tbuckley/cabot-search huggingface dataset:
Avelumab (anti–PD-L1) in patients with platinum-treated advanced NSCLC: 2.5-year follow-up from the JAVELIN Solid Tumor trial.
Authors: Arun Rajan, James L. Gulley, David R. Spigel, Nicholas Iannotti, Jason Claud Chandler, Deborah J.L. Wong, Joseph W. Leach, William Jeffery Edenfield, Ding Wang, Charles H. Redfern, Hans Juergen Grote, Anja von Heydebreck, Mary M. Ruisi, Neru Munshi, Karen Kelly
Journal: Journal of Clinical Oncology (2018)

9090 Background: Avelumab, a human anti–PD-L1 IgG1 monoclonal antibody, is an approved treatment for metastatic Merkel cell carcinoma in various countries and platinum-treated advanced urothelial carcinoma in the US. In phase 1b studies, avelumab has shown antitumor activity and acceptable safety in patients with advanced NSCLC. Here, we report long-term data for avelumab in patients (pts) with platinum-treated NSCLC. Methods: In a phase 1b cohort of JAVELIN Solid Tumor (NCT01772004), pts with stage IIIB–IV NSCLC unselected for PD-L1 status, with progression after platinum doublet therapy, received avelumab 10 mg/kg Q2W as second-line (2L) or later treatment until confirmed progression, unacceptable toxicity, or withdrawal. PD-L1 expression was assessed using PD-L1 IHC 73-10 assay. Time-to-event endpoints were estimated using Kaplan-Meier methods. Results: 184 pts received avelumab. At data cutoff on Feb 15, 2017, median follow-up was 33.9 months (range, 31.0-40.7) and 9 pts (4.9%) remained on treatment. 58 pts (31.5%) had received ≥2 prior lines of therapy for advanced disease. The objective response rate (ORR) was 14.1% (95% CI, 9.4-20.0), including complete response in 1.1%, and median duration of response was 17.5 months (95% CI, 6.9-21.4). Progression-free survival (PFS) rates at 6 months and 1 yr (95% CI) were 24.2% (18.1-30.8) and 16.5% (11.3-22.5). Overall survival (OS) rates at 1 and 2 yrs (95% CI) were 42.5% (35.1-49.7) and 25.0% (18.7-31.8). In evaluable pts with PD-L1+ (n = 122) and PD-L1− (n = 20) tumors ( > 1% tumor cell cutoff), ORR (95% CI) was 16.4% (12.1-21.5) vs 10.0% (2.7-24.5), the 1-yr PFS rate was 19.1% (12.3-27.0) vs 5.0% (0.3-20.5), median OS was 11.1 (8.4-17.3) vs 4.6 (2.8-12.5) months, and the 2-yr OS rate was 30.0% (21.7-38.7) vs 17.1% (4.4-37.0), respectively. Safety findings were consistent with earlier analyses; 14.7% had a grade ≥3 treatment-related adverse event, most commonly ( > 1%) infusion-related reaction (2.2%), lipase increase (1.6%), and pneumonitis (1.1%), and no treatment-related deaths occurred. Conclusions: Avelumab as 2L or later therapy is associated with durable responses and long-term OS in pts with platinum-treated advanced NSCLC. Clinical trial information: NCT01772004.
A phase 1/3 multicenter trial of talimogene laherparepvec in combination with pembrolizumab for unresected, stage IIIB-IV melanoma (MASTERKEY-265).
