tbuckley/cabot-search huggingface dataset:
Public Disclosure of the Filing of New Drug and Therapeutic Biologics Applications With the US Food and Drug Administration
Authors: Harinder Singh Chahal, David Szeto, Anam H. Chaudhry, Daniel W. Sigelman, Stella Kim, Peter G. Lurie
Journal: JAMA Internal Medicine (2019)

This cross-sectional study reviews New Drug Applications for new molecular entities and Biologics License Applications for new and biosimilar biological products submitted to the US Food and Drug Administration to assess how frequently applicants disclose applications in the media.
Incidence of Malignancies in Patients Treated With Sirolimus Following Heart Transplantation
Authors: Rabea Asleh, Alfredo L. Clavell, Naveen L. Pereira, Byron Smith, Alexandros Briasoulis, Hilmi Alnsasra, Walter K. Kremers, Thomas M. Habermann, Clark C. Otley, Xin Li, Brooks S. Edwards, John M. Stulak, Richard C. Daly, Sudhir S. Kushwaha
Journal: Journal of the American College of Cardiology (2019)
Apatinib in the treatment of non-operable or advanced gastric cancer: Evidence of efficacy and safety in a real-world study.
Authors: Ligang Xing, Wei Cao, Gang Cui, Huanhu Zhang, Yiran Shi, Xin Wei, Yuting Dong, Chengye Guo, Bingping Wang, Shu Zhang, Zhiqiang Zou, Zizhi Zhang, Yahong Sun, Guohua Yu, Hongliang Guo, Deyou Wang, Qi Meng, Changzheng Li, Xixun Wang, Jinming Yu
Journal: Journal of Clinical Oncology (2019)

e15515 Background: Apatinib, a small molecule tyrosine kinase inhibitor, has been approved to use in patients with advanced gastric adenocarcinoma or gastroesophageal junction adenocarcinoma after at least two systemic chemotherapy regimens in China. This study aims to observe the efficacy and safety of apatinib in real word clinical practice and preliminarily explore the characteristics of population with more clinical benefit. Methods: This study included patients with non-operative or advanced gastric cancer confirmed by histopathology or cytology, and did not intervene the regimen which was entirely determined by the clinicians and patients. Results: From April 16, 2018 to January 12, 2019, 732 patients enrolled, and all patients had been followed up at least once. Total 342 patients were eligible for efficacy evaluation. Among them, 43 patients achieved partial response (PR), 209 patients achieved stable disease (SD) and 90 patients experienced progression disease (PD). The overall response rate (ORR) was 12.55%, and the disease control rate was 73.6%. The mPFS have not yet reached. For patients ≥65 years, the ORR was 26.32%, and for patients &lt; 65 years, ORR was 8.33%. For patients with non-signet ring cell carcinoma and signet ring cell carcinoma, the ORRs were 15.22% and 6.0%. For patients with and without organ metastasis, the ORRs were 15.25% and 3.75% respectively. The PFS analysis showed that, Combined chemotherapy and age &gt; 65 may predict longer PFS. The OS analysis showed that, ECOG 0-1, combined chemotherapy, AFP positive and male predict longer OS. The overall incidence of adverse events was 84%. The most common adverse events were hypertension (28.8%), fatigue (22.4%), hand-foot syndrome (17.3%), anorexia (12.8%) and nausea (10.5%). Conclusions: Apatinib showed promising antitumor activity in patients with non- operable or advanced Gastric Cancer in this real word study. The prolonging survival benefits maybe could be attenuated by age &lt;65, without organ metastasis, ECOG score &gt;1, treatment regimen, normal AFP, and pathological diagnosis of non-signet ring cell carcinoma. Clinical trial information: ChiCTR1800015701.
Healthcare disparities among cancer patients in the emergency department: How do race and ethnicity affect bounce-back rates?
Authors: Christopher John Coyne, Rebecca Arielle Shatsky, Jesse Brennan, Elena Martinez
Journal: Journal of Clinical Oncology (2019)

