bluuebunny/crossref_metadata_2025 huggingface dataset:
A digital pathology demonstration of an "immune hot" ICOS+/CD45RO+ immunephenotype and the impact on survival in patients with esophageal adenocarcinoma.
Authors: Humphries Matthew Philip , Fisher Natalie , Kacprzyk Rafal , Craig Stephanie G , Bingham Victoria , McQuaid Stephen , Turkington Richard C. , Murray Graeme I , James Jacqueline , Salto-Tellez Manuel
Published: May 2019

4062

Background: Therapies targeting immune checkpoints are changing our understanding of the biology and treatment of cancer. Analysing the immune landscape in esophageal adenocarcinoma (EA) may help future prognostication and therapeutic decision-making. Methods: We assembled 310 EA cases in a tissue microarray format with associated clinicopathological information, including a discovery cohort of 156 EA from Northern Ireland and a 154 EA validation cohort from Aberdeen. We carried out validated immunohistochemistry (IHC), stained for range of adaptive immune (CD3, CD4, CD8 and CD45RO) and immune checkpoint biomarkers (ICOS and IDO-1). Slides were digitised and assessed using QuPath image analysis software program to quantify their expression and correlate them with outcome. Results: In the discovery cohort we identified a group of patients highly expressing several immune biomarkers, conferring a significant positive survival advantage (p = 0.022). CD3, CD4, CD8, CD45RO, and ICOS were individually prognostic for better overall survival (Log rank p = 0.0003; p = 0.0292; p = 0.0015; p = 0.0008; p = 0.0051 and p = 0.0264 respectively). Multivariate and correlation analysis identified a subgroup of CD45RO+/ICOS+ patients with significantly improved overall survival (p = 0.0002). The co-expression of CD45RO+/ICOS+ immunophenotype was investigated in the validation cohort and a confirmed survival advantage was seen (p = 0.042). Additionally, the Opal Multiplex IHC technology revealed the much higher frequency of single-cell, dual labelling of CD45RO+/ICOS+ in immune hot cases. Conclusions: These data demonstrate the advantage of immune markers other than the traditional CD3/CD4/CD8 in EA prognostication. The fact that one of these biomarkers is an immune checkpoint inhibitor may have therapeutic implications.
The impact of postoperative complications on survival outcomes in patients with cT3/4a gastric cancer.
Authors: Tokunaga Masanori , Kurokawa Yukinori , Doki Yuichiro , Machida Ryunosuke , Takiguchi Shuji , Sato Yuya , Katai Hitoshi , Fukushima Norimasa , Nishida Yasunori , Cho Haruhiko , Yamada Takanobu , Kaji Masahide , Fujita Junya , Boku Narikazu , Yoshikawa Takaki , Terashima Masanori
Published: May 2019

4067

Background: Recently, the negative impact of postoperative complications on long-term survival outcomes has been reported in patients with gastric cancer. However, most are single center, retrospective studies with different definitions of postoperative complications. The objective of this study was to evaluate the impact of postoperative complications on long-term outcomes using the data of a multicenter randomized controlled trial (JCOG1001). Methods: This study included 1191 out of all 1204 patients enrolled in JCOG1001 which was aimed to confirm the superiority of bursectomy for patients with cT3/4a locally advanced gastric cancer. Complications were graded by Clavien-Dindo classification. The relationships between the grade (≥grade II or ≥grade III) or type (all or intraabdominal infectious (pancreatic fistula, anastomotic leakage, and intra-abdominal abscess.)) of complications and survival outcomes were evaluated. Results: The incidences of ≥grade II and ≥grade III all complications were 23.0% and 9.7%, and those of ≥grade II and ≥grade III intraabdominal infectious complications were 13.4% and 6.9%, respectively. The hazard ratios for overall survival (OS) of patients with ≥grade II and ≥grade III all complications and those of patients with ≥grade II and ≥grade III intraabdominal infectious complications were shown in Table. With whichever definition we adopted, postoperative complications were significantly associated with OS in both univariable and multivariable analysis. Conclusions: Postoperative complication was identified as an independent prognostic factor in patients with cT3/4a gastric cancer. Hazard ratios for overall survival by univariable and multivariable Cox proportional hazard model. Clinical trial information: UMIN000003688. [Table: see text]
Prognostic significance of sarcopenia in metastatic esophageal squamous cell carcinoma.
Authors: Taylor Kirsty , Espin-Garcia Osvaldo , Romagnuolo Tina , Allison Frances , Ma Lucy Xiaolu , McInnis Micheal , Fares Aline Fusco , Liu Geoffrey , Darling Gail Elizabeth , Wong Rebecca , Chen Eric Xueyu , Veit-Haibach Patrick , Jang Raymond Woo-Jun , Rozenberg Dmitry , Elimova Elena
Published: May 2019