Authors: Georgina V. Long, Reinhard Dummer, Antoni Ribas, Igor Puzanov, Olivier Michielin, Ari M. Vanderwalde, Robert Hans Ingemar Andtbacka, Jonathan S. Cebon, Eugenio Fernandez, Josep Malvehy, Anthony J. Olszanski, Thomas Gajewski, John M. Kirkwood, Olga Kuznetsova, Lisa Chen, Scott J. Diede, Jeffrey Chou, F. Stephen Hodi
Journal: Journal of Clinical Oncology (2016)

TPS9598 Background: Talimogene laherparepvec, an oncolytic viral immunotherapy, was designed to selectively replicate in tumors resulting in lytic cell death, antigen release, and production of GM-CSF to enhance systemic antitumor immune responses. Talimogene laherparepvec improved durable response rate vs GM-CSF in unresectable stage IIIB-IV melanoma (Andtbacka et al, JCO 2015). Pembrolizumab, a human programmed death receptor-blocking antibody approved for the treatment of advanced melanoma, improved PFS and OS vs ipilimumab in patients (pts) with stage III-IV melanoma (Robert et al, NEJM 2015). Combining talimogene laherparepvec + pembrolizumab may further enhance antitumor immune responses. Here we describe the phase 3 design of a phase 1b/3 double-blind, placebo-controlled study assessing the safety and efficacy of talimogene laherparepvec + pembrolizumab in unresected stage IIIB-IV melanoma (NCT02263508). Phase 1b enrolled 21 pts treated with talimogene laherparepvec + pembrolizumab. No dose limiting toxicities were observed (primary endpoint), and preliminary responses were observed in 9 of 16 evaluable pts with median tumor follow-up of 17 weeks (Long et al, SMR 2016). Methods: Approximately 660 pts will receive pembrolizumab + placebo or pembrolizumab + talimogene laherparepvec (1:1 randomization). Co-primary endpoints: PFS and OS. Key secondary endpoints: adverse events and response-based endpoints. Key eligibility criteria: unresectable stage IIIB-IV melanoma naïve to systemic treatment except up to one prior line of BRAF inhibitor-based treatment, measurable and injectable lesions, ECOG PS 0-1, no active cerebral metastases, no autoimmunity/immunosuppression, no active herpetic infection. Talimogene laherparepvec (106 PFU/mL first dose, 108 PFU/mL subsequent doses) or placebo is injected into cutaneous or nodal lesions on day 1, weeks 0, 3, 5, 7 then q3w starting day 1 week 9. Pembrolizumab 200 mg IV is given q3w starting day 1 week 0. Treatment continues until confirmed complete response or progressive disease, intolerance, up to 2 years, or for talimogene laherparepvec or placebo, when there are no longer injectable lesions. Clinical trial information: NCT02263508.
Evaluating survivin as a potential target in neuroendocrine tumors (NETs).
Authors: Ahmad Hanif, Ankush Chander, Kristopher Attwood, Robert Fenstermaker, Jingxin Qiu, Renuka V. Iyer
Journal: Journal of Clinical Oncology (2018)

e16171 Background: Survivin is an inhibitor-of-apoptosis protein (IAP) that is expressed in many human cancers. We explored survivin expression in NETs to test its potential as a therapeutic target using survivin peptide mimic vaccine (SurVaxM). Methods: In tissue microarrays of 132 surgically resected NETs, survivin expression was determined by immunohistochemistry (present/ absent) using a rabbit monoclonal survivin antibody clone EP119 and correlated with clinical variables. Comparisons were made using the Mann-Whitney U and Fisher’s exact tests at α = 0.05. Survival outcomes were analyzed using standard Kaplan-Meier methods and the log-rank test. Results: Significant associations were seen between Survivin expression and age, smoking status, primary site, grade and tumor size. Patients (pts) with survivin-positive tumors were more likely to be younger with larger, high grade tumors, and have tobacco exposure. (Table) Survivin positivity was associated with poor median overall survival (5.8y vs 18.3y, p < 