tbuckley/cabot-search huggingface dataset:
Predictors and outcomes of thyroid dysfunction with immunotherapy: A single institution observational experience.
Authors: Ankit Mangla, Koosha Paydary, Udit Yadav, Jiaxiang Liu, Thomas E. Lad
Journal: Journal of Clinical Oncology (2019)

e14134 Background: Immune-related endocrine dysfunction is unique to immunotherapy (IT). We aimed to explore the clinical parameters associated with development of thyroid disorder (TD) in patients receiving IT and their outcome. Methods: We designed a retrospective study of patients treated with anti-CTLA4 and/or anti-PD1/PDL1 IT at Cook County Hospital, Chicago between January 2015 to January 2018. Patients with incomplete charts and those who received less than two cycles of IT were excluded. Demographics, clinical and pathologic data were recorded at the time of diagnosis and prior to start of IT. Pearson Chi-square, independent sample t-test and logistic regression were used for data analysis. Results: We included 104 patients in the study, out of whom 66 were male and 38 were female. Most common diagnosis was non-small cell lung cancer (42.4%) followed by squamous cell cancer of head and neck (21.2%), renal cell cancer (12.5%), small cell lung cancer (12.5%) and melanoma (8.7%). Majority of patients (91.4%) had metastasized and were treated with either Nivolumab (71.1%) or Pembrolizumab (21.2%) in the 2 nd (50%) or 3 rd line (29.8%) setting. Twenty-eight patients developed TD while on IT, out of whom, 13 developed hypothyroidism, 12 developed hyperthyroidism followed by hypothyroidism and 3 developed hyperthyroidism. TD developed between 1 st to 6 th cycle of IT in 96.5% patients. Older age (p-0.009), history of radiation (RT) to neck (p-0.007), history of RT to chest (p-0.015), history of venous thrombosis (p-0.007) and higher thyroid stimulating hormone (TSH) level (17.76±35.67) prior to starting IT (p-0.029) were significantly associated with TD. Multivariate logistic regression showed that history of RT to neck was a significant predictor of developing TD after adjustment for age, race and sex (adjusted OR 9.64, 95% CI 1.88-49.36, p-0.007). No patient reported thyroid related symptom and IT was continued uninterrupted in all patients. Levothyroxine was the drug of choice for treating hypothyroidism. No patient received steroids or antithyroid medications. Conclusions: History of radiation therapy to neck is significantly associated with development of thyroid dysfunction in patients receiving immunotherapy. Thyroid replacement therapy is sufficient to bring down the levels of TSH and immunotherapy need not be interrupted.
DUO-O: A randomized phase III trial of durvalumab (durva) in combination with chemotherapy and bevacizumab (bev), followed by maintenance durva, bev and olaparib (olap), in newly diagnosed advanced ovarian cancer patients.
