tbuckley/cabot-search huggingface dataset:
Mutation profiling of FGFR genes in solid tumors using comprehensive NGS panel.
Authors: Lingjun Zhu, Rongrong Chen, Gen Lin, Yu Chen, Longbo Zhang, Chunwei Xu, Wen-xian Wang, Xin Yi, Xuefeng Xia
Journal: Journal of Clinical Oncology (2018)

e24241 Background: Fibroblast growth factor (FGFR) signaling pathway is evolutionary conserved, and aberrant FGFR signaling is involved in the pathogenesis of cancer. A number of agents targeting the FGFR signaling pathway are currently in development. However, the prevalence of FGFR mutations in other solid tumors remains largely unknown. Methods: We retrospectively analyzed mutation profiling of 3000 consecutive tissue biopsy samples in our institute. Somatic mutation testing was performed with hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of single-nucleotide variants (SNV), insertions/deletions, rearrangements, and copy-number alterations of at least 59 genes (range 59 – 1021 genes). SNV interpretation followed the ACMG guidelines. Results: Copy number gain or gain of function mutations in FGFR1, FGFR2, FGFR3, FGFR4 were identified in a total of 51 patients (1.7%), as detailed in table 1. For the gain of function mutations, FGFR1 (N546K V561M), FGFR2 (K659M, N549K, C382R, Y375C, W290C, S252W), FGFR3 (K650E, S249C, G380R, R248C, G372C, G382R, G370C), and FGFR4 (P712T, N535K) were identified in this study. Breast cancer had a relatively higher percentage of FGFR1 CNV (3.9%), followed by gastroesophageal carcinoma (3.0%). Meanwhile, gastroesophageal carcinoma also had a relatively high percentage of FGFR2 CNV (4.0%). In terms of rearrangements, we identified 7 FGFR3-TACC3 fusions in 5 lung cancer, 1 malignant glioma and 1 bladder cancer patients. Conclusions: Comprehensive NGS sequencing can detect different types of FGFR mutations in multiple solid tumors. This approach may be cost-effective in finding potential target for refractory cancer patients. Table 1. The prevalence of FGFR mutations in solid tumors Average Lung cancer Breast cancer Colorectal cancer Others FGFR1 CNV 1.1% 0.9% 3.9% 0.7% 1.5% FGFR1 SNV 0.1% 0.0% 0.0% 0.0% 0.2% FGFR2 CNV 0.2% 0.1% 0.7% 0.7% 0.7% FGFR2 SNV 0.1% 0.1% 0.4% 0.0% 0.1% FGFR3 CNV 0.0% 0.1% 0.4% 0.0% 0.0% FGFR3 SNV 0.2% 0.1% 0.2% 0.5% 0.3% FGFR4 CNV 0.0% 0.1% 0.0% 0.0% 0.0% FGFR4 SNV 0.0% 0.0% 0.1% 0.0% 0.0% All 1.7% 1.4% 5.7% 1.9% 2.8%
Dendritic cell (DC) based cryoimmunotherapy (CryoIT) in a prospective phase I trial of metastatic castration resistant prostate cancer (mCRPC): Interim analysis.
Authors: Alfred Honoré, Liv Cecilie Vestrheim Thomsen, Bjarte Almås, Lars Anders Reisæter, Jannicke Frugård, Einar Kleboe Kristoffersen, Guro Kristin Melve, Torjan Haslerud, Jarle Tor Rørvik, Martin Biermann, Svein Inge Helle, Gunnar Kvalheim, Ole Johan Halvorsen, Duke Bahn, Klaus Pantel, Haakon Ragde, Bjorn T. Gjertsen, Anne Margrete Oyan, Karl-Henning Kalland, Christian Beisland
Journal: Journal of Clinical Oncology (2018)