4068

Background: Sarcopenia is defined as low skeletal muscle mass and represents a quantifiable marker of frailty. Disease related symptoms of anorexia, nausea and dysphagia, in addition to reduced physical activity contribute to muscle wasting in metastatic esophageal squamous cell cancer (MESCC) patients. This study set out to evaluate the prognostic utility of sarcopenia and its association with nutritional indices. Methods: MESCC patients (pts) with available abdominal CT imaging, attending Princess Margaret Cancer Centre between 2011 and 2016, were identified from the institutional database. Skeletal muscle index (SMI), normalized by height, was calculated at the third lumbar (L3) vertebra using SliceOMatic software. SMI cutoffs for sarcopenia were 34.4cm2/m2 in females and 45.4cm2/m2 in males based on previously established consensus. Nutritional risk index (NRI) was calculated using weight and albumin with malnutrition defined as < 97.5. Results: Of the 58 pts analyzed, 26 presented with de novo MESCC, median age was 64 (range 48-85), 30 pts were ECOG PS ≤1 and 45% received systemic therapy. 93% of pts experienced weight loss > 5% in the 3 months preceding diagnosis and median BMI was 20.4 (range 16.3-34.9). Twenty-four (41%) pts were sarcopenic (SP) with differences in BMI and NRI (p < 0.05) compared to non-sarcopenic (NSP) pts. Median BMI in SP pts was 18.9 (16.3-25.6), 46% had a BMI < 18.5 and none were obese (BMI ≥ 30). By NRI, 58% of SP pts were malnourished. Males comprised 71% of SP pts (p = 0.03) but no difference from NSP MESCC pts was identified with age, race, ECOG PS or smoking status with univariate analysis. Median overall survival (OS) was 6 months; 4.2 in SP pts and 6.2 in NSP pts. Significant difference was identified with NRI (p = .0.009) but not sarcopenia (p = 0.247) or BMI (p = 0.393). With a multi-variate Cox model for NRI and sarcopenia, including age, sex, race, and ECOG PS, only ECOG PS was a significant predictor of mortality, HR for 2-3 vs 0-1 of 5.4 (2.5-11.9) p < 0.001. Conclusions: Sarcopenia at diagnosis was not associated with OS. NRI was superior to BMI alone with respect to discriminating pt outcomes, however ECOG PS was the only measure significantly associated with survival.
First-line avelumab + axitinib in patients with advanced hepatocellular carcinoma: Results from a phase 1b trial (VEGF Liver 100).
Authors: Kudo Masatoshi , Motomura Kenta , Wada Yoshiyuki , Inaba Yoshitaka , Sakamoto Yasunari , Kurosaki Masayuki , Umeyama Yoshiko , Kamei Yoichi , Yoshimitsu Junichiro , Fujii Yosuke , Aizawa Mana , Robbins Paul B. , Furuse Junji
Published: May 2019

