tbuckley/cabot-search huggingface dataset:
bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: Updated results from a multicenter phase I study.
Authors: Noopur S. Raje, Jesus G. Berdeja, Yi Lin, Nikhil C. Munshi, David Samuel DiCapua Siegel, Michaela Liedtke, Sundar Jagannath, Deepu Madduri, Jacalyn Rosenblatt, Marcela Valderrama Maus, Ashley Turka, Lyh Ping Lam, Richard A. Morgan, Travis Quigley, Monica Massaro, Kristen Hege, Fabio Petrocca, James Kochenderfer
Journal: Journal of Clinical Oncology (2018)

8007 Background: bb2121 is a second-generation chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) to redirect T cells to recognize and kill malignant myeloma cells. Initial data from the dose-escalation (DE) phase of CRB-401, a first-in-human study of bb2121 in relapsed/refractory multiple myeloma (RRMM), have shown promising efficacy and safety. We report updated safety and efficacy results on 43 patients (pts) enrolled in this ongoing study. Methods: CRB-401 (NCT02658929) is a 2-part, phase I study of bb2121 in pts with RRMM. DE pts had received ≥ 3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent, or were double refractory, and had ≥ 50% BCMA expression on plasma cells. In the dose-expansion (Exp) phase, pts had to have received daratumumab and been refractory to last line of therapy; no BCMA expression was required. Following lymphodepletion with Flu (30 mg/m2)/Cy (300 mg/m2) given daily for 3 days, pts received 1 infusion of bb2121. Results: As of 02 Oct 2017, 21 pts had received bb2121 in the 4 DE cohorts (median follow-up, 35 weeks); no DLTs and no grade ≥ 3 neurotoxicities (NTX) were observed. Cytokine release syndrome (CRS), primarily grade 1-2, was reported in 15 of 21 (71%) pts; 2 pts had grade ≥ 3 CRS that resolved in 24 hours. There were 2 deaths on study; both pts had achieved complete response (CR) and had not progressed. Overall response rate in the 18 evaluable pts in DE cohorts ≥ 150 × 106 CAR T cells was 94%; 10 of 18 (56%) pts had CR or unconfirmed CR; 9 of 10 evaluable pts were MRD-negative. With a median follow-up of 40 weeks in ≥ 150 × 106 DE cohorts, median response duration and progression-free survival (PFS) had not been reached; PFS rates at 6 and 9 months were 81% and 71%, respectively. Doses of 150 to 300 × 106 CAR T cells were selected for the Exp phase. Results from an additional 5 months of follow-up and initial data from ~20 pts from the Exp cohort will be presented. Conclusions: bb2121 shows promising efficacy at dose levels ≥ 150 × 106 CAR T cells with deep and durable ongoing responses and manageable CRS and NTX. These data support the potential of bb2121 anti-BCMA CAR T cell therapy as a new treatment paradigm for RRMM. Clinical trial information: NCT02658929.
Epigenetic regulation of immunotherapy and T cell exhaustion by tractinostat in a syngeneic CT26 colon cancer mouse model.
Authors: Hao Shen, Preston Warren, Marshelle Smith Warren, Rosemary Rochford, Ivor Royston, James Woody
Journal: Journal of Clinical Oncology (2018)

e24122 Background: The immune profile in the cancer microenvironment continues to be a key predictor of survival and disease progression. Tractinostat, a class I specific histone deacetylase inhibitor (HDI) is being investigated in a phase 1b/2 trial for the treatment of virally associated EBV lymphoma in combination with valganciclovir. Tractinostat also possesses unique qualities as an immune modulator to enhance an anti-viral and anti-tumor immune response. Methods: This study examined tractinostat in a syngeneic CT26 colon cancer mouse model in combination with an anti-PD-1 monoclonal antibody to evaluate differences in tumor burden. The immune cell profile of the tumor microenvironment was also examined by FACS and specific immune response genes indicative of anti-tumor and anti-viral cell functionality by qPCR. Results: Compared to anti-PD-1 monotherapy, the combination arm showed a reduction in the average day 21 tumor burden by 93%. When examining the microenvironment, the combination group showed a 3.4-fold increase in activated CD8+ T cells, a 2.2-fold increase in Th1 CD4+ T cells, a 51% reduction in Treg FOXP3 expression and a 3.9-fold increase in interferon gamma expression. Conclusions: Tractinostat was able to improve immunotherapy treatment in a partially checkpoint resistant tumor model. The tumor microenvironment was also specifically directed toward an interferon gamma and activated Th1 response. This suggests future epigenetic enhancement of other immunotherapy treatments in which an anti-viral or anti-tumor T cell response is required or preferred.
