tbuckley/cabot-search huggingface dataset:
A phase Ib study of SHR-1210 plus apatinib for heavily previously treated advanced non-squamous non-small cell lung cancer (NSCLC) patients.
Authors: Caicun Zhou, Guanghui Gao, Fengying Wu, Xiaoxia Chen, Wei Li, Anwen Xiong, ChunXia Su, Weijing Cai, Shengxiang Ren, Tao Jiang, Yi Na Wang, Xiaoyan Kang, Quanren Wang
Journal: Journal of Clinical Oncology (2018)

e21017 Background: SHR-1210 is a selective, humanized, high-affinity IgG4-kappa monoclonal antibody against PD-1. Our preclinical data demonstrated a synergistic anti-tumor effect in vivo with simultaneous blockade of VEGF/VEGFR2 and PD-1/PD-L1 pathways. This phase Ib study was conducted to evaluate the safety, tolerability and activity of SHR-1210 plus apatinib for heavily previously treated advanced non-squamous NSCLC patients. Methods: 27 patients after failure of more than 2 lines of systemic therapies were treated with SHR-1210 at a dose of 200mg Q2w in combination with apatinib at a dose of 250mg qd (arm 1) or 375mg qd (arm 2) up to disease progression or intolerable toxicity. Primary endpoint was safety and tolerability and key 2nd endpoints were response rate and PFS. Results: At the cut-off data (Jan. 29. 2018), 27 patients were enrolled (arm 1: 15 patients; arm 2: 12 patients). Median age 58 years old (36-69), M/F: 23/4; Adenocarcinoma/other: 25/2; stage IV 100%; EGFR mutant/wild-type/unknown: 23/2/2. The median treatment duration of SHR-1210 was 22 weeks (range, 4-40 weeks) and apatinib was 24 weeks (range, 1-36 weeks). Dose adjustments were mainly due to apatinib, 2patients interrupted SHR-1210 treatment in arm 1 and 4 patients interrupted SHR-1210 treatment in arm 2. The dose in arm 1 was well tolerated with 1 case developing bronchial-pleural fistula and 1 case anorexia. In arm 2, 4 cases developed grade 3 skin rash, 2 grade 3 hypertension, and 5 patients needed dose reduction to 250mg. Treatment-related SAE occurred in 4 patients (14.8%), including 1 fever, 1 upper gastrointestinal hemorrhage, 1 pain, 1 infection reaction, and 1 pneumonia. 17 patients were included in efficacy analysis. The overall ORR was 41.2% (arm 1: 30.8%, 4/13; arm 2: 75%, 3/4) and DCR was 94.1% (arm 1: 92.8%, 12/13; arm 2: 100%, 4/4). The median PFS was 24 weeks in arm 1 and not reached in arm 2. Conclusions: SHR-1210 in combination with apatinib at a dose of 250mg was well-tolerated with promising anti-tumor effect, even in heavily previously treated NSCLC patients. The dose of 250mg apatinib + SHR 1210 was recommended in the ongoing phase II trial (ClinicalTrials: NCT03083041).
Actionable targets in recurrent bile duct and pancreatic cancer in a prospective cohort of patients evaluated by whole exome sequencing and SNP array analysis.
Authors: Ida Elisabeth Viller Tuxen, Morten Mau-Soerensen, Christina Westmose Yde, Lars Joenson, Olga Oestrup, Jane Preuss Hasselby, Eric Santoni-Rugiu, Ulrik Niels Lassen, Finn Cilius Nielsen
Journal: Journal of Clinical Oncology (2016)