0.001) and HR of 2.89 (95% CI: 1.68-4.95). Due to variability in first therapy, association with freedom from progression in survivin-positive pts (5.6y vs 16y, p = 0.09) was not statistically significant. Conclusions: Survivin expression is associated with poor outcomes and can be a potential target in NET pts. Table. Negative n (%) Positive n (%) Overall n (%) P-value Overall N 64 (48.5) 68 (51.5) 132 (100) Age < 60 18 (28.1) 36 (52.9) 54 (40.9) 0.005 > 60 46 (71.9) 32 (47.1) 78 (59.1) Sex Male 21 (32.8) 26 (38.2) 47 (35.6) 0.59 Female 43 (67.2) 42 (61.8) 85 (64.4) Smoking Status Never 32 (50.0) 11 (16.2) 43 (32.6) < .001 Former 18 (28.1) 30 (44.1) 48 (36.4) Active 14 (21.9) 27 (39.7) 41 (31.1) Primary Site Lung 22 (34.4) 40 (58.8) 62 (47.0) 0.003 Pancreas 14 (21.9) 5 (7.4) 19 (14.4) Small Intestine 18 (28.1) 11 (16.2) 29 (22.0) Other 7 (10.9) 12 (17.6) 19 (14.4) Unknown 3 (4.7) 3 (2.3) Grade I 36 (61.0) 17 (26.2) 53 (42.7) < .001 II 12 (20.3) 10 (15.4) 22 (17.7) III 11 (18.6) 38 (58.5) 49 (39.5) Stage 1 21 (33.3) 27 (40.3) 48 (36.9) 0.45 2 12 (19.0) 11 (16.4) 23 (17.7) 3 11 (17.5) 16 (23.9) 27 (20.8) 4 19 (30.2) 13 (19.4) 32 (24.6) Tumor Size (mm) < 15 17 (29.3) 5 (7.6) 22 (17.7) 0.003 25-40 10 (17.2) 22 (33.3) 32 (25.8) 40+ 31 (53.4) 39 (59.1) 70 (56.5)
TERT rearrangements to identify a subset of aggressive meningiomas.
Authors: Tareq A. Juratli, Ian M Silverman, Ganesh M Shankar, Shilpa S Tummala, Heather A Ely, Jason H. Christiansen, Gabriele Schackert, Daniel P. Cahill, Priscilla Kaliopi Brastianos
Journal: Journal of Clinical Oncology (2018)

e14028 Background: Although a significant proportion of aggressive meningiomas acquire TERT promoter (TERTp) mutations which drive TERT overexpression during progression, alternative mechanisms of telomere maintenance in meningioma are broadly unknown. TERT activating rearrangements are common in some aggressive cancers and associated with poor outcome. We sought to assess TERT rearrangements in a large cohort of patients with progressive meningiomas. Methods: We determined the frequency of TERT mRNA overexpression in 126 temporally- and regionally-distinct specimens from 55 WHO grades II/III meningioma patients using reverse-transcriptase PCR. Subsequently, RNA sequencing was performed in samples with TERT overexpression to detect rearrangements. Additionally, the TERTp region was sequenced in all patients to assess hotspot mutations. Results: We identified 9 samples from 3 patients (5.4%) with highly amplified TERT mRNA expression. RNA sequencing of these samples revealed a novel fusion RETREG1-TERT that was present in 2 patients, in addition to a previously-reported LPCAT1-TERT fusion in a third case. One of the 3 patients had received a course of radiotherapy prior to the emergence of detectable mRNA fusion. In all cases the TERT rearrangements began in either exon 2 or 3, upstream of the reverse transcriptase domain that begins in exon 4, consistent with a proposed activating mechanism-of-action. In total, 10 patients (18%) harbored TERT alterations in our cohort: 3 TERT rearrangements and 7 TERTp mutations. Importantly, patients whose meningiomas harbored TERT alterations had a significantly worse overall survival (5.1 years, 95% CI 3.1 – 7.2) compared to TERT wild-type patients (18.5 years, 95% CI 14.6 – 22.4, p < 0.001). Conclusions: We discovered TERT rearrangements in a subset of aggressive meningiomas, including a novel RETREG1-TERT rearrangement. Two distinct mechanisms for TERT activation, TERT rearrangements and TERTp mutations were associated with a particularly poor outcome, suggesting a central role of telomere lengthening in the pathogenesis of aggressive meningioma. Detection of TERT alterations offers a basis for a more precise identification of patients at-risk for developing early progression of meningioma.
