tbuckley/cabot-search huggingface dataset:
Randomized phase II trial of presurgical androgen deprivation therapy (ADT) with or without axitinib in prostate cancer (PCa) presenting with lymph node (LN) metastasis.
Authors: Amado J. Zurita, Rebecca Slack Tidwell, Patricia Troncoso, Brian Francis Chapin, Deborah Harris, Louis L. Pisters, John C. Araujo, Curtis Alvin Pettaway, Ana Aparicio, Shi-Ming Tu, John N. Papadopoulos, Jennifer Wang, Christopher Logothetis, Lance C. Pagliaro, John W. Davis
Journal: Journal of Clinical Oncology (2019)

5078 Background: Strategies integrating androgen targeted and locoregional therapies are being increasingly used in PCa with regional spread, but are rarely curative. Angiogenesis inhibitors delay progression in castration resistant PCa and may synergize with ADT through endothelial cell apoptosis in hormone naïve patients (pts). We hypothesized that the frontline combination of ADT with the potent VEGF inhibitor Axi would improve PCa control relative to ADT alone and allow for meaningful time off systemic therapy after surgical consolidation. Methods: Pts with either clinically detected LN+ (TxN1M0 or TxNxM1a) or very high risk for LN PCa were treated with ADT for 2 mos and then randomized 2:1 to respectively add open label Axi (5 mg PO bid) vs. continue ADT alone for 4 mos until surgery. Those responding with PSA ≤5 ng/mL were offered prostatectomy and extended pelvic lymphadenectomy (RP). ADT +/- Axi was withheld postoperatively and PSA measured q3 mos until 1 y. Primary objective: proportion of pts progression free (FFP) 12 mos after RP, defined as PSA ≤1.0 ng/mL and no radiation or ADT, aiming to detect a 35% difference favoring ADT+Axi. Results: 72 pts completed accrual. We report on the 54 pts with LN+ disease: median age 62 y (range 42-76), pretreatment PSA 22.9 ng/mL (range 3.6 - 404.4), 38 N1 / 16 M1a. Table shows presurgical therapy outcomes. Path responses in the prostate were similar between arms, but in 5 ADT+Axi vs. 0 ADT LN+ pts there was no residual nodal disease. Testosterone recovery: 24/26 ADT+Axi and 9/9 ADT RP pts by 6 mos. 21/36 ADT+Axi and 15/18 ADT pts have failed; 1 y FFP estimates 48.0% (SE 8.6%) and 16.7% (SE 8.3%), respectively (p = 0.02). 1 y undetectable PSA 9 pts (6 ADT+Axi). No grade 4 toxicities or unexpected side-effects were observed. Conclusions: 1 year after RP, ADT+Axi resulted in proportionally greater number of LN+ PCa pts off treatment and progression free than ADT alone. Tissue analysis is evaluating predictors of benefit to further develop angiogenesis inhibition as part of combination strategies for hormone naïve PCa. Clinical trial information: NCT01409200. [Table: see text]
The interplay between PD-L1 and vimentin in NSCLC patients: An exploratory analysis.
Authors: Giuseppe Bronte, Maurizio Puccetti, Paola Cravero, Sara Ravaioli, Maria Maddalena Tumedei, Paola Ulivi, Marco Angelo Burgio, Alberto Verlicchi, Angelo Delmonte, Federico Cappuzzo, Lucio Crino, Sara Bravaccini
Journal: Journal of Clinical Oncology (2019)

e20688 Background: The immune modulation is emerging as a key strategy in non-small cell lung cancer (NSCLC) patients management. PD-L1 has been the only biomarker validated for immunotherapy but it holds many limitations. Vimentin is one of the marker for epithelial-to-mesenchymal transition (EMT), a biological process which favors immune escape. We explored two issues: the correlation between PD-L1 and Vimentin expression in NSCLC samples and the prognostic value of PD-L1 and vimentin concordance in NSCLC patients. Methods: We collected all the NSCLC samples evaluable for both PD-L1 and Vimentin and recorded the relative available clinical and survival data, if written informed consent was present. PD-L1 and Vimentin were retrospectively assessed through immunohistochemistry (IHC) by using prediluted antibodies clones SP263 (Ventana Medical Systems, Tucson, AZ, USA) and anti Vimentin V9 (Ventana Medical Systems) on Benchmark XT Platform (Ventana Medical Systems). Biomarker expression was detected and semiquantitatively quantified as the percentage of immunopositive tumor cells on the total of tumor cells. We correlated PD-L1 and Vimentin expression through linear regression. We compared survival of patients with both PD-L1 and Vimentin 0% and all the others via Kaplan-Meier method by using MedCalc software version 18.11.3. Results: Ninety-nine samples underwent PD-L1 and Vimentin IHC analysis. A weak positive statistically significant correlation was found between the 2 biomarkers (r = 0.41; p &lt; 0.001). For 40 patients survival data (from first NSCLC diagnosis) were available. Survival analysis showed that PD-L1 and Vimentin negative patients (n = 12) experienced not statistically significant longer survival (HR = 0.35; 95%CI: 0.08-1.51; p = 0.16). Conclusions: These preliminary findings suggest that an interplay can exist between PD-L1 and vimentin in NSCLC, but analysis in a wider population is necessary. Studies on the significance of this interplay for immunotherapy efficacy should be designed.
A modified recursive partitioning analysis for predicting overall survival in patients with non-small cell lung cancer and central nervous system metastases.
Authors: Thiago Pimentel Muniz, Victor Hugo Fonseca Jesus, Victor Aurelio Ramos Sousa, malu barbosa, Vladmir Claudio Cordeiro De Lima
Journal: Journal of Clinical Oncology (2019)

