tbuckley/cabot-search huggingface dataset:
Feasibility of molecular patient selection in rare cancers: Phase II study of gemcitabine, oxaliplatin and capecitabine in KRAS mutated biliary tract cancer.
Authors: Lars Henrik Jensen, Eva Fernebro, John Ploen, Jan Lindebjerg, Anders Kristian Moeller Jakobsen
Journal: Journal of Clinical Oncology (2016)

e15620 Background: KRAS mutations occur in biliary tract cancer (BTC) at a low rate and little is known as to prognosis and response to chemotherapy for this subgroup. This is the first prospective study to report the outcome of combination chemotherapy in BTC patients with a prespecified molecular characteristic of KRAS mutation. The aim was to investigate the feasibility of combination chemotherapy in patients with KRAS mutated BTC. Methods: From 2009 to 2015 25 patients were included from two Scandinavian centers. Main inclusion criteria were non-resectable biliary tract cancer, performance status 0-2 and tumor KRAS mutation. Chemotherapy was given in a two-week cycle with gemcitabine 1000 mg/m2 and oxaliplatin 85 mg/m2 day 1 followed by 7 days of capecitabine 1000 mg/m2 bid. Response evaluation was done every six treatments and the primary endpoint was the fraction of PFS at 6 months. ClinicalTrials.gov NCT00779454. Results: Sixteen females and 9 males were included and the median age was 69 years (range 50-80). Performance status was 0 (n = 7), 1 (n = 11) and 2 (n = 7). Seventeen patients had metastatic disease and 8 had locally advanced disease. Chemotherapy was given for a median of 5 full months (range 0-14). One grade 4 (febrile neutropenia) and 6 grade 3 toxicity (febrile neutropenia, hyperglycemia and urticaria) was observed, while the commonest grade 1-2 toxicities were neurotoxicity, nausea or vomiting. Among 17 patients evaluable for response, 1 complete and 2 partial responses were seen and the rest had stable disease as best response. 18 patients had progression documented with CT-scans, 6 died between planned evaluations and one patient is still alive without progression. Median PFS was 6.8 months (95% CI 3.1-11.0) and median overall survival was 11.2 months (95% CI 6.6-14.3). The fraction of PFS at 6 months was 52% (95% CI 31-69%). Conclusions: Combination chemotherapy was feasible and the results with a PFS and OS of 6.8 and 11.2 months, respectively, point to an effect in patients with KRAS mutation similar to that of unselected patient populations. Clinical trial information: NCT00779454.
Estimated costs of managing treatment-related adverse events (TRAEs) of nivolumab (nivo) and docetaxel (doc) in the CheckMate 017 and CheckMate 057 phase III non-small cell lung cancer (NSCLC) trials.
Authors: Meena Venkatachalam, David D. Stenehjem, Guilhem Pietri, John R. Penrod, Beata Korytowsky
Journal: Journal of Clinical Oncology (2016)