e23256 Background: No standard therapy exists for recurrent bile duct cancer. In this study, we characterized actionable targets in patients with recurrent bile duct- and pancreatic cancer included in a large prospective cohort of solid tumors pts with exhausted treatment options. Pts were included in early clinical trials based on genomic profiling of their tumors. Methods: Pts with bile duct- and pancreatic cancer, included in the Copenhagen Prospective Personalized Oncology (CoPPO) research program had their tumor re-biopsied. Tissue was stored in RNAlater for DNA and RNA purification and as FFPE specimens for histological verification. Tumor DNA was analyzed by CytoScanHD array (Affymetrix) to identify copy number changes and by whole exome sequencing (Illumina HiSeq2500) to call tumor specific mutations. RNA expression levels and chromosomal translocations of therapeutic targets were analyzed by expression arrays and RNA-Seq (Nugens Ovation RNA-Seq system v2). Pts were allocated to targeted therapy according to a consensus reached at bi-weekly tumor board meetings. Results: Among 300+ pts included in the CoPPO research program since May 2013, 20 pts had bile duct cancer and 27 pancreatic cancers. Most frequently mutated genes in bile duct cancers were TP53 (25%), IDH1/2 (25%), KRAS (20%), BRAF (20%), and APC (15%). In contrast, significantly higher frequencies of KRAS (85%) and TP53 (78%) mutations (p < 0.0001, χ2 test) and no IDH1/2 mutations were recorded in pancreatic cancers. The majority of bile duct cancer pts (65%) had actionable targets, including IDH1/2, BRAF, MET, FGFR, BRCA2, and NOTCH,of which 40% were included in clinical trials. In pancreatic cancer, actionable targets (BRCA1, MET, NOTCH, BRAF) were identified in only 19% of pts of whom 30% entered a trial. Major reasons for failure to include pts in clinical trials were reduced performance status and unavailability of targeted therapy (IDH1/2). Conclusions: The genomic landscape of bile duct cancers seems distinctly different from pancreatic cancers. A higher frequency of actionable targets was observed in bile duct cancer. Clinical trial information: NCT02290522.
Circulating tumor DNA analysis for osimertinib resistance Chinese NSCLC patients.
Authors: Weiguang Gu, Yong Li, Hongxi Hong, Bai Liu, Aodi Wang, Wenjin Liu, Shuo Mu, Ming Yao, Kai Wang
Journal: Journal of Clinical Oncology (2018)

e24061 Background: EGFR T790M mutation is the most common acquired EGFR-TKI resistant mutation in NSCLC patients, and is sensitive to the third-generation EGFR-TKI osimertinib. But osimertinib acquired resistance mechanism is still under study. We report the molecular and clinical characteristics of osimertinib resistance patients. Methods: In total 39 advanced NSCLC patients (pts) who had received but become resistant to osimertinib treatment were enrolled in this study. Baseline genetic variants of those patients were documented. Genomic alterations (GAs) were assayed by a next generation sequencing (NGS) based liquid biopsy assay targeting common driver genes in NSCLC. Results: The median age of the 39 pts, including 17 males and 22 females, was 55 years (range: 35-77). As baseline genetic alterations, 20 pts harbored EGFR sensitive mutations, 14 pts harbored EGFR T790M, and 7 harbored both, for a total of 27 pts with EGFR mutations (the EGFR status of 12 pts remained unknown). The median response time to osimertinib was 7 months, ranging from 1 to 32 months. After resistance to osimertinib, EGFR T790M was detected in only 21.4% (3/14) of the pts who were T790M positive at baseline. 11.1% (3/27) of the pts harboring EGFR mutations at baseline were positive for EGFR C797S, one of the known mechanisms of acquired resistance to osimertinib. Besides secondary mutation of EGFR, other most common related mutated TKI-resistant genes was PI3KCA (12.8%, 5/39). Also BRAF, KRAS, PTEN, and RB1 mutations were found each on two out of 39 pts. One ERBB2 amplification and one MET amplification were detected as well. Further analysis of GAs and the response time revealed that there was no significant difference between the median PFS of EGFR T790M negative and positive group (7 months vs. 9.5 months, p = 0.53). Conclusions: In this study we investigated the circulating tumor specific molecular characteristics of advanced NSCLC pts who were resistant to the third generation EGFR-TKI osimertinib. No significant difference of median PFS was found between plasma EGFR T790M positive and negative groups. Further analyses of the genomic alterations of acquired resistance to ostimertinib by plasma ctDNA testing are still needed.
Quality of life and psychological distress in patients with acute myeloid leukemia (AML).
Authors: Netana Markovitz, Lauren Waldman, Julia Carp, Lara Traeger, Gregory A. Abel, Joseph Greer, Amir Tahmasb Fathi, David P. Steensma, Thomas William LeBlanc, Daniel J. DeAngelo, Martha Wadleigh, Gabriela Hobbs, Andrew Mark Brunner, Philip C. Amrein, Richard M. Stone, Jennifer S. Temel, Areej El-Jawahri
Journal: Journal of Clinical Oncology (2018)

