patients after surgery. AFP(H) ( > = 400 ng/mL) and ctDNA(+) patients have the worst prognosis and all of the patients had relapsed, while AFP(L) ( < 400 ng/mL) and ctDNA(-) patients had the best prognosis, with less than 20% of patients had relapsed (Log-rank test, P < 0.0001). The median disease-free survival time was 2.0, 6.0 and 7.0 months in ctDNA(+)-AFP(H) (n = 8), ctDNA(-)-AFP(H) (n = 30) and ctDNA(+)-AFP(L) (n = 13) groups, respectively, while ctDNA(-)-AFP(L) group (n = 46) had not reach the median time statistically (Log-rank test, P = 0.0364). Conclusions: In summary, Perioperative ctDNA detection has great potential value clinically, and it also suggests that patients with positive ctDNA after surgery should receive some adjuvant treatments as soon as possible to improve the survival time.
Australasian Gastrointestinal Trials Group (AGITG) CONTROL NET Study: Phase II study evaluating the activity of 177Lu-Octreotate peptide receptor radionuclide therapy (LuTate PRRT) and capecitabine, temozolomide CAPTEM)—First results for pancreas and updated midgut neuroendocrine tumors (pNETS, mNETS).
Authors: Pavlakis Nick , Ransom David Turner , Wyld David , Sjoquist Katrin Marie , Asher Rebecca , Gebski Val , Wilson Kate , Kiberu Andrew Ddembe , Burge Matthew E. , Macdonald William , Roach Paul , Pattison David A. , Butler Patrick , Price Timothy Jay , Michael Michael , Lawrence Benjamin James , Bailey Dale L. , Leyden Simone , Zalcberg John Raymond , Turner J. Harvey 
Published: May 2020

4608 Background: CAPTEM is an accepted regimen for patients (pts) with advanced pNETs. Single agent 177Lu-Octreotate PRRT is now a standard of care for progressive WHO Grade (G) 1/2 mNETs. High activity was seen with LuTate/CAPTEM in a single arm Phase I/II trial. This study was undertaken to determine the relative activity of adding CAPTEM to LuTate PRRT in pts with mNETs and pNETs. Methods: Non-comparative randomised open label parallel group phase II trial with 2:1 randomisation to PRRT/CAPTEM (experimental arm) vs. PRRT (mNETs control) and CAPTEM (pNETS control). PRRT/CAPTEM: 7.8GBq LuTate day(D) 10, 8 weekly (wkly) x 4, with b.i.d. oral CAP 750mg/m2 D1-14 & TEM 75mg/m2D10-14, 8 wkly x 4; PRRT: 8 wkly x 4; CAPTEM 8 wkly x 4. Primary endpoint: Progression free survival (PFS). mNETS- at 15 months (mo) assuming 15mo PFS 66.4% in control arm, aiming for PFS ³ 80%; pNETS- at 12mo assuming 12mo PFS 60% in control arm, aiming for PFS ³ 75%. Secondary endpoints: Objective tumour response rate (complete or partial) (OTRR), clinical benefit rate (OTRR, stable disease) (CBR), toxicity, quality of life. Results: 75 pts enrolled (Dec 2015 – Nov 2018): mNETs 33 PRRT/CAPTEM and 14 PRRT; pNETS 19 PRRT/CAPTEM and 9 CAPTEM. mNETS: Median follow-up 35mo; 15mo PFS was 90% (95% CI: 73-97%) v 92% (95% CI: 57-99%); OTRR 31% vs 15%; and CBR 97% vs 92% for PRRT/CAPTEM v PRRT respectively. Treatment related adverse events (AEs): 24/32 PRRT/CAPTEM pts had at least one G3 event (75%) vs 5/13 (38%, PRRT); and 4/32 pts at least one G4 event (13%) v 1/13 (8%) respectively, mostly haematologic (haem). Only one patient failed to complete therapy (PRRT/CAPTEM). pNETS: Median follow-up 34mo; 12mo PFS was 76% (95% CI: 48-90%) v 67% (95% CI: 28-88%); OTRR 68% vs 33%; and CBR 100% vs 100% for PRRT/CAPTEM v CAPTEM respectively. Treatment related AEs: 5/18 PRRT/CAPTEM pts had at least one G3 event (28%) vs 3/9 (33%) CAPTEM; 3/18 pts at least one G4 event (17%) v 1/9 (11%) respectively. Conclusions: CAPTEM/PRRT is active, meeting its target landmark PFS for CAPTEM/PRRT (12mo pNETs; 15mo mNETs) with numerically greater OTRR in both pNETs and mNETs, but with more haem toxicity in mNETs. As activity was high in both control arms longer follow up is required to determine if the relative activity of PRRT/CAPTEM is sufficient to warrant Phase III evaluation. Clinical trial information: ACTRN12615000909527 .