TCT-713 Hemodynamic Valve Dysfunction Following Transcatheter Aortic Valve Implantation: Prevalence and Predictors of Elevated Transvalvular Gradients
Authors: Tobias Rheude, Costanza Pellegrini, Salvatore Cassese, Jens Wiebe, Sophia Wagner, Jonathan Michel, Moritz Rumpf, Teresa Trenkwalder, Hector Alvarez, N. Patrick Mayr, Christian Hengstenberg, Markus Kasel, Heribert Schunkert, Adnan Kastrati, Oliver Husser, Michael Joner
Journal: Journal of the American College of Cardiology (2019)
P01.126 Frequent Tp53 and ATRX/DAXX gene alterations in giant cell IDH-Wildtype Glioblastomas
Authors: D Cantero Montenegro, N D’Haene, Á Rodríguez de Lope, J Sepulveda, N de Neve, C Fiaño, M Gutiérrez-Guamán, M Mollejo, I Salmon, A Hernandez-Laín, B Melendez
Journal: Neuro-Oncology (2018)

The 2016 updated World Health Organization (WHO) classification system recognizes the morphological variant giant cell glioblastoma (GBM) as one rare variant of IDH-wildtype (IDH-wt) GBM. This variant account for <1% of all GBMs, occurs in young adults patients and have a slightly better prognosis that ordinary IDH-wt GBM. Histologically, it is characterized by the presence of bizarre and numerous multinucleated giant cells. The lack of a more precise definition of this morphological variant makes that sometimes the giant cell component is not taken into account, even though some evidences may suggest that it may be clinically relevant. This variant has not been characterized yet by specific genetic biomarkers such as other variants of GBM, e.g. epithelioid GBM with BRAF mutations or secondary GBM with IDH mutations. The purpose of our study is to determine whether there is a molecular genetic base underlying the giant cell morphological variant of GBM. We retrospectively studied 31 cases of giant cell GBMs or GBMs in which a giant cell component was specified in the pathological report. We performed next generation sequencing assays by using a targeted panel of 30 genes involved in gliomas to study mutations and copy number variations. The following histological features were recorded: percentage and size of giant cells, presence of lymphocytes, gemistocytes, epithelioid, necrosis, vascular endothelia proliferation and epithelioid or PNET-like morphology. A review of the clinical records of the patients was also performed. Mean age of the patients was 47 years. The most frequently altered genes were: TP53 (74%), PTEN (32%) and ATRX (29%). Strikingly, 39% of the cases presented mutations in ATRX or DAXX in absence of the previously reported driver IDH or H3.3 gene mutations. Moreover, those cases with high amount of giant cells (> 30%), had frequently (around 75% of the cases) molecular alterations in TP53 accompanied of alterations in the chromatin remodeling genes ATRX or DAXX genes. Our results suggest that giant cell GBMs may have specific molecular characteristics, such as the presence of concurrent TP53 and ATRX/DAXX alterations in the absence of IDH or H3F3A driver mutations. These findings may be relevant for the development of targeted therapies and a personalized medicine.
Relevance between PD-L1 expression combined with tumor infiltrating lymphocytes and prognosis in advanced hypopharyngeal squamous cell carcinoma.