154 Background: Older patients with AML face difficult treatment decisions as they can be treated either with multi-drug ‘intensive’ chemotherapy requiring a prolonged hospitalization, or ‘non-intensive’ chemotherapy. Although clinicians often perceive intensive chemotherapy as more burdensome, studies comparing older patients’ quality of life (QOL) and psychological distress while receiving these treatments are lacking. Methods: We conducted a longitudinal study of older patients (≥ 60 years) newly diagnosed with AML receiving intensive (i.e. 7+3: cytarabine/anthracycline combination) or non-intensive (i.e., hypomethylating agents) chemotherapy at two tertiary care hospitals. We assessed patient’s QOL [Functional Assessment of Cancer Therapy-Leukemia], and psychological distress [Hospital Anxiety and Depression Scale [HADS]] at baseline and 2, 4, 8, 12, and 24 weeks after diagnosis. We compared the proportion of patients in each group reporting clinically significant depression or anxiety (HADS subscale cut off ≥ 7) and used mixed linear effects models to compare QOL and psychological distress longitudinally between groups. Results: We enrolled 75.2% (100/133) of eligible patients within 72 hours of initiating intensive (n = 50) or non-intensive (n = 50) chemotherapy. Baseline QOL, depression, or anxiety symptoms did not differ between the groups. At baseline, 33.33% (33/100) and 30% (30/100) of the overall cohort reported clinically significant depression and anxiety, respectively, with no differences between groups. At 4 weeks, 41.98% (34/81) of patients in the overall cohort reported clinically significant depression, with no differences between groups. In mixed linear effects models, there were no differences in QOL (β = -0.71, SE = 1.12, p = 0.527), depression (β = 0.24, SE = 0.20, p = 0.226), or anxiety (β = -0.16, SE = 0.19, p = 0.386) symptoms over all time points. Conclusions: Older patients with AML receiving intensive and non-intensive chemotherapy experience similar QOL and high rates of psychological distress. These findings underscore the need to develop supportive care interventions for older patients with AML, regardless of their initial treatment strategy.
Difference in appearance of KRAS mutated circulating tumor DNA in patients with metastatic colorectal cancer during treatments.
Authors: Yuji Takayama, Koichi Suzuki, Kosuke Ichida, Taro Fukui, Fumiaki Watanabe, Nao Kakizawa, Yuta Muto, Rina Kikugawa, Fumi Hasegawa, Shingo Tsujinaka, Hiroshi Noda, Yasuyuki Miyakura, Fumio Konishi, Toshiki Rikiyama
Journal: Journal of Clinical Oncology (2017)

e23025 Background: Emergence of KRAS mutation in blood is observed in colorectal cancer patients who undergo chemotherapy, but its clinical significance is not well known. In this study, we focused on the difference in appearance of KRAS mutated circulating tumor DNA (MctDNA) and elucidated its association with treatments. Methods: Four hundred and fifty-one plasma samples were collected prospectively from 85 patients (pts) who underwent chemotherapy due to metastatic colorectal cancer in 2014 - 2016. Seven types of KRAS mutation in MctDNA were detected by droplet digital PCR creating oil droplets. To exclude false positive detection, mutation was validated. MctDNA amplified in oil droplets was selectively sorted by On-chip sorting system and mutation was determined by Sanger sequencing. Results: KRAS assessment in tumor tissues showed 29 pts with KRAS mutation (MT), 56 pts without KRAS mutation (WT). Among 29 pts with MT, KRAS assessment in plasma displayed 23 pts with MctDNA and 6 pts without MctDNA. The type of mutation in MctDNA was consistent with that detected in tumor tissues, indicating mutual exclusivity in KRAS mutation was confirmed. In 56 pts with WT, 28 pts showed MctDNA during treatments. Difference in appearance of MctDNA was recognized in several treatments. Gradual increase in detection of MctDNA was observed with anti-EGFR antibody, resulted in treatment resistance. Transient spike elevation was frequently seen in TAS-102, which associated with drug response. No specific appearance was recognized during treatments with other drugs including anti-VEGF antibody. MctDNA in oil droplets were successfully sorted even if a few droplets were targeted, and mutation was confirmed. Conclusions: Difference in appearance of MctDNA may associate with treatment response in patients with metastatic colorectal cancer during treatments. [Table: see text]
Results of a first-in-human phase I study of INVAC-1, an optimized plasmid DNA encoding an inactive form of human telomerase reverse transcriptase (hTERT), in patients with advanced solid tumors.
Authors: Luis Teixeira, Jacques Medioni, Ludovic Doucet, Stephane Culine, Stephane Oudard, Olivier Adotevi, Marie-Agnès Dragon Durey, Jean-Jacques Kiladjian, Mara Brizard, Ludovic Bourré, Simon Wain-Hobson, Rémy DeFrance, Thierry Huet, Pierre Langlade-Demoyen
Journal: Journal of Clinical Oncology (2017)