Cancer patient awareness of the harms of continued smoking.
Authors: Geoffrey Liu, Devon Alton, Jiahua Che, Yuyao Song, Jie Su, Delaram Farzanfar, Rahul Mohan, Olivia Krys, Tom Yoannidis, Robin Milne, M Catherine Brown, Ashlee Vennettilli, Andrew J. Hope, Doris Howell, Jennifer M. Jones, Peter Selby, Wei Xu, David Paul Goldstein, Meredith Elana Giuliani, Lawson Eng
Journal: Journal of Clinical Oncology (2016)

10086 Background: Smoking cessation is becoming an integral part of cancer survivorship. To help improve survivorship education, clinicians need an understanding of patient knowledge of the harms of continued smoking. Methods: Patients with various cancer subtypes were surveyed with respect to self-awareness of the harms of continued smoking on cancer outcomes. Multivariable logistic regression models assessed factors associated with the level of awareness. Results: Among 985 patients, 23% smoked at diagnosis; 34% quit > 1 year prior to diagnosis; 25% had lung, 30% had head and neck cancers; 77% received curative therapy. Many patients reported being unaware that smoking can negatively impact cancer surgery (65%), radiation (74%), chemo outcomes (64%), treatment efficacy (70%), cancer prognosis (54%) and second primary development (52%). Among all patients, those smoking at diagnosis were significantly more likely to be unaware of radiation (aOR = 1.73, 95% CI [1.16-2.57]) and chemo (aOR = 2.10 [1.17-3.79]) toxicities, cancer prognosis (aOR = 1.63 [1.16-2.29]) and second primary risk (aOR = 1.61 [1.14-2.26]). Those with poorer health status were more likely unaware of effects on prognosis (aOR = 1.56 [1.18-2.08]) and second primaries (aOR = 1.54 [1.14-2.08]). Patients with non-tobacco related cancers (non-TRCs) were more likely unaware smoking impacts cancer surgery (aOR = 1.45 [1.04-2.04]) and radiation (aOR = 1.37 [1.01-1.85]). Among smokers at diagnosis, those with non-TRCs (aOR = 4.00 [1.45-11.11]) and those receiving recent ( < 3 months) treatment (aOR = 2.13 [1.06-4.17]) were more likely unaware smoking can impact chemo outcomes. Patients on palliative therapy more likely felt that smoking impacted chemo outcomes (aOR = 2.39 [1.14-5.01]) and efficacy (aOR = 2.03 [1.01-4.07]). Awareness was not associated with stage, second-hand smoke exposure or cessation, but was associated with patients believing that a smoking cessation program would be beneficial to their health (aORs = 2.33-4.35, P< 0.03). Conclusions: Many cancer patients were unaware of the harms of continued smoking; mainly smokers at diagnosis and those with non-TRCs. Patient education should focus on emphasizing awareness, which may help improve patient interest in smoking cessation.
Molecular sequencing and gene fusion detection in non-small cell lung cancer (NSCLC) patients: Impact of co-existing alterations.