e18150 Background: Previous studies have demonstrated that patients with cancer utilize the emergency department (ED) more frequently than the general population. Additionally, cancer patients are more likely to require a repeat ED visit within 7 days of a preceding ED discharge (bounce back). This may be a marker of inadequate care or missed diagnosis. We designed this study to evaluate whether there are differences in bounce-back rates among cancer patients of different races/ethnicities. Methods: We performed a retrospective cohort study to compare all cancer-related ED visits in California based on race/ethnicity using the Office of Statewide Health Planning and Development (OSHPD) database. We queried all cancer-related ED visits in 2016 among patients ≥18 years and recorded general demographics. Our outcome measures were bounce-back rate and admission rate on the second ED visit. All data were analyzed using SPSS software and descriptive statistics are reported. Results: In 2016, there were 73,465 patients with 103,523 cancer-related ED discharges that met study inclusion criteria. 18% (18,491 visits) of these visits resulted in a bounce-back (versus 13.3% in the general ED population). African American patients had the highest bounce-back rate at 19.5%, followed by Hispanics (18.9%), Non-Hispanic Whites (17.3%) and Asians (17%). We observed an inverse trend in admission rates on the bounce-back visit, with Asian patients having the highest admission rate (40.5%), followed by Non-Hispanic Whites (37.7%), Hispanics (35.1%), and African Americans (32.5%). This is in the context of an overall admission rate of 36.7%, and a high mortality rate on the bounce-back visit of 8.4%. All groups were similar with respect to age, gender, and disease burden. Conclusions: Overall, we observed that African Americans and Hispanics returned to the ED at rates above average, which may be a marker of inadequate care or misdiagnosis. Furthermore, these groups were discharged at a higher frequency on the second visit, despite the high mortality associated with a bounce-back visit. Further investigation is needed to identify actionable targets to improve the emergency cancer care of all races/ethnicities.
SGNLVA-002: Single-arm, open label phase Ib/II study of ladiratuzumab vedotin (LV) in combination with pembrolizumab for first-line treatment of patients with unresectable locally advanced or metastatic triple-negative breast cancer.
Authors: Hyo S. Han, Carlos A. Alemany, Ursa Abigail Brown-Glaberman, Timothy J. Pluard, Rajni Sinha, Danielle Sterrenberg, Kathy S. Albain, Reva K. Basho, David Biggs, Valentina Boni, Sami Diab, Michaela L. Tsai, Katherine Hanna Tkaczuk, Yinghui Wang, Zejing Wang, Jane Lowe Meisel
Journal: Journal of Clinical Oncology (2019)

TPS1110 Background: There are currently no curative treatments for patients with metastatic triple-negative breast cancer (mTNBC), and prognosis for this disease is very poor. Emerging treatment combinations of anti-programmed death ligand 1 (PD-L1) agents with chemotherapy have shown promise in mTNBC. SGN-LIV1A, or ladiratuzumab vedotin (LV), is a novel investigational humanized IgG1 antibody-drug conjugate (ADC) directed against LIV-1, which is highly expressed in breast cancer cells. LV mediates delivery of monomethyl auristatin E (MMAE), which drives antitumor activity through cytotoxic cell killing and induces immunogenic cell death (ICD). Preliminary results from an ongoing phase 1 study of LV monotherapy has shown LV to be well tolerated and to have encouraging antitumor activity in patients with mTNBC. Combining LV and pembrolizumab may result in complementary, as well as synergistic, activity through LV-induced ICD that creates a microenvironment favorable for enhanced anti-PD-L1 activity. Methods: This single-arm, open-label, phase 1b/2 study evaluates the safety and antitumor activity of LV in combination with pembrolizumab as first-line therapy for patients with unresectable locally advanced or mTNBC (NCT03310957, 2017-002289-35). Patients must have measureable disease per RECIST v1.1, an ECOG score of 0 or 1, and no prior cytotoxic or anti-PD-L1 treatment for advanced disease. This study has 2 parts that are enrolling sequentially: a dose-finding phase that starts at LV 2.5 mg/kg + pembrolizumab 200 mg intravenously every three weeks, and a dose expansion phase. The primary objectives are to evaluate the safety/tolerability and objective response rate of LV + pembrolizumab, and identify the recommended phase 2 dose of LV. The secondary objectives are to assess duration of response, disease control rate, progression-free survival, and overall survival. Additional objectives include assessing PD-L1 and LIV-1 expression-response relationship. Study enrollment is ongoing in the US and EU. Clinical trial information: NCT03310957.
The Achilles Heel of Malignant Rhabdoid Tumors
Authors: Jing Huang, Ji Luo
Journal: Cancer Research (2019)