Pretherapeutic 68Ga-DOTATATE PET SUV predictors of survival of radionuclide therapy for metastatic neuroendocrine tumors.
Authors: Ladwa Rahul , Pattison David A. , Smith Jye , Goodman Steven , Burge Matthew E. , Rose Stephen , Dowson Nicholas , Wyld David 
Published: May 2020

4609 Background: Peptide receptor radionuclide therapy (PRRT) is an effective treatment option in patients with advanced neuroendocrine tumours (NETs). Patients are pre-selected based on 68Gallium-DOTA-(0-Tyr3)-octreotate Positron Emission Tomography (68Ga-DOTATATE PET) uptake. The level of uptake in tumour on the baseline 68Ga-DOTATATE PET scan has been explored as a predictor of response in NETs with inconclusive evidence. The aim of this study is to determine the correlation between 68Ga-DOTATATE PET SUV parameters to survival outcomes. Methods: We retrospectively analysed 142 lesions (up to five lesions per patient) in 73 patients with NET undergoing PRRT with 177Lutetium octreotate (8.0-8.3GBq) and pretherapeutic 68Ga-DOTATATE PET/CT in a single institution. Standardised uptake values (SUVs) max and mean were correlated with progression-free survival (PFS) and overall survival (OS). Results: A total of 73 patients were included in the analysis. The median age was 63 (28-89) years. NET origin was gastroenteric (49%), pancreatic [pNET] (38%), bronchial (10%) and other (3%). Ki-67 proliferation index ( < 3%: 36%, 3-20%: 36%, > 20%- < 50%: 8%, unknown: 21%) was seen. Pretherapeutic SUV max but not SUV mean was higher in pNETs (P = 0.04). No difference was seen with Ki-67 index. The median PFS was 32 (95%CI: 26-38) months. Median PFS was reduced with increasing ECOG performance status [PS] (P= 0.029), increasing tumour grade (P = 0.003), increasing Ki-67 proliferation index (P = 0.013), reduced SUV max (P= 0.003), reduced SUV mean (P= 0.001). Multivariate analysis confirmed SUV mean (HR =-1.71 [95%CI: -2.66- -0.80]; P<0.01) and Ki-67 index (HR = 1.11 [1.06-1.17]; P < 0.01) as maintaining significance when incorporating ECOG PS (HR = 1.96 [0.68-5.47]; P = 0.22). The mean OS was 40 [37-44] months. A higher SUV max (SUV max < 30: 34 [30-40] months vs SUV max > 30: 48 [44-51]; P<0.01) and higher SUV mean (SUV mean < 20: 33 [28-39] months vs SUV mean > 20: 47 [43-51]; P<0.01) were associated with improved mean OS. Mean OS was not affected by ECOG performance status (P = 0.896), primary site of origin (P = 0.567) and Ki-67 index (P = 0.110). Conclusions: 68Ga-DOTATATE PET SUV measures correlated with an improved PFS on multivariate analysis as well as improved OS in this select group of patients suitable for PRRT. Those patients with lower SUV mean may benefit from escalation of therapy such as increasing administered therapeutic activity.
Toxicity analysis of capecitabine/temozolomide in NETs.
Authors: Al-Toubah Taymeyah E. , Pelle Eleonora , Haider Mintallah , Strosberg Jonathan R. 