Authors: Takeharu Ono, Koichi Azuma, Akihiko Kawahara, Tetsuro Sasada, Satoshi Hattori, Fumihiko Sato, Shun-ich Chitose, Buichiro Shin, Jun Akiba, Hirohito Umeno
Journal: Journal of Clinical Oncology (2017)

e17528 Background: Little information has been available regarding immune-related prognostic factors in patients with advanced hypopharyngeal squamous cell carcinoma (HPSCC). Expression of programmed cell death-ligand 1 (PD-L1) in tumor cells is known to be a mechanism whereby cancer can escape immune surveillance. We investigated the predictive relevance of PD-L1 expression in tumor cells and tumor-infiltrating lymphocyte (TIL) density in patients with locally advanced HPSCC receiving neoadjuvant chemotherapy (NAC). Methods: We retrospectively reviewed 83 consecutive patients with advanced HPSCC who had received NAC. PD-L1 expression and TIL density were evaluated by immunohistochemical analysis. Results: Univariate and multivariate analyses demonstrated that CD8 + TIL density was an independent and significant predictive factor for progression free survival (PFS) and overall survival (OS), whereas PD-L1 expression was not correlated with PFS or OS. Subgroup analysis defined by PD-L1 expression in combination with CD8 + TIL density revealed that the PD-L1 - /CD8 high group showed the longest survival (median PFS and OS were not reached), whereas the PD-L1 + /CD8 low group showed the shortest PFS (median 7.9 months, p = 0.006) and OS (14.3 months, p = 0.011) by Kaplan-Meier curves. Conclusions: Although there was no significant correlation between PD-L1 expression and prognosis in stage III and IV HPSCC patients who received NAC, the subgroup analysis indicated that combination of lack of PD-L1 expression and higher CD8 + TIL density was significantly associated with favorable survival in these patients. These results suggested that PD-L1 expression levels in combination with CD8 + TIL density could be a useful predictive biomarker in patients with stage III and IV HPSCC.
Timeliness of treatment initiation in newly diagnosed breast cancer patients.
Authors: Jinghui Dong, Kimberly Esham, Lauren Boehm, Sabrina A Karim, Mingqian Lin, Daqin Mao, Feng Qing Wang, Daniel E Fein, Hanyin Wang, Christine Studenmund, RuthAnn Weidner, Farzad Noubary, Karen M Freund, John Kalil Erban, Susan K. Parsons
Journal: Journal of Clinical Oncology (2018)

e18637 Background: Delays in breast cancer treatment lead to poor clinical outcomes. Evidence-based timeliness benchmarks have been established to assess quality of care. However, few studies have evaluated how current breast cancer care meets these timeliness benchmarks and factors that delay treatment. Methods: Demographic and disease characteristics of 377 newly diagnosed breast cancer patients who initiated treatment at Tufts Medical Center (2009-2015) were extracted from electronic medical records. Kaplan-Meier plots were generated for time-to-surgery and time-to-hormone therapy. Multivariable logistic regression analysis was performed to identify factors associated with treatment delays. Thematic analysis was performed to determine reasons for delay. Results: Of 322 patients who had surgery recommended as the first treatment, 78% met the 45-day time-to-surgery benchmark (median, 28 days (IQR 19-43 days)). Of 241 patients eligible for hormone therapy initiation, 96% met the 1-year time-to-hormone therapy benchmark (median 147 days (IQR 79-217 days)). After adjusting for insurance, hormone receptor positivity, triple negative status, family history, and prior breast cancer treatment, multivariable regression analysis revealed that younger age (OR, 0.65; 95% CI:,0.05-0.83), lowest quartile median household income (OR, 2.55; 95% CI: 1.04–6.69), and comorbidity (OR, 2.02; 95% CI:, 1.06-3.90) were significantly associated with delays in surgery. Approximately half of the delays were due to clinical complexity and the remainder to logistical reasons including scheduling and insurance. Conclusions: Most patients in this study met timeliness guidelines for surgery and initiation of hormone therapy, although high risk factors (i.e., younger age, income, comorbidity) were identified. Reasons for delay included logistical issues and clinical complexity. Knowledge of reasons for delay of breast cancer treatment may allow targeted interventions towards patients at greatest risk of care delay. Interventions could be targeted at aggressive comorbidity management and logistical coordination.
Validation of the new UICC classification (8<sup>th</sup> ed.) for the staging of GIST in the TKI era.