Authors: Ana Martinez de Castro, Jordi Remon, Susana Cedres Perez, Alejandro Navarro, Alexandre Martinez Marti, Nuria Pardo Aranda, Alberto Hernando, Jorge Zeron-Medina, Juan Aguilar-Company, Eulalia Scheenaard, Sergi Recasens, Fiorella Ruiz-Pace, Guillermo Villacampa, Jose Jimenez, Rodrigo Dienstmann, Paolo Nuciforo, Enriqueta Felip, Ana Vivancos
Journal: Journal of Clinical Oncology (2017)

e23103 Background: There is a growing need for accurate molecular diagnostics for proper targeted therapeutics selection in NSCLC patients (pts). We assess whether next generation techniques increase the identification of alterations in a prospective cohort of NSCLC pts, and evaluate prognostic value of different molecular alterations. Methods: Next generation sequencing (Amplicon-seq, 60 genes) and NanoString Gene fusion (20 genes) testing were conducted in NSCLC pts treated in a single center from November 2014 to May 2016. Overall survival (OS) according to the molecular profile was analysed by Kaplan-Meier method and Cox models. Results: Molecular tests were performed in 73advanced NSCLC pts.Median age was 54 year, 50% were women. Histology: 73% adenocarcinoma; 7% squamous, 20% others (Neuroendocrine, NOS). Tests were performed in biopsies from metastatic sites in 55% of pts.These techniques identified molecular alterations in 89% of cases: TP53 mutation (mut) 37/73 (51%); KRASmut 21/73 (29%); EGFRmut 11/73 (15%) ; CDKN2mut 7/73 (9%); BRAFmut (pG469R), ERBB2mut and METexon14mut in (1/73) 1.3%, respectively; ALKfusion (fus) 2/73 (2.7%); ROS1fus 1/73 (1.3%) , and RET fus 3/73 (4%). Concomitant mutations were identified in 32% of pts mainly with TP53 (TP53/EGFR: (5/11) 45% and TP53/KRAS: (7/21) 33%). Matched targeted treatment was offered in 17/73 (23%), mostly tyrosine kinase inhibitors (TKI); anti-EGFR in 11/17 (65%) and ALK/ROS TKI in 3/17 (17.5%). Three pts (17.5%) received anti-MET or anti-HER2 TKI. OS in this whole population treated with target therapies (n = 17) was 45.7 months (m) (CI95% 26.8-NA). The KRASmut group had median OS of 10 m (CI95% 7.5-NA), while the remaining population with wild type (WT) for all driver alterations had median OS of 23 m (CI95% 20-NA), (HR 1.71 for KRASmut vs WT pts, p = 0.18). The presence of coexisting TP53mut did not negatively impact on OS in the cohorts with EGFRmut and KRASmut (p &gt; 0.1) in a multivariate model. Conclusions: Combined next generation techniques for molecular profile in NSCLC pts identifies molecular alterations that have clinically relevant impact in survival. Coexisting TP53mut alteration shows no detrimental effect in OS.
TCT-676 Could the logistic clinical SYNTAX score have predicted the all-cause mortality in the Global Leaders trial? A prediction prior to the unblinding of the trial
Authors: Ply Chichareon, Rodrigo Modolo, Norihiro Kogame, Kuniaki Takahashi, Taku Asano, Yuki Katagiri, Chun-Chin Chang, Carlos Collet, Franz-Josef Neumann, Keith Oldroyd, Richard Anderson, Farzin Fath-Ordoubadi, Christoph Naber, Scot Garg, Ivo Petrov, Pascal Vranckx, Marco Valgimigli, Stephan Windecker, Yoshinobu Onuma, Patrick Serruys
Journal: Journal of the American College of Cardiology (2018)
Trends in response rate and survival in small cell lung cancer patients between 1997 and 2017.