3087 Background: INVAC-1 is an optimized plasmid encoding an inactive form of human telomerase reverse transcriptase (hTERT). hTERT is a prototype of shared tumor antigen expressed in more than 85% of human tumors. Telomerase activation is associated with maintenance of telomere length and accounts for the unlimited proliferative capacity of cancer cells. In preclinical models, INVAC-1 triggered Th1-polarized hTERT-specific CD8 + and CD4 + T-cell immune responses and anti-tumor effects. Here, we report clinical and pharmacodynamics results of the first clinical study with INVAC-1 as a single agent in solid tumors. Methods: A 3+3 design phase 1 First in Human study evaluating INVAC-1 given monthly for 3 cycles using electroporation-based intra-dermal (ID) injection was conducted. Primary objectives included safety, tolerability and dose limiting toxicities to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives included immune response and anti-tumor activity. Results: 20 patients (pts) with refractory/progressive solid tumors were enrolled in two centers. 3 escalating doses were studied: 100 µg (3 pts), 400 µg (3 pts) and 800 µg (14 pts). At 3-month data cut-off, no dose limiting toxicities or treatment related SAEs have been reported; no MTD was defined. The most common treatment-related adverse events were grade 1 or 2: asthenia and local reaction at injection site. 12 pts experienced stable disease and clinical benefit. For 10 pts, the treatment was extended beyond the per-protocol 3-month duration, up to nine months for 2 pts. IFN-g polarized anti-hTERT immune responses were detected in 55% of pts, in response to INVAC-1 treatment. Conclusions: Results from this study indicate that INVAC-1 ID was safe, well tolerated and strongly immunogenic at the doses and schedule tested. Early anti-tumor activity has been observed. The RP2D of INVAC-1 is therefore a monthly ID injection of 800 µg. These results encourage a future evaluation of INVAC-1 is solid tumors, as well as in hematologic malignancies, either as monotherapy or in combination with various immunotherapeutic drugs. Clinical trial information: NCT02301754.
Improvement of metastatic colorectal cancer patient survival: Single institution experience.
Authors: Elisabetta Fenocchio, Federica Colombi, Maria Grazia Calella, Roberto Filippi, Ilaria Depetris, Giovanna Chilà, Pasquale Lombardi, Donatella Marino, Celeste Cagnazzo, Renato Ferraris, Marco Vaira, Massimo Aglietta, Francesco Leone
Journal: Journal of Clinical Oncology (2018)

e15633 Background: The survival rates of patients with metastatic colorectal cancer (mCRC) has significantly improved over the last 15 years. Both surgery and a more aggressive systemic approach may have contributed to this result. We aimed to analyze the survival of mCRC patients followed at a single institution over last 17 years. Methods: We retrospectively collected data from 899 mCRC patients treated from 2001 to 2016. As molecular targeted agents were introduced in clinical practice in 2007, patients were divided into two groups based on the year of diagnosis: Cohort A (2001-2006) and Cohort B (2007-2014). Results: 788 patients with a minimum follow-up period of two years were analyzed (365 in Cohort A and 423 in Cohort B). The median survival of the whole population was 32.0 months with a significant difference between Cohort A (29.2 months) and Cohort B (33.5 months) (HR 0.832, p = 0.041). Surgical procedures increased from 42% in Cohort A to 58% in Cohort B, p < 0.009: particularly extra-hepatic surgery (from 21.4% to 33.9%; p < 0.005). No significant changes in median survival were observed between Cohorts in patients undergoing surgery (58.9 months Cohort A vs 58.2 months Cohort B, p = 0.822). Similarly, when we compared patients treated with systemic therapy alone (with or without targeted agents), we failed to demonstrate survival improvement (18.9 months Cohort A vs 20.7 months Cohort B; HR 1.0, p = 0.948). At the multivariate analysis, right-sided primary tumour and synchronous metastatic disease were found to be independent unfavorable prognostic factors; in these subgroups, survival improved in Cohort B. In particular, in patients with right-sided tumours, median survival was 18.5 months in Cohort A and 25.8 months in Cohort B (p = 0.041). Conclusions: Improvements of mCRC patient survival might relate to the integrated approach, with more patients undergoing extra-hepatic surgery. The medical approach seems to have had a more favorable impact in recent years on subgroups characterized by a worse prognosis.
PTH-088 Prevalence of low drug levels and anti-drug antibodies in an unscreened population of patients with inflammatory bowel disease receiving infliximab
Authors: R Downey, G Tun, K Swallow, G Wild, K Robinson, A Wright, L Marshall, M Hale, R Sargur, AJ Lobo
Journal: Gut (2017)