e17014 Background: Interim analysis data are presented for 13 pts with mCRPC treated with DC based CryoIT and at least 3 months follow-up (FU). CryoIT exposes tumor antigens in cryoablated tissue to immature DC, thereby mobilizing an immune response against bone and soft tissue metastases. Primary trial aim is safety of CryoIT while secondary objectives include clinical, radiological and immunological treatment responses. Methods: Adverse events (AEs) and blood analyses were registered at all visits and imaging performed before and three months post treatment. Norwegian regulatory authorities have approved the study. CryoIT was performed under general anesthesia with immediate autologous DC injection afterward. Subjects were evaluated according to RECISTv1.1 at inclusion and 3 months post treatment. We identified peripheral blood leukocyte subsets (flow/mass cytometry), circulating tumor cells (CTCs) (Cellsearch System) and ultradeep T-cell receptor (TCR) b-chain sequences (TCRSafe Technology). Results: At inclusion median age was 69 (62-73) years, BMI 26 (25-35), ECOG 0 (0-1) and PSA 8 (5-11). Radiological response categorized participants into Group 1; stable (n = 5) or Group 2; progression (n = 4). Three pts showed mixed response and one had no FU imaging. Of 13 possible DC-related AEs reported by 10 individuals, only one was severe and 12 mild-to-moderate, whereof urinary retention constituted seven. All but one resolved by use of an indwelling urinary catheter for a median of 8 (1-40) days. Group 2 demonstrated higher PSA (p = 0.03) at inclusion. Subjects with elevated CTC counts ( > 5) before therapy had higher rates of progression, while moderate pretreatment CTC numbers (3-5) decreased, and no pt acquired CTCs during FU. Ultradeep TCR-sequencing demonstrated that Group 1 had more prevalent and higher expressed ( > 5-fold) new TCR clonotypes 2-6 weeks after treatment. Conclusions: The treatment seems safe and well tolerated. Higher PSA at baseline suggests more advanced disease in Group 2. The data indicate immune responses to treatment with higher increases in TCR clonotypes in men with radiologic stable disease. Clinical trial information: NCT02423928.
Investigation of profile-related evidence determining individualized cancer therapy (I-PREDICT) in heavily pre-treated patients: A role for combinatorial precision cancer therapy.
Authors: Jason K. Sicklick, Shumei Kato, Maria Clemence Schwaederle, Ryosuke Okamura, Michael Hahn, Casey B. Williams, Pradip De, Amy K. Krie, David Eric Piccioni, Vincent A. Miller, Jeffrey S. Ross, Adam Benson, Jennifer Webster, Philip J. Stephens, J. Jack Lee, Paul T. Fanta, Brian Leyland-Jones, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2018)

2531 Background: With the increasing availability of large gene panels and cognate agents, we hypothesized that offering individualized combination therapies to patients with refractory cancers would improve outcomes. Methods: I-PREDICT (NCT02534675) is a prospective navigation trial (two centers: UC San Diego and Avera Cancer Institute). Comprehensive genomic profiling (CGP, Foundation Medicine; 315 genes), and, if possible, PD-(L)1 immunohistochemistry, tumor mutational burden and circulating tumor DNA were performed. A molecular tumor board discussed results immediately upon receipt, and emphasized use of customized, matched targeted/ immunotherapy combinations. Final decisions were the treating physician’s choice. Results: Overall, 149 patients with advanced cancers were enrolled: 83 (55.7%) have been treated [73 matched (49.0%); 10 unmatched (16.7%)]. Diverse malignancies including gastrointestinal, hepatobiliary, gynecologic, and brain were represented. Median number of prior therapies = 2; median (range) of genomic alterations per patient = 4 (1-20). Each tumor had a unique genomic profile. The median (range) number of agents given was 2 (1-5), dosed individually on an N-of-1 basis. There were no drug-related deaths. We classified the patients based upon their treatment regimens’ molecular Matching Score [number of genomic alterations matched/total number of characterized DNA alterations ( > 50%: “high,” n = 28; ≤50%: “low,” n = 55 (includes unmatched (score = 0))]. High vs low Matching Scores independently correlated with better outcomes: SD≥ 6 months/PR/CR, 50% versus 22% (P = 0.03); median PFS (6.5 vs 3.1 months; P = 0.0004); median OS (not reached vs 10.2 months; P = 0.04) (all multivariate). Conclusions: The use of customized, multi-drug combinations targeting > 50% of identified genomic alterations recommended by timely molecular tumor boards and based on CGP was safe and associated with improvements in all outcome parameters. These findings underscore the feasibility and the importance of designing precision oncology trials that emphasize tailored combinations rather than monotherapies. Clinical trial information: NCT02534675.
Randomized phase III trial of gastrectomy with or without neoadjuvant S-1 plus cisplatin for type 4 or large type 3 gastric cancer: Japan Clinical Oncology Group study (JCOG0501).
Authors: Yoshiaki Iwasaki, Masanori Terashima, Junki Mizusawa, Hiroshi Katayama, Kenichi Nakamura, Hitoshi Katai, Takaki Yoshikawa, Yuichi Ito, Masahide Kaji, Yutaka Kimura, Motohiro Hirao, Makoto Yamada, Akira Kurita, Masakazu Takagi, Masahiro Gotoh, Akinori Takagane, Hiroshi Yabusaki, Naoki Hirabayashi, Takeshi Sano, Mitsuru Sasako
Journal: Journal of Clinical Oncology (2018)