Authors: Mickaël Lattuca-Truc, Matteo Giaj Levra, Stéphane Ruckly, Julie Villa, Isabelle Dumas, Julian Pinsolle, Leonie Ferrer, Pascale Guillem, Denis Moro-Sibilot, Anne-Claire Toffart
Journal: Journal of Clinical Oncology (2018)

e20572 Background: Small cell lung cancers (SCLC) represent 10 to 15% of lung cancers, with a median survival at any stage of one year. In the last two decades, there was no dramatic breakthrough in the clinical care of SCLC. However, the introduction of new drugs, new regimens and the impact of supportive treatments might have slightly improved the prognosis of these patients. We aimed to assess if SCLC patients’ characteristics and their response to chemotherapy (CT) changed over time. Methods: A database from the weekly multidisciplinary thoracic oncology board of Grenoble University Hospital was revisited from 1997-2017. Consecutive patients with SCLC were included. We compared the demographic and clinical behaviors of patients diagnosed between 1997-2009 (period 1) and 2010-2017 (period 2). Results: A total number of 529 patients were identified; among these 499 received a first line treatment (478 (96%) with etoposide-platinum based CT), 279 a second line (126 (45%) with etoposide-platinum based CT and 122 (44%) with a taxane based CT), and 121 a third line. Median age was 64 years [interquartile range (IQR) 25%-75%, 56-71], 208 (42%) patients had a limited disease, 116 (23%) were women. Concomitant or sequential mediastinal radiotherapy in limited disease was performed in 96 (65%) patients in period 1 and in 41 (68%) in period 2. In period 1, 81 (26%) patients benefited from a prophylactic cranial irradiation, and 59 (32%) in the period 2. Response rate (RR) to first line chemotherapy in metastatic patients was 62% and 59% during period 1 and 2 respectively; the RR to second line for all patients was 39% and 29% respectively, and 19% and 20% for the third line. Median overall survival from the onset of treatment was 12 months [IQR 25%-75%, 7-23], 13 months [IQR 25%-75%, 7-24] in period 1 and 11 months [IQR 25%-75%, 7-21] in period 2. In metastatic patients, median overall survival was 9 months [IQR 25%-75%, 5-15] and it was the same in both periods. Conclusions: Since 1997 there was no improvement in survival nor response rate to chemotherapy in SCLC patients. There is a desperate need of new approaches in this setting. Funding source: AbbVie
Metastatic site of loss of oncologic control in colorectal cancer patients.
Authors: Charles Rajadurai, Steph Pang, Jill Ranger, Ivan Barrera, Jean-Sebastien Pelletier, Petr Kavan
Journal: Journal of Clinical Oncology (2018)

e15568 Background: Mortality related to colorectal cancer (CRC) is largely due to regional metastasis to portal/mesenteric lymph nodes and peritoneum as well as distant metastasis to vital organs such as lung, liver, bone and brain. Approximately 50% of patients diagnosed with CRC will develop synchronous or metachronous liver metastases, while 20% will also develop extrahepatic metastases, and the overall survival rate among patients with advanced disease is poor. However, neither the most frequent site (hepatic, pulmonary or extra-hepatic/pulmonary) of loss of oncologic control (clinical/radiological disease progression requiring change in line of Chemotherapy) nor the difference in overall survival between patients with disease progression at liver, lung or extra-hepatic/pulmonary site is well understood. Also, survival benefit of oligometastatic resection among mCRC patients remains to be investigated. Methods: A cohort of 157 patients diagnosed with stage-4 metastatic colorectal cancer (mCRC) between 2008 and 2016, and treated with chemotherapy or chemotherapy plus biologics with or without partial hepatectomy was analyzed. Metastatic disease progression and site of loss of oncologic control was assessed based on radiology data and confirmed with oncology reports (change in lines of treatment & clinical symptoms). Kaplan-Meier survival analysis was performed between different sites of oncological control as well as patients who received partial hepatectomy vs. no resection. Results: Of the 157 patients, 62 died of disease progression at the liver with an average overall survival of 822 days, 26 died of disease progression at extra-hepatic sites with an average overall survival of 996 days and 69 died of disease progression at hepatic and extrahepatic sites with an average overall survival of 887 days. For patients with metastatic disease to the liver, partial hepatectomy provides an overall survival benefit of 12 months (1141 compared to 794 days). Conclusions: This study identifies liver as the most frequent site of loss of oncological control with poor survival among mCRC patients, and data suggest that early liver-directed therapies and better liver would likely improve survival outcome in mCRC patients.