Authors: Johanna Falkenhorst, Juergen Treckmann, Stefanie Bertram, Buu-Phuc Nguyen, Sebastian Bauer
Journal: Journal of Clinical Oncology (2018)

e23517 Background: Clinical staging systems are an important daily tool for risk assessment and patient counseling. For gastrointestinal stromal tumors (GIST) the AFIP classification is most widely used. The UICC classification, a prognosticator for survival, is rarely used in clinical practice; some guidelines even discourage its use. We sought to compare the updated version against established risk classifications. Methods: From our institutional database 285 cases of gastric and small bowel GIST were extracted and recurrence free (RFSR for localized tumors) and overall survival rates (OSR) for UICC, AFIP and Joensuu contour classifications (gastric only) were calculated. Results: With regard to RFSR in gastric GIST, the new UICCC separated stages IB (100%), II (62%), and IIIA/B (15/16%) (p < 0,05) but no difference was seen between IIIA and IIIB. For AFIP, RFR separated well between the different risk groups (low (100%), intermediate (62%) and high (26%) risk groups (p < 0,05)). For small bowel GIST, the UICC stages II, IIIA and IIIB (corresponding to AFIP high risk) showed significant differences in RFSR (II: 75%; IIIA: 53%; IIIB: 4%; p < 0,05). Joensuu risk contour maps were highly concordant with RFR. For gastric GIST, the AFIP risk groups show a 7-year-OS of 88% (low), 82% (intermediate); 68% (high) and 37% (metastastic). The UICC stages were associated with an OSR of IA 86%; IB 88%; II 82%; IIIA 60%; IIIB 82%; IV 48% in gastric GIST and with stage II (100%), IIIA (90%), IIIB (76%); IV (73%)) for small bowel GIST. Conclusions: Clinical stages according to the UICCC show clustered OS curves for stages I-IIIA and IIIB-IV in a “real world” patient cohort. The classification does not appear to provide an advantage over the combination of AFIP classification and Joensuu risk maps with regard to RFS or OS. In the era of TKIs, future classifications should incorporate additional covariates such as genotype and tumor load which may further impact survival.
Association of clinical benefit rate (CBR) with survival: A pooled-analysis of metastatic breast cancer (MBC) trials submitted to the U.S. Food and Drug Administration (FDA).
Authors: Laleh Amiri-Kordestani, Joyce Cheng, Lijun Zhang, Shenghui Tang, Rajeshwari Sridhara, Amna Ibrahim, Geoffrey Kim, Amy E. McKee, Richard Pazdur
Journal: Journal of Clinical Oncology (2016)

e18091 Background: CBR is commonly used as one the secondary endpoints in many cancer clinical trials. There are no comprehensive analyses to demonstrate that CBR adds to the value of the conventional time-to-event efficacy endpoints of progression-free and overall survival (PFS and OS) in clinical trials, and to date, CBR data are not reported in the clinical studies section of the U.S. package inserts for products approved for the treatment of MBC. We conducted a pooled analysis of data from MBC trials submitted to the FDA to understand the association of CBR with PFS and OS. In this analysis, CBR is defined as the percentage of patients with MBC who have achieved complete response, partial response or stable disease ≥ 6 months. Methods: We identified 13 trials of experimental agents with 10,263 patients submitted for treatment of MBC in initial or supplemental New Drug or Biologics License Applications since 2005. Criteria for inclusion of the trials in this analysis were: randomized, active-controlled, multicenter. The estimated PFS hazard ratio (HR) and OS HR versus the estimated odds ratio (OR) of CBR on the log-scale was calculated. Weighted least square regression analyses (weight equal to the number of patients) were performed on log-transformed effects. Responder analysis was performed to compare PFS and OS between patients with and without CBR, irrespective of the treatment assignment. Hazard ratios and 95% confidence intervals of PFS and OS were calculated from stratified Cox regression models with study as a stratification factor. Results: In trial level analysis, there was a moderate association between PFS HR and CBR OR (R2 = 0.52) and little to no association between OS HR and CBR OR (R2 = 0.01). Based on the responder analysis, in the patient level, the CBR was positively associated with PFS (HR = 0.078, 95% CI: 0.073, 0.084) and OS (HR = 0.32, 95% CI: 0.301, 0.340). Conclusions: There was a moderate association between CBR and PFS. An association between CBR and OS was not established. There is insufficient evidence to add CBR in product labeling if PFS and/or OS are reported.