4046 Background: Schirous type cancer, such as linitis plastica (type 4) or large ( > = 8 cm) ulcero-invasive-type (type 3) gastric cancer (GC) is characterized by poorly differentiated adenocarcinoma including signet-ring cell histologically and by frequent peritoneal dissemination clinically. Based on the promising results in our previous phase II study (JCOG0210) evaluating neoadjuvant chemotherapy (NAC) with S-1 plus cisplatin (CDDP), we proceeded to phase III study to confirm the efficacy of NAC in these subtypes of GC. Methods: Eligibility criteria included histologically proven adenocarcinoma of the stomach; clinically resectable gastric cancer of type 4 or large type 3. Patients were randomized to surgery followed by adjuvant chemotherapy (S-1, days 1–28, q42 days for 1 year) (Arm A) or NAC (S-1, 80–120 mg/body, days 1–21 and cisplatin, 60 mg/m2, day 8, q28, 2 courses) followed by gastrectomy plus same adjuvant chemotherapy (Arm B). Primary endpoint was overall survival (OS). A total of 300 eligible patients were required to detect 10% difference in 3-year OS (hazard ratio = 0.74) with a one-sided 5% significance level and power of 80%. OS for the two treatments arms will be compared using a stratified log-rank test. Results: Between February 2007 and July 2013, 300 patients (149 in Arm A, 151 in Arm B) were enrolled. 98 (65.7%) and 112 (74.2%) patients underwent R0 resection in Arms A and B, respectively. Surgery-related death occurred in two in Arm A and one in Arm B. In the Arm B, NAC was completed in 131 patients (86.8%) and Grade 3/4 non-hematological toxicities were seen in 36 patients (22.4%). Pathological response induced by NAC, defined as disappearance of the primary tumor more than one third, was observed in 51.0% (95% CI, 42.7 to 59.2). At the median follow-up of 4.5 years for the 300 patients, the 3-year OS was 62.4% (95% CI, 54.1 to 69.6) in Arm A and 60.9% (52.7 to 68.2) in Arm B. The hazard ratio of Arm B against Arm A was 0.916 (0.679 to 1.236; p = 0.284). OS of both groups were by far better than those reported in the past. The 3-year progression-free survival was 47.7% (95% CI, 39.4 to 55.4) in Arm A and 47.7% (39.5 to 55.4) in Arm B (hazard ratio 0.976, 95% CI 0.738 to 1.292). Conclusions: S-1 adjuvant chemotherapy for 1-year showed remarkable survival results for type 4 or large type 3 gastric cancer and additional NAC with S-1 plus CDDP is not recommended. Clinical trial information: C000000279.
Phase 1 safety of ICOS agonist antibody JTX-2011 alone and with nivolumab (nivo) in advanced solid tumors; predicted vs observed pharmacokinetics (PK) in ICONIC.
Authors: Howard A. Burris, Margaret K. Callahan, Anthony W. Tolcher, Shivaani Kummar, Gerald Steven Falchook, Russell Kent Pachynski, Scott S. Tykodi, Geoffrey Thomas Gibney, Tanguy Y. Seiwert, Justin F. Gainor, Patricia LoRusso, James Hilbert, Josh F Apgar, Fei Hua, John M Burke, Manny Lazaro, Myles Clancy, Baoyu Ding, Elizabeth G. Trehu, Timothy Anthony Yap
Journal: Journal of Clinical Oncology (2017)