Authors: Philipp Harter, Mariusz Bidziński, Nicoletta Colombo, Anne Floquet, Maria Jesús Rubio Pérez, Jae-Weon Kim, Stephanie Lheureux, Christian Marth, Gitte-Bettina Nyvang, Aikou Okamoto, Alexander Reuss, Giovanni Scambia, Fabian Trillsch, Mehmet Ali Vardar, Els Van Nieuwenhuysen, Jasmine Lichfield, Paul Rugman, Philip Twumasi-Ankrah, Carol Aghajanian
Journal: Journal of Clinical Oncology (2019)

TPS5598 Background: Ovarian cancer (OC) is the leading cause of death from gynecologic cancers in US women. Despite high response rates to first-line treatment, ~70% of patients (pts) relapse within 3 years and then remain largely incurable. First-line treatment needs to be improved to achieve long-term remission in pts and improve the cure rate. The Phase III SOLO1 trial showed a meaningful clinical benefit for olap maintenance therapy in newly diagnosed OC pts with a BRCA mutation (Moore et al N Engl J Med 2018). Preliminary data suggest that combining a PD-L1 inhibitor, anti-angiogenic and PARP inhibitor (triplet therapy) may achieve a synergistic antitumor effect. The DUO-O study (NCT03737643) evaluates the efficacy and safety of treatment combinations involving standard-of-care platinum-based chemotherapy (chemo), VEGF inhibitor bev, anti-PD-L1 antibody durva and PARP inhibitor olap, in women with newly diagnosed advanced OC. Methods: Eligible pts for this double-blind, randomized, Phase III study must have newly diagnosed, advanced, high-grade epithelial OC and either have completed primary surgery or plan to have interval debulking surgery. Depending on their tumor BRCA mutation (tBRCAm) status (determined by central test), pts will join one of two independent cohorts. Pts in the non-tBRCAm cohort (n~906) will be randomized (1:1:1) before cycle 2 to: a) chemo + bev + placebo (for 6 cycles) followed by bev (15 mg/kg [total 15 months]) + placebo maintenance treatment (IV and tablets); b) chemo + bev + durva (6 cycles) followed by bev + durva (1120 mg q3w [total 15 months]) + placebo (tablets) maintenance treatment; or c) chemo + bev + durva (6 cycles) followed by bev + durva + olap (300 mg bd tablets [24 months]) maintenance treatment. Pts in the open-label tBRCAm cohort (n~150) will receive 6 cycles of chemo + durva followed by durva + olap maintenance therapy, with optional use of bev. The primary endpoint of progression-free survival will be assessed by modified RECIST 1.1. Key secondary endpoints include overall survival, overall response rate and duration of response. Enrollment began in January 2019. Clinical trial information: NCT03737643.
Prognostic value of PD-L1 gene expression with Recurrence Score and 70-gene signature in patients with ER+/HER2- early breast cancer.
Authors: Ioannis Zerdes, Emmanouil G. Sifakis, Nicholas Tobin, Jonas C. S. Bergh, Alexios Matikas, Theodoros Foukakis
Journal: Journal of Clinical Oncology (2019)

550 Background: We have previously demonstrated that PD-L1 mRNA expression can serve as prognostic biomarker in breast cancer (BC). In ER+/HER2- BC, RS and 70-gene signature are used to predict the risk of recurrence and benefit from chemotherapy. Methods: Discovery cohort (cohort 1) included 302 patients diagnosed with primary ER+/HER2- BC (1997-2005) in Stockholm health care region. Gene expression profiling has been performed using DNA microarrays (GSE48091) while information regarding tumor characteristics, treatment and follow-up have been obtained. TCGA’s dataset including 590 ER+/HER2- patients, was used as validation cohort (cohort 2). Kaplan–Meier estimates and Cox regression univariate/multivariable analyses were performed using breast cancer-specific survival(BCSS) and progression-free interval (PFI) as endpoints in cohorts 1 and 2, respectively. Gene signature scores were calculated using the R genefu package. Likelihood ratio (LR) tests and concordance indices (c-indices) were used to assess each score’s added prognostic value. Results: PD-L1 mRNA expression (treated as a continuous variable) was independently associated with better BCSS in cohort 1 (HR = 0.72; 95% CI = 0.58-0.90;p = 0.003) and with better PFI in cohort 2 (HR = 0.67; 95% CI = 0.50-0.90; p = 0.008) in the multivariable analysis. PD-L1 provided significant additional prognostic information beyond that of both RS alone (LR-Δχ 2 = 9.6; p = 0.002 and LR-Δχ 2 = 9.7; p = 0.002, in cohorts 1 and 2, respectively), and 70-gene signature score alone (LR-Δχ 2 = 10.4; p = 0.001 and LR-Δχ 2 = 9.2; p = 0.002 in cohort 1 and 2, respectively). C-indices for PD-L1 + RS vs RS were 0.65 vs 0.60 (cohort 1) and 0.66 vs 0.60 (cohort 2), and for PD-L1 + 70-gene vs 70-gene were 0.65 vs 0.59 (cohort 1) and 0.64 vs 0.54 (cohort 2), respectively. Conclusions: PD-L1 gene expression was correlated with better outcomes and can provide added prognostic value to RS and 70-gene signature scores in ER+/HER2- BC.