e20604 Background: Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers. Most patients with NSCLC have metastases at diagnosis and 30-50% of them will present brain lesions during follow-up. Nonetheless, patients with central nervous system (CNS) spread are poorly represented in clinical trials and the management of this clinical scenario is not standardized. Prognostic tolls are needed to help to guide the best approach for these patients. Methods: Descriptive, analytical, retrospective, single center study. Patients &gt; 18 years of age diagnosed with NSCLC who developed CNS metastases treated at AC Camargo Cancer Center from January 2007 to December 2017 were included. The primary endpoint was overall survival (OS). The secondary endpoint was intracranial progression-free survival (IC-PFS). An exploratory analysis of prognostic factors associated with OS was undertaken. The Kaplan-Meier method was used to calculate OS and IC-PFS. We used the Cox Proportional Hazard model to assess the prognostic role of clinical and pathological characteristics on IC-PFS and OS. Variables with p &lt; 0.20 at univariate analysis were used to generate a multivariate model. A survival tree was generated based on the two most statistically significant variables in the multivariate model. A p &lt; 0.05 was considered statistically significant. Results: 311 patients were included. Median age was 60 years-old (IQR 54-68), 72.6% had an ECOG performance status 0 or 1 and 18.3% had a driver mutation detected ( EGFR, ALK or ROS1). IC-PFS was 7.1 months (95%CI 6.1-8.6) and OS was 10.3 months (95%CI 8.7-13.1). At multivariate analysis, the two most statistically significant prognostic factors associated with poor OS were ECOG performance status 2-4 (HR 2.12; 95%CI 1.40-3.20; p &lt; 0.01) and the absence of a known driver mutation (HR 3.30; 95%CI 1.50-3.87; p &lt; 0.01). Based on the curves generated by the survival tree, a prognostic model was developed - the Modified Recursive Partitioning Analysis (mRPA). This model stratified our cohort in four subgroups with significantly different OS (3.1 to 43 months). mRPA was better than RPA and GPA to predict prognosis in our population. Conclusions: OS and IC-PFS in patients with NSCLC and CNS metastases were better than previously reported. However, prognosis is widely variable and is directed mainly by performance status and the presence of a driver mutation. We propose a new prognostic model that my help to guide the treatment of these patients in the future. This model needs external validation.
AGEN2373 is a conditionally-active agonist antibody targeting the costimulatory receptor CD137 for the treatment of human malignancies.
Authors: Claire Galand, Yanping Xiao, Cornelia Mundt, Benjamin Morin, Dhan Chand, Christina Riordan, Vignesh Venkatraman, Rebecca Ward, Randi Gombos, Min Lim, Matthew Costa, Cailin Joyce, Olga Ignatovich, Mark Findeis, Dennis Underwood, Robert Benjamin Stein, Marc van Dijk, Nicholas Wilson, David Savitsky
Journal: Journal of Clinical Oncology (2019)