3033 Background: JTX-2011 is an agonist monoclonal antibody that targets ICOS, Inducible CO-Stimulator of T cells. A dual mechanism of action is intended to activate antigen-specific CD4 T effector cells and selectively deplete intratumoral T regulatory cells. JTX-2011 is equally potent across human, rodent, and non-human primate species. Methods: A quantitative systems pharmacology (QSP) model describing target binding by JTX-2011 and target mediated drug disposition in blood, tumor and non-tumor tissues was based on preclinical potency and non-linear PK data across species. The model was translated to predict PK and target engagement (TE) in humans to facilitate dose selection. The QSP model predicts &gt; 95% TE for 21 days at the top planned dose. We present safety and actual/predicted PK from a Phase 1 study of JTX-2011 alone (Part A) and safety in combination with nivo (Part B). Results: 25 subjects have been dosed, 19 in 4 cohorts of JTX-2011 alone at .003, .01, .03, and .1 mg/kg IV q 21 days, and 6 in 2 cohorts of JTX-2011 .01 mg/kg and .03 mg/kg IV plus nivo 240 mg IV q21 days. Safety data from ≥ 1 cycle is available for 12 subjects in Part A (7 ≥ 3 cycles), and 3 in Part B (all ≥ 3 cycles). PK data is available for cycle 1 of Part A. Mean age (±SD) is 60 (±10.6). Mean prior systemic therapies is &gt; 5 (range 1-11). Tumor types include endometrial, triple negative breast, melanoma, lung, pancreatic and colorectal cancers. No dose limiting toxicities have been reported. 3 Grade 3 adverse events (AEs) were reported in 2 Part A subjects: anemia and hypoxia (unrelated SAE) at .003 mg/kg and JTX-2011 related diarrhea at .1 mg/kg. Grade 1-2 AEs in ≥2 subjects are chills, pyrexia, neck pain, dizziness, and nausea. 5 subjects had JTX-2011 related Grade 1-2 infusion reactions up to 6 hours post infusion. Non-linear exposure increase was observed. While PK at lower doses is consistent with model predictions, AUC and t 1/2 at 0.03 and 0.1 mg/kg doses are higher than predicted, suggesting higher than predicted TE. Conclusions: JTX-2011 has been well tolerated up to 0.1 mg/kg and with nivo at .01 mg/kg IV q 21 days. Greater than linear exposure increase was observed and TE may be higher than QSP model prediction. Clinical trial information: NCT02904226.
Performance of cancer recurrence algorithms post ICD10 coding scheme switch.
Authors: Debra P. Ritzwoller, Nikki Carroll, Matthew P. Banegas, Maureen Cecelia O'Keeffe-Rosetti, Angel M. Cronin, Hajime Uno, Michael J. Hassett
Journal: Journal of Clinical Oncology (2018)

e18576 Background: ICD-codes are integral to oncology health services research (HSR). These codes are used by Medicare, Medicaid, private payers, and many EHRs; and they provide structured, standardized data elements for diagnoses and procedures. In 2015, Medicare mandated a change from ICD version 9 to 10 when submitting reimbursement claims. This could have a broad impact on HSR that relies on well-established ICD-based algorithms. Yet, we know little about the impact this conversion had on the tools used by oncology researchers. We sought to validate the ICD9 to ICD10 crosswalk of the relevant codes used in the breast (BC), colorectal (CRC), and lung cancer (LC) RECUR recurrence detection and timing algorithms. Methods: We performed an ICD9 to ICD10 translation of the RECUR algorithm codes using a crosswalk query tool, published sources, and input from clinicians/certified medical coders. We evaluated performance using patients from two Kaiser Permanente regions diagnosed 1/1/13-12/31/16 with BC, CRC, and LC (stages I-IIIA), and followed through 12/31/17. Gold standard recurrence status was provided by the tumor registries. Validation performance statistics – sensitivity, specificity, positive predictive value, and negative predictive value – were estimated for recurrence probability thresholds that maximized both the accuracy of the algorithms and the Youden Index. Results: Performance of the algorithm after the ICD10 update were consistent with original published estimates. The algorithms’ area under the ROC remained high ( > 0.92) in all models. The ICD10 updated LC algorithm performed the best relative to the original. For both CRC and BC, the ICD10 updated algorithms had slightly lower performance for some metrics than the ICD9 versions, although not statistically significantly different. All three ICD10 algorithms estimated the timing of recurrence within 6 months better that the ICD9 versions. Conclusions: We found stable performance of the RECUR algorithms, indicating consistent reliability using ICD9 or ICD10 codes. The approach used to update oncology HSR tools following ICD conversion may be applied to other claims-based algorithms.
Accuracy of a model to predict cancer trial accrual compared to prediction accuracy by investigators at sixteen cancer centers.
Authors: Wendy R. Tate, Lee D. Cranmer, Ivo Abraham
Journal: Journal of Clinical Oncology (2016)