4072

Background: Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for treatment of advanced/metastatic (a/m) hepatocellular carcinoma (HCC). Avelumab is a human anti–PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a tyrosine kinase inhibitor selective for VEGF receptors 1/2/3. VEGF Liver 100 (NCT03289533) is a phase 1b study evaluating safety and efficacy of avelumab + axitinib in treatment-naive patients (pts) with HCC; interim results are reported here. Methods: Eligible pts had confirmed a/m HCC, ≥1 measurable lesion, a fresh or archival tumor specimen, ECOG PS ≤1, and Child-Pugh class A. Pts received avelumab 10 mg/kg IV Q2W + axitinib 5 mg orally BID until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and objective response (RECIST v1.1; modified [m] RECIST for HCC). Results: Interim assessment was performed after a minimum follow up of 6 months based on the released study data set (clinical cut-off date: Aug 1, 2018). As of the cut-off date, 22 pts (median age: 68.5 y) were treated with avelumab (median: 20.0 wk) and axitinib (median: 19.9 wk). The most common grade 3 treatment-related adverse events (TRAEs) (≥10% of patients) were hypertension (50.0%) and hand-foot syndrome (22.7%); no grade 4/5 TRAEs were reported. Immune-related AEs (irAEs) (≥10% of pts) were hypothyroidism (31.8%) and hyperthyroidism (13.6%). No grade ≥3 irAEs were reported; no pts discontinued treatment due to TRAEs or irAEs. Based on Waterfall plot calculations, tumor shrinkage was observed in 15 (68.2%) and 16 (72.7%) pts by RECIST and mRECIST, respectively. ORR was 13.6% (95% CI, 2.9%-34.9%) and 31.8% (95% CI, 13.9%-54.9%) by RECIST and mRECIST, respectively. OS data were immature at data cutoff. Conclusions: The preliminary safety of avelumab + axitinib in HCC is manageable and consistent with the known safety profiles of avelumab and axitinib when administered as monotherapies. This study demonstrates antitumor activity of the combination in HCC. Follow-up is ongoing. Clinical trial information: NCT03289533. [Table: see text]
DNA damage repair (DDR) gene alterations as a predictive biomarker for response to platinum-containing chemotherapy in advanced biliary tract cancer (BTC).
Authors: Chae Heejung , Yoo Changhoon , Kim Deokhoon , Jeong Jae Ho , Chang Heung-Moon , Kim Kyu-Pyo , Ryoo Baek-Yeol
Published: May 2019

4078

Background: Although many studies using whole-exome sequencing or targeted sequencing have reported the molecular profile of BTC, its clinical implications remains unclear. In this study, we assessed a predictive role of DDR gene mutations in advanced BTC patients treated with platinum-containing regimen. Methods: Eighty-eight patients with pathologically-confirmed BTC who received first-line gemcitabine-cisplatin combination (n = 69) or fluoropyrimidine-oxaliplatin combination (n = 19) were included in this analysis. Targeted exome sequencing was performed using Foundation Medicine T7 assay or in-house OncoPanel AMC. Germline or somatic mutations in ATM, ATR, BAP1, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, FAM175A, GEN1, MLH1, MSH2, MSH6, MRE11A, NBN, PALB2, PMS2, RAD50, RAD51, RAD51C, RAD51D, and XRCC2 were classified as DDR gene mutations. Data regarding baseline characteristics and treatment outcomes were retrospectively obtained from medical records. Results: The median age was 62 years (range, 25-78), with male comprising 64.8% (n = 57). By primary tumor site, 21 patients with GBC (23.9%), 44 with ICC (50.0%) and 23 with ECC (26.1%) were included. Most patients received palliative chemotherapy for their initially metastatic (50.0%) or recurred (44.3%) disease; the rest 5.7% had locally advanced disease. The median PFS and OS of overall patients were 7.1 and 16.1 months, respectively with median follow-up duration of 20.2 months. DDR gene mutations were found in 63.5% of patients. BRCA2 (18.2%) was most frequently mutated, followed by ATM (13.6%), and ATR (8.0%). DDR gene mutations were significantly associated with prolonged PFS (presence vs. absence; median, 6.9 vs. 5.7 months; P = 0.013) and OS (median, 21.0 vs. 13.3 months, P = 0.009). The impact of DDR gene mutations remained significant in multivariate analyses for PFS that included other prognostic factors (hazard ratio, 0.51; P = 0.009), but not for OS. Conclusions: The presence of DDR gene mutations might be a promising predictive biomarker for response to platinum-based chemotherapies in advanced BTC. Future investigation using novel agents targeting DDR gene alteration in BTC are warranted.
CT-based radiogenomic signature to identify isocitrate dehydrogenase (IDH)1/2 mutations in advanced intrahepatic cholangiocarcinoma.
Authors: Idris Tagwa , Barghash Maggie , Kotrotsou Aikaterini , Huang Helen J , Subbiah Vivek , Kaseb Ahmed Omar , Piha-Paul Sarina Anne , Hong David S. , Meric-Bernstam Funda , Javle Milind M. , Janku Filip , Colen Rivka R.
Published: May 2019

