tbuckley/cabot-search huggingface dataset:
Reassessing existing expanded access programs and planning forward in the time of Right to Try.
Authors: Anne Cropp, Alita Hassan, Sarah Alummootil
Journal: Journal of Clinical Oncology (2019)

e18172 Background: Desperately ill patients who have exhausted treatment options often seek access to therapy through investigational therapies. Participation in a clinical trial may be one option. When a clinical trial is not an option, physicians and patients are left with Expanded Access (EA), and Right to Try (RTT). The 21 st Century Cures legislation requires pharmaceutical manufacturers to make information on their EA policy, contact information, and response time readily accessible. RTT became law in 2018, and this path is rarely an option. Methods: To determine best practice in the age of changing legislation of pre-approval access to investigational drugs, we compared pathways by which pharmaceutical companies are providing access to investigational medications. Data has been gathered on presentation of policy, intake of expanded access requests, and education to the public on the company’s internal pathway to access. We conducted a survey of the top 100 Pharma companies to assess compliance with regulations, policy availability, and RTT information. Results: The data has shown that companies show a range of compliance in expanded access. Many companies have published all required aspects outlined in the legislation to be fully adherent to the guidelines with additional education and guidelines for patients and physicians. Others have provided the minimum requirement to be compliant: a policy and contact information. We also see companies that have not established a stance of process in expanded access and therefore provide no public facing information on their policy and pathways toward treatment. Information on RTT remained elusive. Conclusions: While RTT is increasingly requested as a possible path, the mechanism to request RTT remains a barrier and source of confusion to physicians and patients. Companies should take the opportunity to clearly define their policy and process for Expanded Access as well as reevaluate the organization of their current procedure to ensure highest efficiency and full compliance with legislation.
Effect of radiotherapy on the residual circulating epithelial tumor cells (CETCs) and their programmed cell death ligand 1 (PD-L1) status in breast cancer patients.
Authors: Dorothea Schott, Monika Pizon, Katharina Pachmann, Ulrich A. Pachmann, Matthias Maeurer
Journal: Journal of Clinical Oncology (2019)

e14034 Background: Preclinical studies have suggested that radiotherapy (RT) followed by immunotherapy could be a promising strategy for synergistic enhancement of treatment efficacy. RT induces immunogenic changes in cancer cells which can lead to adaptive up-regulation of PD-L1 expression. Moreover, radiotherapy reduces not only local recurrence but also improves overall survival by preventing distant metastases, which indicates its influence on the remaining occult tumor, such as circulating tumor cells. For this reason the aim of this study was to determine the PD-L1 status on CETCs before and during RT. Methods: CETCs were determined in 54 primary breast cancer patients in early and locally advanced stages. The number of CETCs and their expression of PDL-L1 were investigated using the maintrac method. The fraction of PD-L1 positive CETCs was assessed prior to (baseline), 3 and 6 weeks after the start of radiotherapy. Results: We found a correlation between the PD-L1 status of CETCs and aggressiveness of cancer disease prior to radiotherapy. Patients with positive lymph node status presented more PD-L1 positive CETCs compared to patients with negative lymph nodes (mean 73% vs. 50%, p &lt; 0.01). Moreover, the HER2 expression of the primary tumor was also positively correlated with PD-L1 expression. Lower numbers of CETCs were detected in patients who had not received chemotherapy or adjuvant chemotherapy before RT than in those who received neoadjuvant chemotherapy (median 20 vs 25 vs 120 CETC/100µl blood, p &lt; 0.001). Surprisingly, the fraction of PD-L1 positive CETCs decreased during radiotherapy only in patients who had received neoadjuvant chemotherapy. Conclusions: Although the number of CETCs and the fraction of PD-L1 positive CETCs were higher in patients who had received neoadjuvant chemotherapy, radiotherapy reduced both measured biomarkers. In the future PD-1/PD-L1 checkpoint inhibitors after radiotherapy might have additional benefit in breast cancer patients.
Burden and Outcomes of Heart Failure Hospitalizations in Adults With Chronic Kidney Disease
Authors: Nisha Bansal, Leila Zelnick, Zeenat Bhat, Mirela Dobre, Jiang He, James Lash, Bernard Jaar, Rupal Mehta, Dominic Raj, Hernan Rincon-Choles, Milda Saunders, Sarah Schrauben, Matthew Weir, Julie Wright, Alan S. Go, Lawrence J. Appel, Harold I. Feldman, Alan S. Go, Jiang He, James P. Lash, Panduranga S. Rao, Mahboob Rahman, Raymond R. Townsend
Journal: Journal of the American College of Cardiology (2019)
Analysis of lipid metabolism genes in advanced small cell lung cancer.
Authors: Maria Merino, Lara Fernández, Maria Sereno, Ana Ramirez de Molina, Juan Moreno, Gonzalo Colmenarejo, César Gómez, Miriam Lopez-Gomez, Sandra Falagan, Cristina Aguayo, Francisco Zambrana, Ana Maria Jimenez Gordo, Enrique Casado
Journal: Journal of Clinical Oncology (2019)