Germ cell tumors: Survival analysis and experience from a low- to middle-income country.
Authors: Samia Yasmeen, Abdul Hannan
Journal: Journal of Clinical Oncology (2017)

e16044 Background: We performed a retrospective analysis of Germ-Cell Tumor patients presenting to Shaukat Khanum Cancer Hospital, Pakistan to have a greater understanding of the presentation &amp; outcomes in South-east Asia. Methods: A search of hospital registry identified 105 patients between Jan-Dec 2013, out of which survival data was available for 99. Final cut off for data collection: Sept 2016. Electronic records were reviewed &amp; analyzed for outcomes, survival &amp; relapse. Results: Median age: 29(18-66) years. Median Follow-up: 33(6-46) months. Testicular primary 96(91.4%). Retroperitoneal 5(4.76%). Mediastinal GCT 4(3.8%). 87(82.85%) underwent orchiectomy while upfront chemotherapy was started in 9(9.45%). Pure Seminoma 46(43.8%). Non-Seminoma 59(56%). Highest level of B-hCG for seminoma: 3607IU/L (Minimum 2.9). Highest level of AFP for Non-Seminoma: 30000IU/L (Range 0.35-30000). Median LDH: 533IU/L (Range 253-23760). Most common Non-Seminoma components: embryonal and yolk-sac tumors. Chemotherapy regimen: Etoposide/Carboplatin 39(37.1%), Bleomycin/Etoposide/Cisplatin 29(27.6%). Carboplatin for Stage-I Seminoma: 17(16.1%). 11(11.5%) patients expired due to advanced disease. Lost to follow up 14(14.7%). 76(79.8%) were alive without any disease while 4(4.02%) were alive with PD. One stage-I seminoma relapse was successfully cured with EP, while 14 Non-seminoma relapses were retreated with VeIP. Eight relapses achieved cure, while 6 had refractory disease. Off total 11 deaths, five had PD, Cisplatin induced stroke: 1, Bleomycin toxicity: 3, Neutropenic sepsis: 1. One relapse as melanoma. Median survival: yet not reached. Conclusions: Our data suggest almost same results corresponding to international literature. Most of our patients present with huge disease burden, which may not change the risk stratification, but alters prognosis. [Table: see text]
Audiograms and hearing loss before and after cisplatin-based chemotherapy (CBCT) in testicular cancer survivors (TCS).
Authors: Hege Sagstuen Haugnes, Niels Christian Stenklev, Marianne Brydoy, Tom Wilsgaard, Einar Laukli, Sophie D. Fossa
Journal: Journal of Clinical Oncology (2017)

e16047 Background: 80% of TCS were reported to have a hearing loss based on post-CBCT audiograms (American Speech-Language-Hearing Association (ASHA) definition; Frisina et al, JCO 2016:34) Methods: 46 TCS treated with CBCT 1980-1994 with audiograms (0.25-8 kHz) pre chemotherapy (PRE) and at a survey (SURV) after median 10 years were included (cases). Audiograms at SURV from 46 age-matched TCS without CBCT were included as controls. Linear regression was performed to evaluate predictors for change in hearing threshold level (HTL) from PRE to SURV. Mean HTL for both ears exceeding 20 dB at any frequency 0.25-8 kHz were classified as a hearing loss (ASHA definition). We also applied the WHO definition of hearing loss, present if the average HTL threshold for the four frequencies 0.5, 1, 2 and 4 kHz exceeded 20 dB (M4 definition). At SURV, self-reported hearing loss was assessed by a questionnaire (categorized as “a little”, “quite a bit” and “very much” vs. “not at all”). Results: Age and PRE HTL was associated with change in HTL for most frequencies. Cisplatin dose was significantly associated with change in HTL for the frequencies 2 to 8 kHz, with a gradually greater change in HTL and lower p-value with increasing frequencies. For the 8 kHz frequency, each 100 mg increase in cumulative cisplatin dose was associated with a deterioration