Introduction  Infliximab (IFX) is widely used for induction and maintenance of remission in inflammatory bowel disease (IBD). It has been suggested that monitoring drug levels and antibodies to infliximab (ATI) may allow treatment optimisation.  The aim of this study was to examine the initial results, and their potential significance, from a programme of therapeutic drug monitoring (TDM), in a large, single, referral centre.  Method  Since May 2016, all IBD patients receiving intravenous IFX for maintenance treatment have undergone TDM. Serum IFX trough levels and ATI were measured by a drug tolerant enzyme-linked immunosorbent assays (Biohit, UK). IFX trough levels were considered as undetectable ( 7 mg/L). ATI were considered positive if >10 mg/L. Clinical remission was defined as a Harvey Bradshaw Index or Simple Colitis Activity Index≤4.  Results  Initial screening of 162 maintenance patients (110 Crohn’s disease, 49 ulcerative colitis, 3 IBD-U; median age 36 years (16-82)), is shown in Table 1. Median duration of treatment was 88 weeks (range 12–581). 123/162 (76%) had drug levels that were undetectable (n=48) or low (n=75). Of these, 54/123 (44%) were ATI positive. 118/162 (73%) patients were in clinical remission, of whom 88/118 (75%) had low/undetectable drug levels while 35/44 (80%) patients with active disease had low/undetectable drug levels. Overall, 65 (40%) patients were ATI positive at initial screening. Positive ATI were associated with a lower level of IFX (median 1.4 vs 2.2 mg/L; p=  In those ATI positive, infusion reactions occurred in 3/180 (1.7%) infusions vs 0/342 in those ATI negative (OR of 11.49, p=0.03).  Figure 1 shows the relationship between ATI status and IFX trough levels at initial TDM screening.  Conclusion  In an unscreened population, 17% of patients have undetectable drug levels and positive ATI, and therefore, may derive no benefit from continued treatment, although 61% of those were in clinical remission. The high overall prevalence of sub-therapeutic drug levels is important in planning strategies to optimise dosing in a clinic setting. Although ATI detected by this assay are associated with a low risk of infusion reactions, these were more common than when ATI were negative.  Disclosure of Interest  None Declared
11C-Choline PET guided resection of thoracic metastases from prostatic adenocarcinoma.
Authors: Justin Moser, Aaron Scott Mansfield, Roxana Stefania Dronca, Fernando Quevedo, Eugene D. Kwon, Stephen D. Cassivi
Journal: Journal of Clinical Oncology (2016)

e16528 Background: 11C-choline positron emission tomography (11C-PET) is an FDA approved test for the identification of recurrent and metastatic prostate cancer in patients with biochemical recurrence. Although 11C-PET is able to identify disease in a significant portion of these patients, the clinical benefit of 11C-PET guided metastasectomy is unknown. Methods: Clinical records were retrospectively reviewed of patients with biochemically recurrent prostate cancer, without detectable disease by standard imaging, who were imaged with 11C-PET and were found to have and underwent resection of oligometastatic thoracic disease. Results: 28 patients were initially identified as having undergone surgical resection of thoracic metastases from prostate cancer that was initially identified via 11C-PET imaging. Of these, 15 patients had oligometastatic disease and had no evidence of disease after resection. Thirteen of these patients received systemic adjuvant therapy; 9 received docetaxel and androgen deprivation while three received androgen deprivation alone and 1 received abiraterone. After surgery thirteen patients (87%) had a downtrending PSA, one patient had a stable PSA, and another had a rising PSA. Of the two patients who did not initially receive adjuvant therapy, one was subsequently started on androgen deprivation due to a biochemical relapse. Nine patients (60%) had no evidence of recurrent disease at last follow up with a median follow up time of 11 months (m) [interquartile range (IQR) 9.2-13]. Six patients (40%) had biochemical recurrence after surgery, of which the median time to recurrence was 5.2 m (IQR 3.2-8.4). Five of these patients developed radiographic recurrence with a median time to recurrence of 8.1 m (IQR 4.0-14). Conclusions: These data suggest that 11C-PET guided metastasectomy of oligometastatic prostate cancer in the thorax may provide clinical benefit to select patients. However, future, prospective studies are needed to fully clarify the role of 11C-PET guided metastasectomy in patients with metastatic prostate cancer.