e14737 Background: Lung cancer is the leading cause of cancer death worldwide. Although most of the knowledge about metabolic dysregulation in cancer focuses on carbohydrates, the importance of alterations related to lipid metabolism is starting to be recognized. There is increasing data on lipid metabolism and non-small lung cancer, but much less is known about this in small cell lung cancer (SCLC). In order to improve our knowledge of these alterations we evaluated a genetic profile related to lipid metabolism and studied clinical outcomes. Methods: We performed a retrospective analysis of 22 genes related to lipid metabolism in 37 tumoral tissue samples of SCLC patients and evaluated clinical features and outcomes. Advanced SCLC patients enrolled from November 1, 2008 through December 31, 2015 were included in this analysis. Clinical data were collected from medical records at the time of enrollment. The study was approved by an Ethics Comittee and all patients signed an Informed Consent form. We used formalin-fixed, paraffin- embedded tumor tissue. Samples were deparaffinated and total RNA was extracted. A Taq-Man Low Density Array (Applied Biosystems) was specifically designed and gene-expression assays were performed in a HT-7900 Fast Real time PCR. RT-StatMiner software was used to detect and determine the quality control and differential expression analyses of data. Results: We included 37 patients, 73 % males and 27 % women, with a median age of 62. 29 patients (78%) had stage IV tumor and nearly all of them (92%) were treated with platinum- based chemotherapy. 11 % (4/37) received thoracic radiotherapy and 5% (2/37) received whole brain radiotherapy. 6 patients (16%) were on chronic treatment with metformin and 15 (40%) on statins. We performed a multivariable analysis and found that overexpression of two metabolic genes (a mitochondrial enzyme and a lipid metabolism regulator) led to longer overall survival. (HR 0.13 (0.04-0.42), p 0.0019, p adjusted 0.04 and HR 0.11 (0.03-0.35) p 0.0006, p adjusted 0.01, respectively). Conclusions: These genes contribute to normal functioning and regulation of lipid metabolism and could be considered as potential prognostic biomarkers. There is no previous evidence of association between levels of expression of these genes and overall survival in SCLC. Validation in a larger series of patients is ongoing.
QOL assessment in head and neck cancer patients undergoing neoadjuvant chemotherapy and its impact on overall survival.
Authors: Sachin Dhumal, Vijay Maruti Patil, Vanita Noronha, Amit Joshi, Atanu Bhattacharjee, Somnath Roy, Sudeep Das, Kumar Prabhash
Journal: Journal of Clinical Oncology (2019)

e17519 Background: NACT (neoadjuvant chemotherapy) is one of the treatment options in advanced head and neck cancer (H&amp;N cancer); however there is limited quality of life data available in these patients. Methods: Between August 2013- April 2014, 90 technically unresectable H&amp;N cancer patients who were underwent NACT at our centre were selected for this analysis. EORTC QLQ-C30 and HN35 version 3.0 was used for quality of life assessment at baseline and after 02 cycles of NACT. PFS and OS was estimated by Kaplan Meier method. The mean change in QOL at various domains was calculated with 95% CI. The relationship between change in QOL domain and OS was analysed. Results: The median age of the cohort was 45 years (Range 21-65 years). The predominant subsite was oral cavity, in 62 patients (68.9%).The median PFS and OS was 10.53 months (95%CI 8.1-13.0) and 20.8 months (95%CI 15.1-26.5). The mean scores for all domains of QOL are shown in table 1. Conclusions: NACT leads to improvement in QOL in patients treated with head and neck cancers and its has impact on OS.[Table: see text]
Intracerebral immunotherapy for brain tumors.
Authors: Guido Carillio, Luigi Santaguida, Eugenio Donato Di Paola, Anna Maria Lavecchia, Virginia Vescio, Alfonso Iannello, Rosa Molè, Maria Gabriella Serrao, Rosanna Mirabelli, Giuseppe Mauro, Stefano Molica
Journal: Journal of Clinical Oncology (2019)