Abstract Malignant rhabdoid tumors (MRT) are rare but deadly pediatric tumors characterized by mutations in the SMARCB1/SNF5/INI1/BAF47 gene. Currently, there are no targeted therapies for MRTs. In a previous issue of Cancer Research, Howard and colleagues utilize the power of genome-wide RNAi and CRISPR screening to identify MDM2 and MDM4 as potential drug targets for MRTs. Most MRTs retain an intact p53 pathway and the authors show that these cells are particularly sensitive to MDM2 and MDM4 inhibition due to SMARCB1's role in regulating p53-depedent apoptotic genes. This discovery suggests potential clinical trials of MDM2 inhibitors in patients with MRT. See related article by Howard and colleagues; Cancer Res 79(9):2404–14.
Oncogenic activation of the HRR pathway drives RAD54L expression in early stage lung adenocarcinoma.
Authors: Shaopeng Zheng, Jin Xia, Yunfang Yu, Fanjun Zeng, Luyu Huang, Fasheng Li, Guoqing Liao, Zenan Lin, Hongyuan Zhu, Michael Lanuti, HaiYu Zhou
Journal: Journal of Clinical Oncology (2019)

e20037 Background: In recent years, there has been a better understanding of ways to use DNA damage and repair (DDR) mechanisms to improve overall sensitivity and/or overcome resistance to traditional DNA damage treatments. The DDR network is quite complex and highly dynamic with as many as 450 proteins integral to the DNA repair. The current study is to identify the key dysregulated genes and its related pathways especially DDR pathways in early progression of lung adenocarcinoma. Methods: TCGA dataset of lung adenocarcinoma (LUAD) including 59 healthy lung tissues and 517 tumor tissues was utilized to detect the differentially expressed mRNAs and lncRNAs. Gene ontology (GO) analysis was conducted with DAVID, while Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of differentially expressed genes was performed using gene set enrichment analysis (GSEA) methods. Results: 41 lncRNAs and 2,047 mRNAs were screened out to be differentially expressed in LUAD. Besides, 38 lncRNAs and 1,801 mRNAs were found to be differentially expressed in T1 stage LUAD. The homologous recombination repair (HRR) pathway was found to be significantly up-regulated in LUAD, with four genes in this pathway up-regulated. In these genes of HRR pathway, PPP4R4 and RAD54L were recognized to be significantly differential expressed in T1 stage, compared with T2 stage and T3 stage, which were putative biomarkers of early stage LUAD. The survival analysis revealed that the expression of RAD54L was significantly related to the survival rate of patients with tumor of T1 stage. Conclusions: HRR pathway was up-regulated in lung adenocarcinoma, in which the expression of PPP4R4 and RAD54L were found to be tumor stage specific and RAD54L was related with survival rate of T1 stage patients. This study provided a further insight into the mechanism of the progression in early stage lung adenocarcinoma.
Predictors of death for patients treated with palliative intent radiation using prospective databases.
Authors: Namita Agrawal, Shearwood McClelland, Kevin Shiue, Gregory Bartlett, Richard C. Zellars, Gordon A Watson, Lautenschlaeger Tim, Susannah G. Ellsworth
Journal: Journal of Clinical Oncology (2019)