6617 Background: Nivo, a PD-1 antibody, received FDA approval based on superior overall survival in metastatic squamous (SQ) and non-squamous (NSQ) NSCLC patients who have progressed on or after platinum-based doublet chemotherapy. The purpose of this study was to assess the frequency and associated costs of grade 2–4 AEs in the CheckMate 017 (SQ) and CheckMate 057 (NSQ) phase III pivotal trials of nivo vs doc in stage IIIB/IV NSCLC. Methods: Patient-level data from these two trials were utilized to estimate the frequency of TRAEs requiring management in the nivo and doc arms, including serious and non-serious TRAEs. Minimum follow-up for AE reporting at database lock was 12 months. Grade 3–4 AE costs by event were identified from Healthcare Cost and Utilization Project (HCUP) data in 2010, which were adjusted to reflect 2012-equivalent US costs. Healthcare utilization associated with grade 2 AEs was based on clinical opinion and costs were based on HCUP or other sources as appropriate. Results: In both trials, more TRAEs were observed with doc than with nivo (Table), and the cost of managing TRAEs was 15.8 and 10.7 times higher in the doc arm vs the nivo arm for the CheckMate 017 and CheckMate 057 trials, respectively. Patients in the doc arm incurred an additional $6,585 and $5,422 per patient in managing AEs compared with patients in the nivo arm in the above two trials, respectively. The total estimated costs of managing TRAEs during these trials are presented in the Table. Conclusions: Large estimated differences in costs were observed in managing TRAEs, favoring nivo in the CheckMate 017 and CheckMate 057 pivotal trials. The reduction in costs for managing AEs with the use of nivo should be considered when assessing the value of nivo in this patient population. Clinical trial information: NCT01642004, NCT01673867. CheckMate 017 (SQ) CheckMate 057 (NSQ) Doc (N=129) Nivo (N=131) Doc (N=268) Nivo (N=287) Total no. of TRAEs 172 52 370 157 Total cost of managing TRAEs, $ 906,104 57,506 1,591,987 148,603 Average cost per TRAE, $ 5,268 1,106 4,303 947 Average cost per treated patient in each trial, $ 7,024 439 5,940 518
Osteoponstin expression and presence of EGFR-positive liver macrophage to predict outcome after liver transplantation for hepatocellular carcinoma.
Authors: Kaoru Tsuchiya, Wolfgang Sieghart, Merima Herac, Florian Hucke, Georg Oberhuber, Maria Sibilia, Markus Peck-Radosavljevic
Journal: Journal of Clinical Oncology (2017)

e15664 Background: Orthotopic liver transplantation (OLT) is the most effective therapy for patients with hepatocellular carcinoma (HCC) of limited extent. We focused on biomarkers, which could serve as tools for patient selection for OLT with good outcome even when transplanted beyond the standard size limits. Methods: Osteopontin(OPN) expression and presence of Epidermal Growth Factor Receptor (EGFR)-positive liver macrophage had been shown previously to be associated with the risk of tumor recurrence post OLT and were investigated immunohistochemically in 125 HCC-patients undergoing OLT between 1982 and 2002. Multivariate analyses of these and other well-described factors associated with median overall survival (OS) and time to recurrence (TTR) were performed. Results: The OS rates of the 125 patients at 1, 3, 5, 7 and 10 years were 77%, 52%, 43%, 37% and 32%. The 3-, 5-, and 7-year survival rates for patients without expression of both biomarkers (OPN and EGFR-positive liver macrophage) were 66.1%, 61.0% and 54.1%. These were significantly better than for the other groups (p &lt; .0001), whereas the 3- and 7-year survival rates for patients with expression of both biomarkers were 25.0% and 5.0%. Fifty-eight patients (38.4%) developed tumor recurrence.There was no significant difference in OS and TTR between the patients beyond the Milan criteria (MC) without expression of both biomarkers (n = 26) and the patients within MC with expression of one or two biomarkers (n = 20).On multivariate analysis, vascular invasion and presence of EGFR-positive liver macrophage in HCC were independent factors associated with OS. Both biomarkers were independent factors associated with TTR.On multivariate analysis, morphologic criteria including MC and Up-to-7 criteria were not significantly associated with OS and TTR once OPN and EGRF+ macrophage presence was introduced into the analysis. Conclusions: Staining for OPN and EGFR-positive liver macrophage in HCC can give important prognostic information. The discussion about the selection for OLT in HCC patients should likely consider the expression of biomarkers in addition to relying on morphologic criteria.
Total and out-of-pocket costs of different primary management strategies in ovarian cancer.
Authors: Rudy Sam Suidan, Weiguo He, Charlotte C. Sun, Hui Zhao, Karen H. Lu, Sharon Hermes Giordano, Larissa Meyer
Journal: Journal of Clinical Oncology (2017)