Disparities in lung cancer outcomes for veterans with comorbid mental disorders.
Authors: Jacob E Berchuck, Craig Meyer, Ning Zhang, Neil Trivedi, Beth Cohen, Sunny Wang
Journal: Journal of Clinical Oncology (2019)

6577 Background: Emerging evidence suggests that cancer patients with comorbid mental disorders have worse outcomes. Lung cancer is the leading cause of cancer-related death in the United States, yet the impact of specific mental disorders on outcomes for patients diagnosed with lung cancer is not well known. Methods: Stage at diagnosis and receipt of stage-appropriate treatment were assessed for 55,315 Veterans with non-small cell lung cancer (NSCLC) in the Veterans Affairs (VA) Central Cancer Registry from 2000 to 2011. Patients were stratified by the presence of specific comorbid mental disorders. Multivariate analysis evaluated the association between mental disorders and survival, as well as the impact of VA treatment programs on survival. Results: Patients with schizophrenia had lower rates of localized disease at diagnosis compared to those without mental disorders. Schizophrenia and dementia were associated with significantly lower rates of stage-appropriate treatment for localized, locoregional, and metastatic disease. Conversely, patients with depression or PTSD were more frequently diagnosed with early-stage disease and significantly more likely to receive stage-appropriate treatment across all stages. After adjusting for baseline differences, stage, and rates of stage-appropriate treatment, hazard of death was higher for patients with schizophrenia (hazard ratio [HR] 1.10; 95% CI, 1.03-1.16; P &lt; .005) and dementia (HR 1.11; 95% CI, 1.06-1.18; P &lt; .0005). Participation in VA-based programs to address mental illness, substance use, and homelessness was associated with a significant reduction in all-cause mortality (HR 0.71; 95% CI, 0.68-0.75; P &lt; .0001) and lung-cancer specific mortality (HR 0.73; 95% CI, 0.69-0.77; P &lt; .0001). Conclusions: Schizophrenia and dementia are strong negative predictors of survival among Veterans diagnosed with NSCLC. VA-based mental health treatment programs are associated with reductions in all-cause and lung cancer-related mortality, highlighting the importance of funding and promoting mental health and supportive programs.
Avelumab in newly diagnosed glioblastoma multiforme: The SEJ study.
Authors: Francois Henri Jacques, Garth Nicholas, Ian Lorimer, Victorine Sikatifoko, Jasmine Prévost
Journal: Journal of Clinical Oncology (2019)

e13571 Background: Glioblastoma Multiforme (GBM) has well documented systemic and local immunosuppressive mechanisms to escape immune surveillance and grow. GBM tumor cells as well as the microglia within it have a high PD-L1 surface expression which may make it susceptible to anti-PD-L1 antagonism and ADCC with avelumab therapy. Standard combination temozolomide/radiotherapy is associated with a median survival of 14.6 months and a median progression free survival of 6.9 months. Methods: This is a single center, phase 2, open label study of avelumab 10 mg/kg Q2W for 156 weeks duration in patients receiving standard therapy for newly diagnosed GBM. Thirty patients will be entered into the study within 3 weeks of completing combined radiotherapy/temozolomide. Here, we report the results of the first interim analysis completed when the first eight patients completed 52 weeks or an end of study visit. Results: To date 24 patients have started therapy. The median follow-up is 4.9 months (1-22 months). There has been overall no unexpected treatment emergent adverse event (TEAE). The most common TEAE was elevated liver or pancreatic enzymes. Two patients transiently withheld therapy because of immune related TEAE’s (both hepatitis) and none permanently. The objective response rate by iRANO criteria, at week 52 for the first eight patients was 4 (50%) with 2 (25%) having a complete response, 1 (12.5%) a partial response and 1 (12.5%) stable disease. The median progression free survival was 11.9 months. Conclusions: These preliminary results suggest that the addition of avelumab to standard combination therapy early on, in patients with GBM is safe. Efficacy trends look promising. Clinical trial information: NCT03047473.