e14005 Background: Agonist antibodies targeting CD137 are potent inducers of tumor-reactive T cell proliferation, cytokine production, and cytotoxicity, and have been explored clinically for their ability to enhance immune cell-mediated destruction of tumor cells. Despite early signs of clinical activity, the development of first-generation anti-CD137 antibodies has been hampered by on-target dose-limiting hepatotoxicity or poor clinical activity. Subsequent CD137 therapies have therefore sought to localize CD137 agonism to the tumor microenvironment (TME) to potentially improve tolerability in patients. However, these approaches may also limit the potential benefit of CD137 signaling outside the TME that contributes to anti-tumor immunity, such as T cell priming in tumor draining lymph nodes. Here we describe the pharmacologic and non-clinical safety profile of a next-generation anti-CD137 monospecific antibody, AGEN2373. Methods: Flow cytometry and surface plasmon resonance-based binding, superantigen-driven immune cell activation, and luminescent reporter cell line assays were developed to test the ability of AGEN2373 to induce CD137 signaling. A non-clinical, multi-dose safety study was conducted wherein cynomolgus monkeys were injected intravenously with 100 mg/kg doses of AGEN2373. Results: AGEN2373 engages cell-expressed human and cynomolgus monkey CD137, and provides potent CD137 co-stimulation only in the presence of CD137 ligand and/or Fc gamma receptor-expressing antigen presenting cells. No changes in clinical parameters, importantly no sign of liver toxicity, were observed after administration of AGEN2373 in cynomolgus monkeys. Conclusions: AGEN2373, a novel conditionally-active anti-CD137 agonist antibody that is well-tolerated in non-human primates, is expected to have clinical activity in patients with human malignancies by its ability to selectively enhance tumor immunity in the context of immune co-stimulation.
Phase Ib study of MIW815 (ADU-S100) in combination with spartalizumab (PDR001) in patients (pts) with advanced/metastatic solid tumors or lymphomas.
Authors: Funda Meric-Bernstam, Shahneen Kaur Sandhu, Omid Hamid, Anna Spreafico, Stefan Kasper, Reinhard Dummer, Toshio Shimizu, Neeltje Steeghs, Nancy Lewis, Craig C. Talluto, Sinead Dolan, Andrew Bean, Robert Brown, Damian Trujillo, Nitya Nair, Jason J. Luke
Journal: Journal of Clinical Oncology (2019)

2507 Background: MIW815 (ADU-S100) is a novel synthetic cyclic dinucleotide that activates the STimulator of INterferon Genes (STING) pathway impacting tumor cells, tumor microenvironment, vasculature, tumor-associated fibroblasts, and priming APC and CD8+ T cells. Spartalizumab is a humanized IgG4 mAb that blocks the binding of PD-1 to PD-L1/2. Preclinical data support synergistic antitumor effects when MIW815 (ADU-S100) is combined with checkpoint inhibitors. Methods: In this Phase Ib dose escalation study, pts with advanced/metastatic solid tumors or lymphoma received MIW815 (ADU-S100) (intratumoral injections [50–800 µg] either weekly [3 weeks on/1 week off] or Q4W) and spartalizumab (400 mg IV Q4W). Injected and non-injected tumor biopsies were obtained at baseline and on treatment. Primary objectives are to determine safety and identify a dose/schedule for future studies. Preliminary activity, pharmacokinetics (PK), and pharmacodynamics (PD) are also being explored. Results: As of Jan 11, 2019, 66 pts (median age: 61 y) with various solid tumors or lymphomas have been treated. Treatment was discontinued in 49 pts (74%) due to disease progression (n = 28), pt/physician decision (n = 18), AE (n = 2), or death (n = 1). No DLTs were reported during the first cycle at any dose level. Most common (≥5 pts) treatment-related AEs (TRAEs) were injection site pain (12%), pyrexia (11%), and diarrhea (9%). Grade 3/4 TRAEs (in ≥2 pts) were increased AST and ALT (3% each). Serious TRAEs were pyrexia (3%), increased amylase, increased lipase, diarrhea, fatigue, hyperthyroidism, partial seizures, dyspnea, and pneumonitis (all 2%). Partial responses in pts with PD-1–naive TNBC and PD-1–relapsed/refractory melanoma have been observed. MIW815 (ADU-S100) plasma exposure generally increased in a dose-dependent manner with a rapid terminal half-life. Response data, PK and PD analyses will be presented. Conclusions: Thus far, MIW815 (ADU-S100) + spartalizumab has demonstrated antitumor activity in PD-1–naive TNBC and PD-1–relapsed/refractory melanoma. The combination is well tolerated, with no DLTs reported to date. The MTD has not been reached and dose escalation is ongoing. Clinical trial information: NCT03172936.
Racial comparisons in receipt of timely guideline-based colon cancer treatment in an equal-access health system.
Authors: Yvonne L Eaglehouse, Matthew W. Georg, Craig D. Shriver, Kangmin Zhu
Journal: Journal of Clinical Oncology (2019)