6602 Background: Communicating healthcare costs to pts is an important component of delivering high-quality value-based care, yet cost data are lacking. This is especially relevant for epithelial ovarian cancer (OC), where no clinical consensus on optimal first-line treatment exists. Our objective was to generate cost estimates of different primary management strategies in OC. Methods: All women who underwent primary treatment for OC from 2006 – 2015 were identified from MarketScan, a claims database of commercially insured US pts (n = 12,761). Pts were classified based on: 1) whether they underwent primary debulking surgery followed by postoperative chemotherapy, or neoadjuvant chemotherapy followed by interval debulking; 2) type of chemotherapy regimen administered (intravenous [IV] every 3 weeks [Standard], IV every week [Dose-dense], or intraperitoneal [IP]/IV); and 3) if regimens included bevacizumab (Bev). Total and out-of-pocket (OOP) costs were calculated using all claims within 8 months from initial treatment and were normalized to 2015 US dollars. A generalized linear model was used to assess cost by strategy adjusting for clinical and demographic factors. Results: Mean adjusted total and OOP costs for the different treatment strategies/regimens are shown in the table. Among pts who did not receive Bev, 25% paid ≥$3964 and 10% paid ≥$5875. For pts who received Bev, 25% paid ≥$4201 and 10% paid ≥$6222. Among pts enrolled in high-deductible health plans, mean OOP costs were $4680, with 25% of pts paying ≥$6264 and 10% paying at least $9144. Conclusions: Costs vary across different treatment strategies and pts bear a significant OOP burden, especially those enrolled in high-deductible plans. As no consensus exists on optimal first-line management for OC, these data may help inform value-based discussions between providers and pts. [Table: see text]
Matrix metalloproteinase as a prognostic marker of malignancy in melanocytic tumors.
Authors: Elena Petrovna Ulianova, Oleg Ivanovich Kit, Inna Arnoldovna Novikova, Natalia A. Maksimova, Viktoria V. Pozdnyakova, Aleksandr B. Sagakyants, Oksana G. Shulgina, Maria I. Maksimova, Anastasia O. Sitkovskaya
Journal: Journal of Clinical Oncology (2018)

e21597 Background: The purpose of the study was to determine the expressions of matrix metalloproteinase (MMP-2) in tissues of melanocytic tumors and to evaluate it as a prognostic marker. Methods: The study included 30 patients with benign pigmented tumors and 30 patients with melanoma. Sections of tissues embedded in paraffin blocks were studied by immunohistochemistry. The UltraVision Quanto Detection System HRP DAB was used for the visualization. The intensity of staining and the number of antigen-positive cells were recorded to assess the ММР-2 reaction, and the marker expression was determined. The immunohistochemical reaction was considered as weak positive (+, < 10% positive cells), moderate positive (++, ≥10-50% positive cells) or strong (+++, > 50% positive cells). Results: A high expression of MMP-2 in the cytoplasm was observed in both groups of patients (benign pigmented lesions – 30%, 9 of 30 cases; melanoma – 30%, 9 of 30 patients). The highest MMP-2 expression was found in melanoma cells – 54.2±5.1, compared to benign tumors – 49.4±4.1. However, the range was very wide, and the differences were insignificant (p≥0.05). A weak positive MMP-2 reaction (+) was observed in 43% (13 of 30) benign melanocytic lesions and in 16.7% (5 of 30) melanoma; a moderate positive reaction (++) was observed in 37% (11 of 30) and in 33.3% (10 of 30), respectively; and a strong positive reaction (+++) – in 50% (15 of 30) and 20% (6 of 30), respectively. Conclusions: A tendency to the strong reaction was found in melanoma cells, but the expression was not uniform; therefore, matrix metalloproteinase cannot serve as a definite prognostic marker of malignancy of melanocytic lesions.
Randomized, double-blind, placebo-controlled trial of evofosfamide (Evo) and pemetrexed (Pem) in advanced non-squamous non-small cell lung cancer (n-s NSCLC).
Authors: Tibor Csõszi, Jonathan Wade Goldman, Maria Szilasi, Joachim Von Pawel, Silvia Novello, Corey Allan Carter, Tudor-Eliade Ciuleanu, Alessandro Del Conte, Gurkamal Chatta, Michael Schenker, Francisco Robert, Sergey Orlov, Katarzyna Zajda, Filippo De Marinis, Charles L. Bennett, Stew Kroll, Tillman E. Pearce, Chandra Belani
Journal: Journal of Clinical Oncology (2016)