e13522 Background: Immunotherapy is a promising approach for the treatment of brain tumors, but available data are still inconclusive. The main drawback is represented by transport across the blood–brain barrier of high molecular weight drugs. Convection-enhanced delivery (CED) has been designed to overcome some difficulties. We wondered whether a CED strategy based on the use of novel immune checkpoint inhibitors could be effective. Methods: Frameless biopsy by fluorescein tracer and neuronavigation-assisted system, followed by an injection of nivolumab 40mg/4mL into the brain lesion, were offered to patients with: a) high grade gliomas (HGG) inoperable or progressed during or after standard treatment (i.e. surgery and radio-chemotherapy); b) HGG at first diagnosis or after disease progression treated with radical surgery (nivolumab delivered in the surgical cavity after tumor removal); c) other brain tumors or solitary metastases judged suitable for surgical procedure. PD-L1 expression was assessed in all patients, but it was not a strict criterion for accrual. Standard therapy, usually based on chemotherapy, radiotherapy or both, was sequentially administered to patients able to tolerate such an approach. End-points were safety, response rate, disease control, predictive value of PD-L1 expression. This is a non-sponsored monocentric, real life, basket trial approved by Ethical Committee (EudraCT number: 2018-001560-33). Results: Since August 2018, 17 patients with brain tumors (16 HGG and 1 heavily pretreated medulloblastoma) and 5 patients with brain metastasis (of lung and gastrointestinal cancers) were enrolled. Median age was 63 years (range 26-83). After a median follow up of three months (range 1-6), all patients are alive and in good clinical conditions. No signs of neurologic toxicity due to intracerebral nivolumab were observed. Brain MRI performed at 4 to 12 weeks after nivolumab CED revealed findings suggesting a perivascular lymphocyte infiltration. Correlation between PD-L1 expression and treatment efficacy will be evaluated over time. Conclusions: Intracerebral nivolumab appears to be a feasible and safe option for patients with HGG and brain metastases at the dose investigated in the study. Long-term follow up could contribute to well understand the role of this strategy. Clinical trial information: 2018-001560-33.
Anticancer therapy within the last 30 days of life: Results of an audit and re-audit cycle from a regional cancer center.
Authors: Mike Nguyen, Alysson Wann, Babak Tamjid, Arvind Sahu, Javier Torres
Journal: Journal of Clinical Oncology (2019)

e18260 Background: The therapeutic landscape in medical oncology continues to expand significantly. Newer therapies, especially immunotherapy, offer the hope of profound and durable responses with more tolerable side effect profiles. Integrating this information into the decision making process is challenging for patients and oncologists. Systemic anticancer treatment within the last thirty days of life is a key quality of care indicator and is one parameter used in the assessment of aggressiveness of care. Methods: A retrospective review of medical records of all patients previously treated at Goulburn Valley Health oncology department who died between 1 January 2015 and 30 June 2018 was conducted. Information collected related to patient demographics, diagnosis, treatment, and hospital care within the last 30 days of life. These results were presented to a hospital meeting and a quality improvement intervention program instituted. A second retrospective review of medical records of all patients who died between 1 July 2018 and 31 December 2018 was conducted in order to measure the effect of this intervention. Results: The initial audit period comprised 440 patients. 120 patients (27%) received treatment within the last 30 days of life. The re-audit period comprised 75 patients. 19 patients (25%) received treatment within the last 30 days of life. Treatment rates of chemotherapy reduced after the intervention in contrast to treatment rates of immunotherapy which increased. A separate analysis calculated the rate of mortality within 30 days of chemotherapy from the total number of patients who received chemotherapy was initially 8% and 2% in the re-audit period. Treatment within the last 30 days of life was associated with higher use of aggressive care such as emergency department presentation, hospitalisation, ICU admission and late hospice referral. Palliative care referral rates improved after the intervention. Conclusions: This audit demonstrated that a quality improvement intervention can impact quality of care indicators with reductions in the use of chemotherapy within the last 30 days of life. However, immunotherapy use increased which may be explained by increased access and perceived better tolerability.
Review of therapeutic approaches for B-cell malignancies with immune checkpoint blockade and chimeric antigen receptor t-cell therapies: Development, benefits, and limitations.
Authors: Priya Hays
Journal: Journal of Clinical Oncology (2019)