of 3.6 dB (p &lt; .001). According to ASHA, the prevalence of a hearing loss among cases was 33% PRE, 70% at SURV, and 65% among controls at SURV (cases vs. controls, p = .66). According to M4, the prevalence of hearing loss among cases was 6.5% PRE, 13% at SURV, and 2.2% among controls at SURV (cases vs. controls, p = 0.05). Overall 29% of cases, and 33% of controls (p = .70) reported some degree of hearing impairment at SURV, of whom only 6.5% of cases reported more than “a little”. Self-reported hearing loss was not associated with hearing loss according to ASHA (p = .20), but was associated with the M4 definition (p = .02). Conclusions: Cisplatin is associated with a moderate hearing loss particularly at higher frequencies. Ageing is important for hearing loss regardless of treatment. The ASHA definition of hearing loss overestimates the hearing problem and should not be used as a clinical tool.
EGFR T790M mutation in treatment-naïve tumor samples: Low frequency, evidence for interaction with EGFR TKI-sensitizing mutations and lack of clear predictive value
Authors: E. Imyanitov, A. Ivantsov, E. Lavdovskaia, A. Iyevleva, N. Mitiushkina, I. Bizin, S. Orlov, A. Togo, F. Moiseyenko, E. Levchenko
Journal: Annals of Oncology (2018)

Background: EGFR T790M mutation is associated with acquired resistance of lung cancer (LC) to first-generation TKIs. Several studies suggest that LCs often contain a small fraction of T790M-mutated cells even before the treatment, and the persistence of these mosaic clones renders poor tumor response to gefitinib or erlotinib. Methods: We utilized a spectrum of methods to detect EGFR T790M allele in tumor and normal human tissues. Results: Allele-specific PCR (AS-PCR) analysis of treatment-naïve tumor samples revealed somatic T790M mutation in 3/394 (1%) LCs carrying TKI-sensitizing EGFR mutation, but in none of 334 LCs lacking EGFR exon 19 deletions (ex19del) or L858R substitutions and in none of 235 non-lung carcinomas. Cis-/trans- analysis of the ex19del and the T790M was performed on samples from two treatment-naïve LCs and revealed the location of both mutations in the same allele. In one of these tumors, T790M mutation was present only in a fraction of ex19del-containing cells, suggesting that the T790M was acquired later than the ex19del during natural tumor evolution. None of 920 LCs analyzed carried EGFR T790M in germ-line. Use of highly-sensitive and quantitative assays, such as ddPCR and NGS, produced high number of T790M-specific signals even in presumably T790M-negative DNA specimens. This background noise was evidently higher in degraded DNA isolated from formalin-fixed paraffin-embedded tissues as compared to high molecular weight DNA. Combination of AS-PCR, ddPCR and NGS revealed mosaic EGFR T790M allele only in 2 (3%) out of 68 LCs treated by the first-generation TKI. Both these tumors produced evident and durable response to gefitinib. Conclusions: The occurrence of EGFR T790M mutation in treatment-naïve LC samples is significantly lower than reported in some previous studies. Interestingly, the emergence of EGFR T790M allele is linked to the presence of TKI-sensitizing mutations even in the absence of drug exposure, thus suggesting a biological interaction between these two genetic events. The detection of mosaic EGFR T790M mutations may be compromised by yet unresolved technical issues and may have limited clinical value. Legal entity responsible for the study: N.N. Petrov Institute of Oncology. Funding: AstraZeneca (Research Agreement with the N.N. Petrov Institute of Oncology); Russian Science Foundation (grant 17-75-30027). Disclosure: All authors have declared no conflicts of interest.