9075 Background: Tumor hypoxia is associated with chemo- and radioresistance. Evo is a hypoxia-activated prodrug that releases the bis-alkylating DNA crosslinker Br-IPM when reduced in severe hypoxia. The study was initiated following a Phase 1/2 study (NCT00743379). Methods: This international, multicenter, randomized, double-blind, placebo-controlled trial investigated Evo+Pem vs placebo (Pbo)+Pem as 2nd line therapy for patients (pts) with stage IIIB/IV n-s NSCLC. Pts had one prior platinum-based non-Pem chemotherapy, RECIST 1.1 measureable disease and ECOG 0-1. Evo (400 mg/m2) or matched Pbo was dosed on Days 1 and 8 with Pem (500 mg/m2) on Day 1 of a 21-day cycle. OS was the primary endpoint; secondary endpoints include safety, PFS and response rate. The study was designed to enroll 440 patients randomized 1:1 to obtain 321 events (deaths) to assure 85% power to detect a hazard ratio of 0.715 for OS with a two-sided α of 0.05. An interim futility analysis was conducted after approximately 1/3 of deaths required for final analysis were reported. Results: From June 2014 to Dec 2015, 259 pts were randomized (131 Evo+Pem, 128 Pbo+Pem). Baseline characteristics were balanced. Median age: 62 (range 24-82); 43% Female; 73% ECOG 1; 31% M1A, 68% M1B. Median cycles were 4 in both arms. At interim analysis with 112 deaths, enrollment into the study was stopped based on OS futility analysis: HR = 0.96 (95% CI: 0.66-1.41) with conditional power under current trend of < 5%. mOS was 8.9 mo with Evo+Pem vs 8.5 mo with Pbo+Pem. Best response was greater on Evo+Pem, 16.2% vs 7.8%: odds ratio = 2.30 (95% CI: 1.00 – 5.33, p = 0.047) and mPFS was longer on Evo+Pem, 4.5 mo vs 2.8 mo: HR = 0.67 (95% CI: 0.47-0.93, p = 0.017). Most common Grd 3/4/5 AEs were neutropenia (13%), anemia (10%) and asthenia (6%). Grd 1 or 2 skin toxicity was greater on Evo+Pem. Treatment discontinuations for AE were higher with Evo+Pem, 15.3% vs 5.3%. AEs leading to death were 13.0% on Evo+Pem vs 13.8% on Pbo+Pem. Conclusions: The combination of Evo+Pem did not improve OS vs Pbo+Pem. Anti-tumor activity was reported with a higher response rate and longer PFS on Evo+Pem. The safety profile was consistent with that previously reported. Clinical trial information: NCT02093962.
European Union standard for tuberculosis care on treatment of multidrug-resistant tuberculosis following new World Health Organization recommendations
Authors: Giovanni Battista Migliori, Giovanni Sotgiu, Senia Rosales-Klintz, Marieke J. van der Werf
Journal: European Respiratory Journal (2018)

<b>The key changes to treatment of multidrug-resistant tuberculosis (World Health Organization, August 2018) should be taken into account when applying standard 12 of the European Union Standards for Tuberculosis Care</b>http://ow.ly/nVwl30lI8aF
Genomic alterations and clinical outcomes in patients with advanced liposarcoma.
Authors: Edward S. Kim, Michael B. Livingston, Qing Zhang, Nury Steuerwald, William Ahrens, Jeffrey Kneisl, Joshua Patt, Jennifer L. Ersek, Alexander Howard, Adam G Abel, David Spetzler, Carol J. Farhangfar
Journal: Journal of Clinical Oncology (2018)