First-time in-human study of VMD-928, an allosteric and irreversible TrkA selective inhibitor, in patients with solid tumors or lymphoma.
Authors: Vincent Chung, Ling Wang, Margaret S. Fletcher, Erminia Massarelli, Karen L. Reckamp, Mihaela C. Cristea, Nikeeta Prajapati, Aruna Parikh, Roger Lewis Whiting, Maggie Wang, Jay Wu
Journal: Journal of Clinical Oncology (2019)

TPS3146 Background: Tropomysin receptor kinase A (TrkA) is a protein encoded by the NTRK1 gene. NTRK fusions involving the kinase domain are oncogenic for multiple tumor types and larotrectinib was recently approved for advanced solid tumors harboring NTRK gene fusions. Larotrectinib, an ATP-competitive, reversible pan-TrkA/B/C inhibitor, has shown impressive response rates in patients harboring these fusions; however, resistance can develop due to acquired ATP-site mutations. This has been previously identified in other oncogenic driver kinases such as ALK and EGFR treated with ATP-competitive kinase inhibitors. A newly approved allosteric ALK/EGFR inhibitor brigatinib was able to clinically overcome acquired resistance of many ATP-competitive ALK/EGFR inhibitors (1). Also, irreversible EGFR inhibitors such as afatinib (ATP-competitive) were active against tumors resistant to first-generation inhibitors (2), although their efficacy can be compromised by acquired ATP-site mutations (3). VMD-928 is the first oral small-molecule TrkA (NTRK1) selective inhibitor with dual allosteric and irreversible mechanisms of action. It inhibits TrkA non-competitively at an allosteric (non-ATP) site and has no resistance in vitro to acquired ATP-site mutations such as G667C. VMD-928 in vitro has little or no activity against 348 other kinases including TrkB (NTRK2) and TrkC (NTRK3). We are conducting the first time in human phase 1 trial of oral VMD-928, a novel allosteric and irreversible TrkA selective inhibitor. Methods: This is an open label, Phase 1 study investigating the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of oral VMD-928 in adults with advanced solid tumors or lymphoma (NCT03556228). In part 1 of the study, an accelerated titration scheme will be utilized to determine the recommended phase 2 dose and evaluate PK / PD of VMD-928. In part 2, expansion cohorts including patients with thymic, pancreatic, triple-negative breast carcinoma, or solid tumors with TrkA alterations will be accrued to further evaluate safety and efficacy. Part 3 of the study will characterize the biologically active dose. The study is open and accruing patients at City of Hope. Clinical trial information: NCT03556228.
New generation of oncolytic herpesviruses embodying immunotherapeutic genes encoding IL-12 and anti-PD-1 antibody.