4081

Background: IDH1/2 mutations have a high prevalence (20%) in intrahepatic cholangiocarcinoma (iCCA) and can be associated with therapeutic benefit from IDH inhibitors. Radiomics, a developing field within imaging, has shown its ability to discriminate between tumors of distinct genomic profiles and mutational status. Methods: We developed a radiogenomic signature to robustly predict IDH1/2 mutation status (mutated versus wild-type [WT]) in 22 patients with iCCA using the pretreatment CT scans. The triphasic hepatic CT scan was used to segment the lesion. After semiautomatic segmentation of the tumor, the extracted volume of interest (VOI) was imported into our in-house radiomic pipeline and 610 radiomic features were extracted. The least absolute shrinkage and selection operator regression (LASSO) and minimum redundancy and maximum relevance (mRMR) were used for feature selection. Selected features were used to build a classification model for prediction of IDH1/2 mutation status (XGboost). The performance of the radiomics model was assessed using leave-one-out cross-validation (LOOCV). Results: Of 22 patients, 16 patients (male, 6; female, 10; average age, 55.5 years) had IDH1 (N = 14) or IDH2 (N = 2) mutations and 6 patients (male, 4; female, 2; average age = 55.5 years) had IDH1/2 WT.The CT-derived radiomic signature robustly predicted presence of IDH1/2 mutations versus WT with an area under the curve (AUC), sensitivity and specificity of 98.4%, 83.3% and 93.8%, respectively ( P = 0.037) and in a subgroup analysis presence of IDH1 mutation versus WT with an AUC, sensitivity and specificity of 98.2%, 83.3% and 92.8%, respectively ( P = 0.035). Conclusions: To our knowledge, this is the first study investigating the ability of radiogenomics as a potential method to predict the IDH1/2 mutation status in iCCA patients. Our data suggest that radiogenomic signature may correlate with IDH1/2 mutations and represent a promising non-invasive tool to stratify the patients based on molecular alterations.
Association of adverse events (AEs) with efficacy outcomes for cabozantinib (C) in patients (pts) with advanced hepatocellular carcinoma (aHCC) in the phase III CELESTIAL trial.
Authors: Abou-Alfa Ghassan K. , Meyer Tim , Cheng Ann-Lii , Cicin Irfan , Bolondi Luigi , Klümpen Heinz Josef , Chan Stephen Lam , Dadduzio Vincenzo , Milwee Steven , Dubey Sarita , Kelley Robin Kate , El-Khoueiry Anthony B.
Published: May 2019

4088

Background: Class-specific AEs occurring with tyrosine kinase inhibitors have been associated with improved efficacy outcomes in several tumor types including aHCC. In the phase 3 CELESTIAL trial (NCT01908426), C, an inhibitor of VEGFR, MET, and AXL, improved overall survival (OS) and progression-free survival (PFS) vs placebo (P) in pts with previously treated aHCC. Here, we retrospectively evaluate the association of palmar-plantar erythrodysaesthesia (PPE) and hypertension (HTN) with OS and PFS for C in the CELESTIAL trial. Methods: 707 pts with aHCC were randomized 2:1 to receive 60 mg C or P once daily. Eligible pts had Child-Pugh score A, ECOG PS ≤1, must have received prior sorafenib, and could have received up to two prior regimens of systemic therapy for HCC. OS and PFS with C were evaluated for pts with any grade PPE or grade ≥3 HTN within the first 8 weeks of study treatment. Results: Overall, 374 (80%) pts in the C arm and 179 (76%) pts in the P arm completed ≥8 weeks of treatment. In the first 8 weeks, 188 (40%) of C-treated pts developed any grade PPE vs 11 (5%) of P-treated pts, and 61 (13%) of C-treated pts developed grade ≥3 HTN vs 3 (1%) of P-treated pts. Median OS with C was 14.4 mo for pts with any grade PPE vs 8.4 mo for pts without PPE (HR 0.59, 95% CI 0.47-0.74), and median PFS with C was 6.5 mo vs 3.7 mo, respectively (HR 0.63, 95% CI 0.51-0.78). Median OS with C was 16.1 mo for pts with grade ≥3 HTN vs 9.5 mo for pts without grade ≥3 HTN (HR 0.56, 95% CI 0.39-0.80), and median PFS with C was 7.4 mo vs 4.4 mo, respectively (HR 0.59, 95% CI 0.43-0.82). Some imbalances in baseline characteristics were present. Pts with PPE had better ECOG PS (60% vs 47% ECOG 0), better liver function (48% vs 34% ALBI grade 1), and less macrovascular invasion (24% vs 30%) than those without. Likewise, pts with grade ≥3 HTN had better ECOG PS (61% vs 51% ECOG 0), better liver function (56% vs 37% ALBI grade 1), and less macrovascular invasion (20% vs 29%) than those without. Conclusions: The development of PPE or grade ≥3 HTN with C was associated with prolonged OS and PFS in pts with previously treated aHCC although some imbalances in baseline characteristics between comparator groups were present. Clinical trial information: NCT01908426.
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.
Molecular profile of ampulla of vater carcinoma (AVC): A rare tumor type with meaningful molecular alterations.
Authors: Pinto João , Verdaguer Helena , Salcedo Maria Teresa , Pedrola Anna , Hernando-Cubero Jorge , Pastrana Juan David Assaf , Acosta Daniel , Vivancos Ana , Dienstmann Rodrigo , Mercade Teresa Macarulla
Published: May 2019