e14069 Background: Immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR) T-cell therapies have emerged as approaches to treat B-cell malignancies. Methods: PubMed/NCBI/MEDLINE databases were accessed with keywords "immune checkpoint inhibitors and B-cell malignancies" "CAR T-cell and B-cell malignancies", and various permutations including "clinical data" "toxicities", "reviews", "quality of life", and "adverse effects". Results: The first-in-class approved immune checkpoint inhibitor was ipilimumab, which is a fully humanized mAb that blocks the immunosuppressive signal by cytotoxic T-lymphocyte antigen. Thereafter, nivolumab was also approved for use in the treatment of Hodgkin's lymphoma in 2016. In phase I, open-label, dose-escalation, cohort-expansion study, patients with relapsed or refractory B-cell lymphoma received the anti-PD-1 monoclonal antibody nivolumab. Eighty-one patients were treated and drug-related adverse events occurred in 51 (63%) patients. Objective response rates were 40%, 36%, 15%, and 40% among patients with follicular lymphoma and other hematologic malignancies. Clinical trial results describing CD19-targeted CAR T-cell therapy of patients with relapsed B-ALL were published in 2015. In this study, all five patients treated with CAR T cells achieved minimal residual disease negative complete remission. Updated results describing the treatment of 16 patients with relapsed or refractory B-ALL treated with CAR T cells were published: the overall CR rate in this trial was 88% and 12 of 14 patients were classified as minimal residual disease negative. 44% of these patients went on to standard-of- care allogeneic hematopoietic stem cell transplant. Initial studies also reported potent anti-leukemic effects of CD19 CAR T cell therapy in three patients with refractory chronic lymphocytic leukemia where two of the three patients achieved MRD-CR. Infused CAR T cells proliferated up to 10,000-fold and persisted in recipients for at least 6 months and shown to retain antitumor activity after six months. Costs for CAR T-cell therapies remain exorbitant, reaching over $1M (USD) per patient. Conclusions: Clinical data reveal safety and efficacy, and also associated toxicities for both approaches.
Efficacy of systemic therapy for metastatic renal cell carcinoma in patients over 75 years of age.
Authors: Ryuichi Mizuno, Kimiharu Takamatsu, Nozomi Hayakawa, Takeo Kosaka, Nobuyuki Tanaka, Mototsugu Oya
Journal: Journal of Clinical Oncology (2019)

e16080 Background: In the last decade, approval of targeted agents and immune checkpoint inhibitors (ICI) have dramatically changed the scenario of systemic treatment of metastatic renal cell carcinoma (mRCC) with improved survival. Although elderly individuals represent a consistent proportion, clinical trials have not directly compared the efficacy and safety of targeted agents in the elderly population. Methods: A total of 195 patients were retrospectively reviewed. All patients received systemic therapy for mRCC at Keio University hospital in Japan (Institutional review board approval No 2013-0425). Patients were divided into two groups (≥75 or &lt; 75 years) according to their age at the time of systemic therapy initiation. The disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were compared between the two cohorts. Results: The elderly cohort (≥75 years old) comprised of 42 patients (21.5%). The DCR for first line treatment in patients ≥75 years old and &lt; 75 years old was 75.0 and 76.2 %, respectively (p = 0.8728). The median PFS for first line treatment in patients ≥75 years old and &lt; 75 years old was 10.7 (95% CI 7.5–20.7) and 11.6 (95% CI 9.7–16.3) months, respectively (p = 0.6074). The median OS for systemic treatment in patients ≥75 years old and &lt; 75 years old was 37.3 (95% CI 18.0–65.2) and 45.5 (95% CI 35.1–56.8) months, respectively (p = 0.0424). Conclusions: Systemic treatment for mRCC was feasible and effective in Japanese patients over 75 years of age.
A machine learning based prediction model of anti-PD-1 therapy response using noninvasive clinical information and blood markers of lung cancer patients.
Authors: Beung-Chul AHN, Kyoung Ho Pyo, Dongmin Jung, Chun-Feng Xin, Chang Gon Kim, Min Hee Hong, Byoung Chul Cho, HyeRyun Kim
Journal: Journal of Clinical Oncology (2019)