Authors: Grace Zhou, Dongyao Ni, Runbin Yan, Xiaoqing Chen, Xianjie Liu, Jie Ma, Yuxin Tang
Journal: Journal of Clinical Oncology (2019)

e14250 Background: Systemic administration of checkpoint inhibitors alone and especially concurrent with intratumoral administration of oncolytic herpes simplex viruses (oHSV) have a major impact on cancer therapy marred by rare failures of healthy organs. Methods: We constructed 3 families of recombinant oHSVs expressing no immunomodulatory genes (T1 series), murine or human IL-12 (T2 series) and murine or human IL-12 and anti-PD-1 antibody (T3 series). We compared the oncolytic effects of a single or multiple intratumoral injection(s) of T1, T2 and T3 series oHSVs. We also compared the effectiveness of intratumoral injection of T3 oHSV with systemic administration of anti PD-1 ab and IL12 alone or in combinations with T1. Results: Insertion of the gene encoding PD-1 Ab significantly augmented the oncolytic activity of oHSV bereft of immunostimulatory genes (T1 series) or expressing IL-12 alone (T2 series). In syngeneic mice the T3 series oHSV expressing murine IL-12 and PD-1 Ab was effective against a variety of murine tumors. Concurrent with enhanced cytolytic activity the T3 oHSV induced the production and significant intratumoral accumulation of IL-12, PD-1 Ab and IFN-γ. Consistent with an earlier report we noted an inverse correlation between the volume of the tumor and the quantity of retained IFN-γ. The most effective oncolytic effect resulted from the administration of T3855 expressing both IL12 and anti PD-1 antibody or T2850 concurrently with intraperitoneal administration of anti PD-1 antibody alone. The least effective were single intraperitoneal administration of IL12 or PD-1 antibody. Intratumoral injection of T3 oHSV was most effective against murine tumors in comparison of either systemic administration of anti PD-1 ab and IL12 or intratumoral injection of T1 in combinations of systemic administration of anti PD-1 ab and IL12. Conclusions: We report the marriage in a single therapeutic agent of three distinct cancer therapies: the targeting of cancer cells by oncolytic viruses, the stimulation of immune system by IL12, and the production of immunotherapeutic antibodies against PD-1. The significant finding reported in this article is that the anti-tumor responses remain concentrated in the tumor environment.
Efficacy of retreatment with anti-EGFRs in mCRC is not predictable by clinical factors related to prior lines of therapy: A multi-institutional analysis.
Authors: Daniele Rossini, Filippo Pagani, Antonio Pellino, Emanuela Dell'Aquila, Nicole Liscia, Maria Bensi, Marco Maria Germani, Gianluca Masi, Roberto Moretto, Daniele Santini, Lisa Salvatore, Mario Scartozzi, Sara Lonardi, Gemma Zucchelli, Elena Ongaro, Alfredo Falcone, Filippo Pietrantonio, Chiara Cremolini
Journal: Journal of Clinical Oncology (2019)

3540 Background: Retrospective analyses and phase 2 studies suggest that administering an anti-EGFR in advanced lines may be effective in mCRC pts who achieved benefit from a 1 st -line anti-EGFR containing regimen. The identification of clinical features associated with benefit from anti-EGFR re-treatment (re-tx) in pts experiencing PD during 1 st -line anti-EGFR (rechallenge) or after its interruption (reintroduction), is a major clinical need. Methods: A real-life data-base including a total of 5530 pts treated at 6 insitutions from December 2010 to October 2018 was queried. Pts retreated with anti-EGFRs, with RAS/ BRAF wild-type status on tissue samples, who had received a 1 st -line anti-EGFR-based tx with at least SD as best response, and at least one further line of therapy before anti-EGFR re-tx, were included. The association with RECIST response (RR), PFS and OS was investigated for the following variables: RR (PR or CR vs SD) and PFS during 1 st -line; time from the last anti-EGFR administration to 1 st -line PD (i.e. re-introduction vs rechallenge); reason for anti-EGFR discontinuation in 1 st -line (PD vs. other); number of anti-EGFR-free lines of therapy before re-tx; anti-EGFR free interval (time between the last anti-EGFR administration in 1 st -line and the time of re-tx); primary tumor side; time from the diagnosis of metastatic disease to re-tx (≥ vs. &lt; 18 mos). Results: Data from 86 patients were retrieved, 56 (65%) and 30 (35%) received anti-EGFR rechallenge or reintroduction, respectively. Median anti-EGFR free interval was 15.1 mos. The RR during re-tx was 19.8%, with a DCR of 46.5%. Median PFS and OS were 3.6 and 10.2 mos, respectively. No significant association of investigated features with RR and PFS was observed. No differences in RR or PFS were observed among patients receiving anti-EGFR re-tx as rechallenge or reintroduction (20.4% vs 23.1%, p = 0.99; median PFS: 3.49 vs 4.97 mos, p = 0.61). Patients with left-sided tumors had longer OS (HR: 0.50, 95%CI: 0.26-0.93, p = 0.005). Conclusions: Clinical factors that are generally believed to affect the efficacy of anti-EGFR re-tx are not confirmed in our series. Therefore, clinicians should not rely on those characteristics in their decision-making on anti-EGFR re-tx, and adequate studies for implementing liquid biopsy in clinical practice are urgently needed.