6563 Background: Non-Hispanic Black (NHB) adults with colon cancer may have longer time-to-treatment and be less likely to receive guideline-based therapy than Whites (NHW) in the U.S. This may be largely related to racial differences in access to care and insurance coverage. This study aimed to determine whether there were racial differences in receipt of timely guideline-based colon cancer treatment in the equal-access Military Health System (MHS). Methods: Patients age 18-79 years diagnosed with colon adenocarcinoma between January 1, 1998 and December 31, 2007 were identified in linked databases from the Department of Defense Central Cancer Registry and MHS Data Repository. Odds ratios (ORs) and 95% confidence intervals (CIs) of receiving stage-specific treatment within recommended timeframes [surgery within 6 weeks of diagnosis (stages I-III); adjuvant chemotherapy within 8 weeks of surgery (stages II-III); treatment within 4 weeks of diagnosis (stage IV)] for NHB relative to NHW patients were estimated using multivariable logistic regression. Results: Patients (n = 2,170) had a mean age at diagnosis of 59.6 (SD 11.8) years and the racial distribution was 78.6% NHW and 21.4% NHB. The likelihood of receiving timely surgery between races was similar across the stage groups (I-III). NHB patients were equally likely to receive adjuvant chemotherapy as NHW patients (OR 0.90, 95% CI 0.57, 1.41) and to receive it within 8 weeks of surgery (OR 1.19, 95% CI 0.75, 1.87). The likelihood of receiving timely treatment for patients with stage IV disease was similar between races (OR 0.82, 95% CI 0.39, 1.69). The overall likelihood of receiving treatment adherent to stage-specific guidelines in the study sample was similar between NHB and NHW patients (OR 1.00, 95% CI 0.77 to 1.31). Conclusions: In the MHS population, the likelihood of receiving timely treatment adherent to recommended guidelines was similar between races. Our results support the role of equal access to medical care and insurance coverage in reducing racial disparities in colon cancer treatment.
Factors associated with delays in diagnosis of pediatric, adolescent and young adult patients with central nervous system tumors.
Authors: Diane Marie Puccetti, Lena Winestone, Jeffrey McPheeters, Jennifer Jill Wilkes, Henry J. Henk, Elysia Marie Alvarez
Journal: Journal of Clinical Oncology (2019)

e13532 Background: Central Nervous System (CNS) tumors are the most common solid tumor in children and have the highest mortality. Delays in diagnosis (Dx) may lead to reduced survival. We identify factors associated with delays in Dx in pediatric, adolescent and young adult (AYA) patients with CNS tumors. Methods: A retrospective cohort from the OptumLabs Data Warehouse, which includes claims data for privately insured enrollees in a large US health plan, was identified. Patients diagnosed with CNS tumors between 2001-17 continuously enrolled 6 months prior to diagnosis (Dx) were included. The onset of cancer symptoms was identified by the date of the first encounter associated with cancer symptoms. Time to Dx was calculated as the days between cancer symptom onset and Dx date. The likelihood of presenting with symptoms and the time to Dx (among those with symptoms) was modeled using logistic regression and included sociodemographic and clinical factors. A delay in Dx was defined as &gt; 3 months after a symptom. Results: We identified 6,627 eligible patients, 5,637 (85%) of whom presented with symptoms prior to Dx. Likelihood of a delay appears greatest in those first presenting to a specialist (OR 1.28 vs PCP; P = .24 ) but lowest in those presenting to Urgent care/ER (OR .56 vs PCP; P &lt; 0.001) and was greatest among children &lt; 5 years of age were more likely to present with a symptom (table). However, among those with a symptom, children &lt; 5 had the longest time to Dx (Median 122 days). Males were less likely to present with a symptom prior to Dx (OR .80, P = 0.040) and when experiencing a symptom they experienced shorter time to Dx compared to females (Median 85 vs 110 days). Race, income, and census region were not significant predictors of either likelihood of presenting with symptoms or delay in time to Dx. Conclusions: This study indicates that young children &lt; 5 years had a longer delay in diagnosis compared to older patients. [Table: see text]
Real-life use of nivolumab and pembrolizumab in four adult university teaching hospitals in Québec, Canada.
Authors: Nathalie Letarte, Layal El Raichani, Chantal Guevremont, Nathalie Marcotte, Ghislain Berard, Marie-Claude Michel, France Varin, Elaine Pelletier, Paul Farand, Louise Deschênes, Daniel Froment, Philippe Ovetchkine, Marie-Andrée Fournier, Normand Blais, Raghu Rajan, Rahima Jamal
Journal: Journal of Clinical Oncology (2019)