6525 Background: Multiple studies underscore poor clinical trial accrual, leading to increased costs, longer enrollment periods, and incomplete trials. We previously reported single center development and validation of a predictive trial accrual model that can be used when considering a prospective clinical trial. Here, we present the results of extending this methodology nationally. Methods: Eligible studies included treatment and supportive care intervention studies permanently closed to accrual between 2009 and 2015 at sixteen U.S.-based cancer centers. Center data included: disease management team (DMT), use of local IRB, local start date, DMT predicted accrual, actual total accrual, and clinicaltrials.gov number. Protocol level data abstracted from clinicaltrials.gov included: sponsor, randomized design, placebo use, phase, inclusion of pediatric subjects, endpoint, and national data (number of sites, enrollment goal, start date, and closure date). Accrual predictions were generated from site specific models and model accuracy, sensitivity, and specificity calculated. Results: Sixteen institutions submitted 5787 eligible trials (range: 93-697). Local accrual ranged from 363 to 6716 subjects. Of all studies, 1053 (18%), accrued no subjects. Actual average accrual was 8.5 subjects; median 4. DMTs predicted 221% of actual accrual (average 19 subjects per study; median 10) whereas the model predicted 55613 subjects, 113% of actual. The model correctly predicted whether a study would accrue 4+ subjects 74% of the time (site range 70-84%) versus 57% for DMT (range 29-72%). The model correctly predicted accrual at the category level (e.g. 1 < 4 subjects) 38% of the time compared to 22% for DMTs. Overall, model sensitivity was 82%, specificity 66% versus 98.6% sensitive, 14.5% specific for the DMTs, demonstrating DMT biased perception that most studies will accrue 4+ subjects. Conclusions: Using a systematic method and consistent national and local factors to develop a site-specific prediction model resulted in models that predicted clinical trial accrual better than DMTs at all 16 cancer centers. This may better inform study planning and resource allocation decisions within clinical research.
Communicating antimicrobial resistance and stewardship in the national press: Lessons from sepsis awareness campaigns
Authors: L. Rush, C. Patterson, L. McDaid, S. Hilton
Journal: Journal of Infection (2018)

•Antimicrobial resistance (AMR) and sepsis have been the subject of increasing media focus.•Reporting of these issues in UK newspapers contains potentially conflicting messages about antibiotic use.•Articles about sepsis frequently document its impact using personal narratives that rarely feature in articles about AMR.•Few articles balance messages about early antibiotic treatment in sepsis with the need to reduce unnecessary prescribing.• Integratingmedia discourses about AMR and sepsis may help improve public understandings about the importance of antimicrobial stewardship.
Avelumab and cetuximab in combination with FOLFOX in patients with previously untreated metastatic colorectal cancer (MCRC): Results of the safety run-in phase of the phase II AVETUX trial (AIO-KRK-0216).
Authors: Alexander Stein, Mascha Binder, Salah-Eddin Al-Batran, Axel Hinke, Lisa Waberer, Eray Goekkurt, Tobias Meyer, Donjete Statovci, Reinhard Depenbusch, Jorge Riera-Knorrenschild, Sylvie Lorenzen, Thomas Jens Ettrich, Steffen Doerfel, Carsten Bokemeyer, Susanna Hegewisch-Becker
Journal: Journal of Clinical Oncology (2018)

3561 Background: Single agent PD-1/L1 inhibition is efficacious in mismatch repair deficient tumours - about 5% of MCRC patients (pts). For the remaining MCRC pts the role of immunotherapy still needs to be determined. FOLFOX and cetuximab in combination with avelumab (AVETUX regimen) in 1st line RAS/BRAF wildtype MCRC is currently evaluated in a phase II trial independent of mismatch repair status (NCT03174405). Methods: This is a single arm exploratory investigator-initiated trial planned to include 43 pts to receive mFOLFOX6 and cetuximab in combination with avelumab (AVE) (10mg/kg day 1 from cycle 2 onwards). Primary endpoint is 12 months progression-free survival rate. Secondary endpoints are response rate, tolerability and translational research evaluating tissue and serial ctDNA. A safety analysis was planned after the 15th patient has passed 2 months to inform about tolerability. Results: As of 1st of February 2018 24 of 43 pts were enrolled and treated with the AVETUX regimen at 8 German sites. The safety analysis of the run-in phase was conducted on the 1st of February after a median of 3.2 months of treatment. The following adverse events were noted: 19/5 grade 3/4 (CTC AE 4.03) in 9 patients, including neutropenia (n = 11/4), nausea (n = 3), and infection (n = 3/1), mostly related to chemotherapy with only two grade 3 AE related to AVE. In 7 out of 15 patients 9 SAEs (one related to AVE), were noted including one case of grade 3 hepatitis, which resolved quickly with steroid treatment, 4 infections/fever, one diarrhea and three nausea (in one patient). Despite the relatively high absolute rate of G3/4 toxicity and SAEs, adverse events were manageable and did not relevantly impact on treatment feasibility. Two pts developed uncomplicated fever the day after the first infusion of AVE, both among the highest T cell infiltrated tumors. The IDMC recommended trial continuation based on these safety data. Updated safety and translational data and efficacy results will be presented at the meeting. Conclusions: The interim safety analysis has supported the feasibility of the AVETUX regimen in 1st line MCRC. The trial is ongoing. Clinical trial information: NCT03174405.