A novel biophysical based marker with multilevel, multiparameter expression for early stage cancer detection.
Authors: Junjie Wu, Gengxi Jiang, Jiansong Ji, Xuedong Du, Yue Lin, Hongmei Tao, Xing Tang, Chris Chang Yu
Journal: Journal of Clinical Oncology (2019)

e20673 Background: Early stage cancer detection remains to be elusive despite of many years of efforts. In this work, a bio-physical based marker (named Cancer Differentiation Analysis (CDA)) with multi-level and multi-parameter expression features has been developed which has shown a number of clear advantages over the traditional approaches such as bio-chemistry based marker, circulating tumor cell (CTC) and circuiting DNA (ct-DNA). In stage I non-small cell lung cancer (NSCLC), sensitivity and specificity reached a record high of 85.2% and 93.0%, respectively. Methods: In this study, 832 NSCLC cancer samples with pathological information and 642 samples from healthy individuals were measured in a single blind test. Peripheral blood of each individual was drawn in EDTA tubes. One class of bio-physical property in blood samples was utilized for CDA tests. The CDA data were first processed using an algorithm built from data base and subsequently analyzed using SPSS. The results were shown in the table. Results: The results indicated that CDA technology has a very good sensitivity and specificity even at stage I (85% and 93%, respectively), which is much better than those previously reported results by other methods. Conclusions: Initial results showed that CDA technology could effectively screen NSCLC patients from healthy individuals. As a novel bio-physical based cancer detection approach with multi-level and multi-parameter expressions, CDA technology could be a potential candidate for early stage cancer screening. [Table: see text]
Surrogate end points for overall survival in patients with advanced non-small-cell lung cancer in trials of immunotherapy.
Authors: Qiyun Ou, Yunfang Yu, Anlin Li, Yongjian Chen, Ying Wang, Wei Ren, Chenchen Li, Herui Yao
Journal: Journal of Clinical Oncology (2019)

e14122 Background: Our objective was to evaluate progression-free survival (PFS) and objective response rate (ORR) as surrogate end points for overall survival (OS) among patients with advanced non-small-cell lung cancer (NSCLC) in randomized trials of immunotherapy. Methods: Individual patient data (total N = 569 patients) were available from two multicentre, randomized, phase II/III trials (POPLAR and OAK). Analysis of OS, PFS and ORR were computed using the Kaplan-Meier estimates method and compared with the log-rank test, hazard ratios [HRs] and 95% confidence intervals [CIs] were calculated by using the Cox regression model. The surrogacy was evaluated using Spearman’s correlation coefficient (ρ) and coefficient of determination ( R²) between treatment effects on the surrogate end point and OS. We further validated the surrogacy in trial-level analysis with 26 NSCLC immunotherapy trials (total N = 12,094 patients) published prior to June 2018. Results: In the patient-level analyses, patients who achieved a response had better OS compared with nonresponders (HR 0.18; 95% CI, 0.11 to 0.29; P &lt; 0.001). Greater OS was also observed in landmark anlyses at 6-month PFS (HR 0.21; 95% CI 0.11 to 0.39; P &lt; 0.001) and 12-month PFS (HR 0.16; 95% CI 0.11 to 0.24; P &lt; 0.001). PFS correlated with OS at the individual level (Spearman ρ = 0.37; P &lt; 0.001). In the trial-level analysis, PFS moderately correlated with OS (Spearman ρ = 0.64; P &lt; 0.001), and the R² was 0.50 (95% CI 0.39 to 0.64). Conclusions: In NSCLC immunotherapy trials, responders and patients with longer PFS had better OS. ORR and PFS are acceptable surrogates for OS in trials of immunotherapy, but caution must be taken when interpreting efficacy in the absence of OS data.