e23558 Background: Patients with liposarcoma have poor overall outcomes. Few genomic alterations have been identified and limited therapeutic options exist. Methods: Patients with de-differentiated liposarcoma were identified from the Levine Cancer Institute database. We performed genomic testing (600 genes), IHC, FISH/CISH, and expression analysis (Modaplex, RNASeq). Confirmation of genomic alterations was performed by orthologous method (PCR, Sanger sequencing) and correlated with clinical outcomes. Interactions between pathways were explored. Univariate Cox regression was used to identify genomic alterations that were associated with overall survival (OS). Results: Patient characteristics included: median age at diagnosis (65 yrs), Caucasian (88%), median follow-up time (7.62 yrs) and median OS (3.3 yrs). Tumor tissue from initial diagnosis (56%), first recurrence/progression (13%), or later (13%) was tested. 33 of 41 patients had adequate tissue for genomic profiling. Many genes were amplified including CDK4 (64%), MDM2 (73%) and WNT/Notch pathway markers (HMGA2, LGR5, MCL1, CALR, CDKN2A; 18-27%). EGFR was overexpressed in 38% (IHC). PDE4DIP E243fs and FOXO3 L382fs was mutated in 33% of patients, neither previously reported. Mutations in several genes predicted a worse OS including MN1 (HR = 5.8, p < 0.001), RB1 (HR = 13.3, p < 0.001), IRS2 (HR = 4.2, p = 0.02), RECQL4 (HR = 2.6, p = 0.04). Mutations in MAML2 (HR = 0.2, p = 0.03) correlated with improved OS. TOP2A expression predicted worse OS (HR = 3.0, p = 0.006). Expression data was most notable for changes in RB1 and E2F gene family with EGFR, TOP2A, CDK4, and CCND1 over-expression confirmed. Conclusions: This is one of the first reports of large genomic testing correlated with clinical outcomes in patients with liposarcoma. Therapies targeting these abnormalities should be explored and confirmation of potential prognostic markers in key cell cycle and proliferation pathways should be obtained.
Serum interleukin 8 (IL-8) may serve as a biomarker of response to immuno-oncology (I-O) therapy.
Authors: Michael Carleton, Ming Zhou, Olivier De Henau, Penny Phillips, Tian Chen, Ye Feng, Shu-Pang Huang, Alice Walsh, Timothy P. Reilly, Ignacio Melero Bermejo
Journal: Journal of Clinical Oncology (2018)

3025 Background: Biomarkers are needed to identify pts responsive to I-O therapies. IL-8 is a proinflammatory chemokine that promotes tumor immune escape. High serum IL-8 levels are associated with poor prognosis (Sanmamed et al. Clin Cancer Res. 2014); changes in serum IL-8 levels were associated with response to anti–PD-1 therapy in a small cohort of pts with melanoma (MEL) and NSCLC (Sanmamed et al. Ann Oncol. 2017). Here we report a large, cross-study, retrospective association analysis of baseline (BL) serum IL-8 levels with clinical efficacy and biomarkers in pts receiving nivolumab (NIVO)-based therapy. Methods: Data were analyzed from ≈2000 pts with MEL, NSCLC, and renal cell carcinoma enrolled in 8 clinical trials. Serum IL-8 was measured using an immunoassay platform (Myriad RBM, Austin, TX). Correlative efficacy metrics included BL tumor burden, overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Receiver operating characteristic (ROC) curve analyses for 12-month OS were used to determine IL-8 cutoffs associated with response. Additional tumor and peripheral correlative markers were assessed. Results: Quartile stratification of serum IL-8 levels showed that elevated BL IL-8 was associated with poor OS. ROC analysis of NIVO-based therapy from pooled study data identified 23 pg/mL as an IL-8 threshold that could be used to enrich for pts who may be more likely to benefit from I-O. Additional IL-8 correlates were identified, including elevated tumor CXCL8 mRNA and peripheral neutrophil count, but these were not statistically significant across all indications. Detailed analyses in pts with MEL showed the correlation of BL IL-8 with OS was independent of BL tumor burden or PD-L1 tumor expression. Absolute BL and post-BL IL-8 levels were more strongly associated with OS, PFS, and ORR than changes from BL. Conclusions: Association of serum IL-8 with response to NIVO-based therapy suggests that IL-8 may serve as a clinically useful biomarker to select for pts who can benefit from I-O therapy. We hypothesize that IL-8 neutralization in pts with elevated BL IL-8 may restore sensitivity to anti–PD-1 therapy; this will be tested clinically with an anti–IL-8 antibody (NCT03400332).
A prospective biomarker study to assess IGF-1 score ability to sub-stratify Child-Turcotte-Pugh classes and predict response to systemic therapy in hepatocellular carcinoma.
Authors: Ahmed Omar Kaseb, Reham Abdel-Wahab, Manal Hassan, Lianchun Xiao, Kanwal Pratap Singh Raghav, Lauren Girard, Hesham M. Amin, Jeffrey Morris, Robert A. Wolff, James C. Yao
Journal: Journal of Clinical Oncology (2017)