e14138 Background: Immune checkpoint inhibitors have become breakthrough therapy for various types of cancers. However, regarding their total response rate around 20% based on clinical trials, predicting accurate aPD-1 response for individual patient is unestablished. The presence of PD-L1 expression or tumor infiltrating lymphocyte may be used as indicators of response but are limited. We developed models using machine learning methods to predict the aPD-1 response. Methods: A total of 126 advanced NSCLC patients treated with the aPD-1 were enrolled. Their clinical characteristics, treatment outcomes, and adverse events were collected. Total clinical data (n = 126) consist of 15 variables were divided into two subsets, discovery set (n = 63) and test set (n = 63). Thirteen supervised learning algorithms including support vector machine and regularized regression (lasso, ridge, elastic net) were applied on discovery set for model development and on test set for validation. Each model were evaluated according to the ROC curve and cross-validation method. Same methods were used to the subset which had additional flow cytometry data (n = 40). Results: The median age was 64 and 69.8% were male. Adenocarcinoma was predominant (69.8%) and twenty patients (15.1%) were driver mutation positive. Clinical data set (n = 126) demonstrated that the Ridge regression (AUC: 0.79) was the best model for prediction. Of 15 clinical variables, tumor burden, age, ECOG PS and PD-L1, were most important based on the random forest algorithm. When we merged the clinical and flow cytometry data, the Ridge regression model (AUC:0.82) showed better performance compared to using clinical data only. Among 52 variables of merged set, the top most important immune markers were as follows: CD3 + CD8 + CD25 + /T eff -CD28, CD3 + CD8 + CD25 - /T eff -Ki-67, and CD3 + CD8 + CD25 + /T eff -NY-ESO/T eff -PD-1, which indicate activated tumor specific T cell subset. Conclusions: Our machine learning based model has benefit for predicting aPD-1 responses. After further validation in independent patient cohort, the supervised learning based non-invasive predictive score can be established to predict aPD-1 response.
A pilot presurgical study evaluating anti-PD-L1 durvalumab (durva) plus anti-CTLA-4 tremelimumab (treme) in patients (pts) with high-risk muscle-invasive bladder carcinoma (MIBC) who are ineligible for cisplatin-based neoadjuvant chemotherapy (NAC).
Authors: Jianjun Gao, Arlene O. Siefker-Radtke, Neema Navai, Matthew T Campbell, Rebecca Slack Tidwell, Charles Guo, Ashish M. Kamat, Surena F. Matin, John C. Araujo, Amishi Yogesh Shah, Pavlos Msaouel, Jorge M. Blando, Luis M. Vence, Fei Duan, Sreyashi Basu, Shalini Singh, Hao Zhao, James Patrick Allison, Colin P.N. Dinney, Padmanee Sharma
Journal: Journal of Clinical Oncology (2019)

4551 Background: In MIBC pts, especially in those with high risk features including lymphovascular invasion, hydronephrosis, T3b disease, or variant histology, cisplatin-based NAC followed by cystectomy improves overall survival as compared with cystectomy alone. However, it is estimated that over 50% of pts with MIBC are ineligible for cisplatin-containing therapy. Therefore, we propose this pre-surgical trial with durva + treme for this population of pts. Methods: This is a single-arm, pre-surgical clinical trial with durva + treme in pts with localized, high-risk MIBC (cT2-T4a) who are ineligible for cisplatin-based NAC due to decreased renal function, neuropathy, hearing loss, or heart failure; or refuse cisplatin-based NAC (NCT02812420). Each patient receives durva (1500 mg) plus treme (75 mg) on weeks 1 and 5. Pts then undergo surgery at week 9-11. Pre- and post-treatment blood and tumor samples are collected for correlative biological analyses. Results: Twenty eight of 35 pts have been enrolled on this trial. Twenty-one pts have completed cystectomy as of 11/16/19. Of these 21 pts, 9 (43%) had pathologically complete response (pCR) and two (10%) had pathologic T1N0 (pT1) disease (≤pT1N0 rate = 52%). Fourteen of 21 (67%) had down-staging of disease. Of note, 10 of these 21 pts had 3-D mass (T3) on exam under anesthesia or clinical T4a disease; 5 of these 10 pts (50%) had pCR and one (10%) had pT1 disease (≤pT1N0 rate = 60%). Only 5 of 28 (17%) pts developed grade 3 immune related toxicity including hepatitis and amylase/lipase elevation, and two (7%) resulted in surgery delay for &gt; 30 days. Immune profiling with CyTOF analysis of baseline peripheral blood indicates that pts with pCR have significantly lower frequency of a Th2 subset as compared to pts with up-staging of disease. In addition, gene expression profiling analysis of baseline tumor tissues demonstrates a significantly less immunosuppressive microenvironment in pts with pCR as compared to pts with up-staging of disease. Conclusions: Our data indicate that durva plus treme is an effective and safe neoadjuvant therapy for pts with MIBC ineligible for cisplatin-based therapy. Therefore, neoadjuvant therapy with durva + treme and a number of potential biomarkers warrant testing in a larger phase 3 trial. Clinical trial information: NCT 02812420.