Published: May 2020

4614 Background: The capecitabine/temozolomide regimen has significant activity in advanced NETs. Concerns exist regarding risk of opportunistic infections and long-term myelotoxicity. Analysis of large patient cohorts is needed for evaluation of rare toxicities and for assessment of risk factors. Methods: Retrospective study of all patients with advanced neuroendocrine neoplasms seen at the Moffitt Cancer Center between 1/2008 and 6/2019 who received treatment with CAPTEM. Patients who initiated treatment at outside institutions were included if they were prescribed treatment at appropriate doses and if complete records were available. Results: 462 patients met eligibility criteria for evaluation: 210 (45%) females and 252 (55%) males with a median age of 59. Median starting doses of CAP and TEM were 658mg/m2 and 180mg/m2 respectively. Median duration on treatment was 8 months. 25% of patients required a dose reduction and 16% discontinued due to toxicity of any grade. Incidence of grade 4 thrombocytopenia was 7%: 10% in females and 5% in males (p = 0.02). 4 cases were complicated by bleeding (0.8%). Incidence of grade 4 neutropenia was 3%: 5% in females and 1% in males (p = 0.004). Incidence of grade 4 lymphopenia was 2%. Only one case (0.2%) of suspected PCP was observed in a patient taking corticosteroids. There were 5 cases of herpes zoster and no other opportunistic infections. 3 patients developed myelodysplastic or myeloproliferative disease, all of whom had also received prior PRRT with Lutetium-Dotatate. There were no acute treatment related deaths, although one patient died 2 months after a thrombocytopenic bleed. Conclusions: Severe myelotoxicity is rare, but risks of grade 4 thrombocytopenia and neutropenia are significantly increased in females compared to males. Gender-based dosing should be considered. While alkylating agents are often associated with MDS, there were no cases except among patients who also had received PRRT, a known risk factor. PCP is not a significant risk with this regimen in patients not concurrently on corticosteroids.
Olaparib sensitivity observed in metastatic pancreatic cancer (mPaC) with a wide spectrum of germline BRCA1 and BRCA2 mutations (gBRCAm).
Authors: Golan Talia , Kindler Hedy L. , Schatz Philipp , Goranova Teodora , Locker Gershon Y. , Cui Karen , Schlienger Katia , McGuinness David , Williams J. Andrew , Orr Maria , Gutjahr Thorsten , Liu Yu-Zhen 
Published: May 2020

4621 Background: The POLO study (NCT02184195) showed that mPaC patients (pts) with a deleterious or suspected deleterious gBRCAm, and whose disease had not progressed during ≥16 weeks of first-line platinum-based chemotherapy, had significantly longer progression-free survival (PFS, primary endpoint) with maintenance olaparib vs placebo: median 7.4 vs 3.8 months, hazard ratio (HR) 0.53; P=0.004. PFS benefit was observed in pts with g BRCA1m (HR 0.40) and g BRCA2m (HR 0.63). The POLO study represents the largest BRCAm prevalence study in pancreatic cancer. We report additional exploratory analysis to further characterize patient gBRCAm profiles, including the relationship with efficacy. Methods: Pts were enrolled based on either a previously identified gBRCAm status from a local test result and subsequently confirmed by central testing, or a prospectively identified gBRCAm. Pts received maintenance olaparib 300 mg twice daily (tablet) or placebo. PFS was assessed by blinded independent central review (modified RECIST v1.1). Results: Of 3194 prospectively screened pts, a valid BRCA test result was obtained for 3175 (99%) from 12 countries; gBRCAm prevalence was 6.2% in pts not previously known to harbor a gBRCAm (196/3175; 1.6% g BRCA1m, 4.5% g BRCA2m). In countries (n=8) with >100 pts prospectively tested, highest gBRCAm prevalence was 9.2% (USA) and lowest 4.0% (Spain). Prevalence by race (>100 pts); 6.4% Caucasian, 4.6% Asian. In total, 154 pts with a gBRCAm satisfied all eligibility criteria and were randomized (106 prospectively tested and 48 by local test [44/48 subsequently confirmed by Myriad testing]). 37/154 (24%) randomized pts carried a common Ashkenazi Jewish founder mutation, the majority being from Israel (21 pts). From a total of 151 variants, frameshift mutations were most frequent (g BRCA1m 69.6%, g BRCA2m 71.4%) followed by nonsense mutations (g BRCA1m 6.5%, g BRCA2m 17.1%). The efficacy (PFS) of olaparib vs placebo in the different subgroups are shown in the table. Conclusions: In pts with mPaC enrolled in POLO, g BRCA2m were more prevalent than g BRCA1m and mutation type was predominantly frameshift. PFS benefit was consistent across a heterogenous spectrum of gBRCAm and with the previously reported full analysis set. Clinical trial information: NCT02184195 . [Table: see text]