4119

Background: AVC is a rare type of cancer with dismal prognosis and limited therapeutic options due to the lack of specific clinical trials. Two histologic subtypes predominate, namely pancreatobiliary and intestinal. A variety of molecular alterations have been described in AVC, but their clinical and therapeutic implications have not been studied in detail. Methods: Retrospective cohort study of patients (pts) diagnosed with AVC treated in our institution from 2010 to 2018. We routinely performed Next Generation Sequencing in all AVC tumors. Our main objectives were to describe the molecular profile of AVC and correlate with clinical outcomes. Results: Out of 26 pts with AVC, 13 pts were male (50%), median age 65 (range 43-83), 7 pts (27%) had stage IV disease at diagnosis. Histologic type was pancreatobiliary in 18 pts (69%), intestinal in 7 pts (27%) and mixed in one case (4%). We identified KRAS mutations (mut) in 10 pts (7 pancreatobiliary, 2 intestinal, 1 mixed), TP53 mut in 6 pts (4/1/1), PIK3CA mut in 3 pts (3/0/0), ERBB2 mut in 3 pts (2/1/0), CTNNB1 mut in 3 pts (2/1/0). In pancreatobiliary we found single cases with RNF43, BRCA1 and CHEK2 mut; while in intestinal we found single cases with NRAS and BRAF mut. One tumor of intestinal subtype had microsatellite instability (MSI). Three pts were included in phase I clinical trials, 2 of them with trials based on tumor profile (ERBB2 mut with pan-HER inhibitor and MSI with immunotherapy). Median overall survival (OS) was 21 months for pts with stage I, II and III disease (95% CI 12.37-not reached) and 13.2 months for stage IV disease at diagnosis (95% CI 5.73-not reached). In cox models, median OS was not dependent on KRAS or TP53 mutation status, or histological subtypes. Conclusions: AVC is a rare type of cancer with two differentiated histological subtypes harboring unique molecular alterations that can be matched to investigational therapies. A broader knowledge of the biology of these tumors is needed to improve patient outcomes.
The effect of neoadjuvant chemotherapy with gemcitabine and S-1 for resectable pancreatic cancer (randomized phase II/III trial; Prep-02/JSAP-05).
Authors: Satoi Sohei , Unno Michiaki , Motoi Fuyuhiko , Matsuyama Yutaka , Matsumoto Ippei , Aosasa Suefumi , Shirakawa Hirofumi , Wada Keita , Fujii Tsutomu , Yoshitomi Hideyuki , Takahashi Shinichiro , Sho Masayuki , Ueno Hideki , Yamamoto Tomohisa , Kosuge Tomoo
Published: May 2019