e15662 Background: Our recent studies showed that lower insulin like growth factors-I (IGF-I) associated with shorter overall survival (OS) in HCC. Furthermore, integrating IGF-I into Child Pugh Score (CTP) (IGF-CTP) led to better prognostic stratification (Kaseb et al., JNCI 2014). Since CTP class A is the standard criterion for active therapy and trials entry, we aimed at assessing the ability of IGF-CTP to predict systemic therapy outcome. Methods: 78 patients were prospectively enrolled and treated with sorafenib. Pre-treatment blood sample were tested for IGF-I and IGF-CTP was calculated after study completion. Survival analysis was done to measure the estimated median OS and progression free survival (PFS), and log rank test was used to compare PFS and OS between subgroups of IGF-CTP score of patients. Results: For CTP A patients, the estimated median OS in months (95% confidence interval, CI) was 9.1m (5.3 – 19.7) and PFS was 5.6m (3.8 – 7.9). Patients who were reclassified as IGF-CTP (B) (OldA/newB = AB) had significantly shorter OS 5.2m (2.8 - NA) and PFS of 4.3m (2.1 – NA), as compared to patients’ who classified as class A by both scoring systems (AA), who had OS of 11.1m (5.7 – 21.3) and PFS of 7.2 m (3.9 – 15.1), P &lt; .001. Interestingly, patients who classified as CTP-B but IGF-CTP-A ( = BA) had significantly longer OS 10.2 (2.89 – NA) and PFS 8.1 (2.9 – NA), as compared to (BB) patients who had OS of 5.8 (3.2 –NA) and PFS of 5.1 (3.19 – NA), P &lt; .001 Conclusions: Our study concluded that IGF-CTP score was more accurate than original CTP score in predicting survival outcomes of systemic therapy in HCC. If validated, this approach may change the standard stratification criteria for active therapy in routine clinical practice and patient selection for clinical trial entry in HCC.
Phase 1 study to evaluate the safety and efficacy of immunotherapy with tremelimumab and durvalumab in multiple myeloma patients receiving high dose chemotherapy and autologous stem cell transplant (HDT/ASCT) + peripheral blood lymphocyte (PBL) reinfusion.
Authors: Alexander M. Lesokhin, David J. Chung, Hearn J. Cho, Lisa Shohara, Paul Schwarzenberger, Toni Ricciardi, Mary J. Macri, Aileen Ryan, Ralph Rudolph Venhaus
Journal: Journal of Clinical Oncology (2017)

TPS8051 Background: Multiple myeloma (MM) remains an incurable hematologic malignancy despite the advent of new classes of drugs, including immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies. The success and synergistic activity of immunotherapy (IMT) in solid tumors and hematologic malignancies has fueled their investigation in MM. HDT/ASCT as consolidation or as treatment for relapse remains a cornerstone for improving overall survival. HDT/ASCT transiently eliminates immune-suppressive cell populations and provides a viable IMT platform. Reinfusion of PBLs harvested pre-HDT induces immune responses, supporting its inclusion in IMT combinations. This study evaluates the effect of IMT, using tremelimumab (T), an anti-CTLA-4 monoclonal antibody, and durvalumab (D), an anti-PD-L1 monoclonal antibody, together with autologous PBL reinfusion and starting T ± D at Day 100 and earlier (Day 30) post-ASCT. Methods: This ongoing Phase 1, open-label, multicenter study (NCT02716805) evaluates the safety and preliminary efficacy of T and D administered on 2 schedules in MM patients at high risk for relapse as outlined below. Cohort initiation requires dose-limiting toxicity in &lt; 2/6 patients in the previous cohort. The primary endpoint is safety. Secondary endpoints are objective response rate per IMWG, minimal residual disease, progression free and overall survival, and 100-day ASCT-related mortality. Exploratory endpoints include immunological effects and immune response. Enrollment opened 18 Nov 2016. As of 31 Dec 2016, 1 patient is enrolled in Cohort 1; enrollment is ongoing. Clinical trial information: NCT02716805. [Table: see text]