e14125 Background: Nivolumab and pembrolizumab, two anti-PD1 agents, were approved and funded in Québec since 2016 for non small cell lung cancer (NSCLC), renal cell carcinoma (RCC) and melanoma. The objectives were to describe and assess the “real-life” use, efficacy and security of nivolumab and pembrolizumab in NSCLC, RCC and melanoma in the general population. Methods: Medical records of every patient who received nivolumab or pembrolizumab between January 1 st 2011 and October 31 st 2017 were reviewed retrospectively. Data analysis cut-off was Dec 31 st 2017. Results: In total, 532 patients received at least one dose of anti-PD1 during the study period. Median number of doses received varied for each indication (medians varied from 4 to 9.5). Adverse events were pooled together by drug. 47.7 % of patients receiving pembrolizumab suffered from any grade immune-related adverse event (IRAE), most of them of grade 1 or 2. 12.2 % of patients reported grade 3-4 IRAE. Most of the patients reported only one type of IRAE. For nivolumab, 44.6% of patients presented with any IRAE, including 8.3% of grade 3-4. Dermatologic IRAE were more frequent in the melanoma patients whereas gastrointestinal and pulmonary IRAE were more frequent in NSCLC patients. Treatment discontinuation due to adverse events varied from 6 to18% depending on indication. Conclusions: Nivolumab and pembrolizumab seemed less effective and caused more IRAE in “real-life” population than in the pivotal clinical trials. Caution and regular follow-up are warranted when using these drugs in general population. Longer follow-up is needed.[Table: see text]
Discovery and characterization of actionable tumor antigens
Authors: Grégory Ehx, Claude Perreault
Journal: Genome Medicine (2019)

The nature of the tumor antigens that are detectable by T cells remains unclear. In melanoma, T cells were shown to react against major histocompatibility complex (MHC)-associated peptides (MAPs) that are derived from exonic mutations. A recent multi-omic study of hepatocellular carcinomas suggests, however, that mutated exonic MAPs were exceedingly rare, bringing the accuracy of the current methods for antigen identification into question and demonstrating the importance of broadening tumor-antigen discovery efforts.
Shifting patterns of care in localized prostate cancer: Impact on patient reported outcome measures (PROMs).
Authors: Brendan James Connell, Rima Patel, Hong Chang, Tony Luongo, Liyan Zhuang, Thomas A. DiPetrillo, John Mignano, Gennaro Carpinito, Paul Mathew
Journal: Journal of Clinical Oncology (2019)

e16603 Background: In localized prostate cancer (LPC), evolving therapeutic techniques and patterns of care including the use of active surveillance (AS) are expected to have had a positive effect on quality of life. A longitudinal assessment of changes in disease presentations and patterns of care in LPC correlated to PROMs is required. Methods: All cases of LPC (T1-T4, N0-N1) at a tertiary care institution were identified between 2005 and 2015. Two cohorts (C1: 2005-10, C2: 2010-15) with a minimum of 2-years follow-up, were identified. Demographics, disease characteristics and management strategies were compared across cohorts. To assess PROMs, a one-time questionnaire including EPIC-26 and Clark’s Quality of Life was administered. Domain summary scores were compared across cohorts. Results: 873 patients met criteria [C1: 422, C2: 535]. Demographics were well balanced (p = 0.10): overall 64.1% white, 12.7% AA, 12.7% Asian. D’Amico risk scores increased over time (p = 0.001): fewer low-risk cases [C1: 49.2%, C2: 43.7%], higher intermediate-risk disease [C1: 34.6%, C2: 40.3%], and stable high-risk proportions [C1: 15.7%, C2: 14.9%]. Patterns of care shifted significantly (p = 0.005) with a marked decrease in radiation therapy [C1: 25.7%, C2: 15.4%], unchanged radical prostatectomy rates [C1: 47.9%, C2: 51.0%], a shift to robotic surgery [C1: 23.8%, C2: 90.3%], and an increase in AS [C1: 21.8%, C2: 30.8%], particularly in low-risk disease [C1: 32.4%, C2: 53.5%]. Questionnaire response rate was 45.1%. Using multivariate regression, C2 demonstrated an improvement in bowel function (p = 0.031) but not in urinary, sexual, or psychometric scores. Conclusions: Notwithstanding an increase in AS utilization for low-risk disease, an improvement in bowel function and lack of improvement in urinary/sexual PROMs in LPC across time-cohorts was noted. This may be accounted for by increased presentations of higher-risk disease managed with robotic surgeries at the expense of radiation therapy. Although time-length bias can influence comparisons, given national trends with a similar shift in presentation and care patterns, these PROM correlations are likely generalizable to the U.S. population.