4126

Background: Despite recent progress of adjuvant chemotherapy for resected pancreatic ductal adenocarcinoma (PDAC), its survival remains limited. We conducted a randomized controlled trial to compare neoadjuvant chemotherapy (NAC) with upfront surgery (UP-S) for patients with resectable PDAC. Methods: Patients with resectable PDAC, all confirmed cytologically or histologically were enrolled. Patients received 2 cycles of gemcitabine and S-1 regimen (GS) followed by surgery (NAC) or UP-S after randomization (1:1). Patients in both arms received adjuvant chemotherapy using S-1 for 6 months after surgical resection. The primary endpoint was overall survival (OS); secondary endpoints included adverse events, resection rate, recurrence-free survival, residual tumor status, nodal metastases, and tumor marker kinetics. Results: A total 362 patients were randomly assigned to NAC-GS (n=182) or UP-S (n=180) for 3 years (2013-16). The median OS was 36.7 months in NAC-GS and 26.6 months in UP-S; HR 0.72 (p=0.015, stratified log-rank test) at 2.5 year after final enrollment. Crude resection rate for NAC and UP-S were 77%, 72% respectively. There was no operative mortality in both groups. Although G3/4 adverse events were observed frequently (73%) during NAC, no significant difference for both groups was observed for perioperative outcomes including blood loss, operation time, R0 resection rate and post-operative morbidity. Significant decrease of pathological nodal metastases in NAC was noted compared to those in UP-S by pathological evaluation for resected patients(p<0.01). Although significant decrease of viable tumor cells was observed in primary tumor after NAC compared to UP-S (p<0.01), Evans IIb or more was found in only 14 % of resected patients in NAC. Hepatic recurrence after surgery was significantly reduced in NAC (30.0%) compared to UP-S (47.5%) in observed period. Conclusions: The strategy of NAC showed significant longer survival compared to that of UP-S with acceptable feasibility. The effect of NAC might imply the control of subdiagnostic liver metastases before surgery for resectable PDAC. Clinical trial information: UMIN000009634.
Homologous recombination deficiency (HRD): A biomarker for first-line (1L) platinum in advanced pancreatic ductal adenocarcinoma (PDAC).
Authors: Park Wungki , Wong Winston , Yu Kenneth H. , Varghese Anna M. , Riaz Nadeem , Balachandran Vinod P. , El Dika Imane H. , Raj Nitya Prabhakar , Khalil Danny , Ku Geoffrey Yuyat , Segal Neil Howard , Li Jia , Chalasani Sree Bhavani , Chong Curtis Robert , Kelsen David Paul , Abou-Alfa Ghassan K. , Berger Michael F. , Schultz Nikolaus , Iacobuzio-Donahue Christine A , O'Reilly Eileen Mary
Published: May 2019

4132

Background: HRD is an emerging biomarker for platinum therapy in PDAC. The clinical implications regarding differences in outcome between germline and somatic HRD in advanced PDAC treated with 1L platinum is unexplored. Methods: We evaluated overall survival (OS) for advanced PDAC (stage III/IV) based on their pathogenic germline (gHRD) and somatic HRD (sHRD) using integrated genomic profiling from MSK-IMPACT and 1L platinum use. HRD defined by pathogenic alterations from the following genes: BRCA1/2, PALB2, ARID1A/B/2, ATR, ATRX, ATM, BAP1, RAD50/51C/D, BRIP1, NBN, CHECK1/2, FANCA/C, CDK12, and MRE11. Results: Advanced PDAC patients (n=461) treated at MSK enrolled in a prospective database, were evaluated. Median follow-up was 27.6 months (95% CI, 24.6-30.6). Both germline and somatic profilings were available for n=350 (76%) but only somatic profiling was available for n=111 (24%). We identified n=52 patients with gHRD (11.3%), n=42 patients with sHRD (9.1%), and 48 patients with somatic VUS for HRD genes. From all 461 patients, the OS was not different between 1L non-platinum vs. 1L platinum groups (19 M vs. 19.3 M), regardleess of their HRD status. (Table) The OS was superior for gHRD vs. non-gHRD (28.7 M vs. 18.2 M), regardless of 1L treatment choice. However, similar significant OS superiority was neither observed in sHRD vs. non-sHRD, nor in VUS sHRD vs. non-VUS sHRD. In a subgroup analysis of 1L platinum treated patients, the OS was superior in gHRD vs. non-gHRD (NR vs. 17.9 M); however, there was no OS difference between sHRD and non-sHRD. Conclusions: In advanced PDAC patients, only gHRD predicted better overall survival for first-line platinum chemotherapy. These findings emphasize the importance of germline mutation testing of HRD in PDAC. Biomarker validation and functional definition of HRD such as loss of heterozygosity analysis is underway. [Table: see text]