e18325 Background: Radiation therapy (RT) effectively palliates pain and other symptoms due to cancer and is frequently offered to patients with metastatic disease. Standard palliative RT schedules range from one to ≥10 fractions; however, prognostic variables related to survival following palliative RT are not well studied. A better understanding of prognostic factors in this setting will assist in selecting appropriate palliative RT regimens for patients with short life expectancies. Methods: Prospectively maintained institutional databases tracking morbidity and mortality and outcomes of a departmental peer review process were used to identify patients who received palliative RT between April 2015 - December 2018. Cox proportional hazards model was used to identify factors correlated with overall survival (OS) and mortality within 30 days (30DM) after completing palliative RT, including age, sex, admission status (inpatient versus outpatient), Karnofsky Performance Status (KPS), treated site and primary site. Results: Of 421 patients, 389 received palliative RT; 30DM rate was 25.7% (n = 100). Median age was 61, median KPS was 70, and 196 patients (50.4%) were female. The most common primary sites were thorax (N = 121, 31.1%) and genitourinary tract (N = 60, 15.4%), while the most commonly treated sites were brain (N = 136, 35.0%) and bone (N = 71, 18.3%). KPS and treatment site were strong independent predictors of both OS and 30DM. Patients with KPS &lt; 70 had an HR 2.61 (95% CI 1.54 – 4.43, p &lt; 0.0001) for 30DM and an HR of 2.22 (95% CI 1.57 – 3.13, p &lt; 0.0001) for death at any time after RT. Treatment site was also independently associated with OS and 30DM (p = 0.01 and p = 0.03, respectively). Median OS durations (95%CI) were: abdomen/pelvis not reached, bone 340 days (133.9-546.1), spine 207 days (28.0 – 386.0), head and neck 184 days (55.2 – 312.8), brain 104 days (34.3 – 173.7) and thorax 76 days (10.3 – 141.7). Age, sex, admission status and primary site were not correlated with OS or 30DM. Conclusions: RT can effectively palliate distressing symptoms related to primary or metastatic cancers. However, early mortality is common following palliative RT and is associated with poor performance status and treated site. Hypofractionated RT courses should be considered in patients with such risk factors to reduce the burden of prolonged therapy on patients and their families at the end of life.
First-in-human study of AZD5153, a small molecule inhibitor of bromodomain protein 4 (BRD4), in patients (pts) with relapsed/refractory (RR) malignant solid tumor and lymphoma: Preliminary data.
Authors: Judy Sing-Zan Wang, Serena De Vita, Janet L. Karlix, Carl Cook, Gillian M. Littlewood, Maureen M. Hattersley, Ganesh Moorthy, Helena Edlund, Giulia Fabbri, Kris F. Sachsenmeier, Chris Davison, Edwin Clark, Kathleen N. Moore, Todd Michael Bauer, Susanna Varkey Ulahannan, Manish R. Patel, Erika Paige Hamilton
Journal: Journal of Clinical Oncology (2019)

3085 Background: BRD4 is a bromodomain and extraterminal (BET) protein that regulates oncogenic programs by modifying gene transcription and additional mechanisms. AZD5153 is a novel, reversible BRD4 inhibitor with bivalent mechanism of action and enhanced antitumor activity in preclinical models. This phase 1, multicenter, dose escalation study (NCT03205176) assesses AZD5153’s safety, pharmacokinetics (PK), and pharmacodynamics (PD). We report here preliminary, unvalidated data from AZD5153 monotherapy in pts with RR solid tumor, including lymphoma. Methods: Adult pts received oral AZD5153 QD/BID to determine the MTD. During dose escalation, a continual reassessment model was used to estimate toxicity and all final decisions were made by the Safety Review Committee. PK and PD were characterized using standard methods. Results: As of 1 Nov 2018, 28 pts (78.6% female, median age 66.5 y) were treated in 7 cohorts: 2 mg QD (3 pts), 5 mg QD (3 pts), 10 mg QD (3 pts), 10 mg BID (5 pts), 15 mg BID (4 pts), 20 mg BID (7 pts), and 30 mg QD (3 pts). Treatment was ongoing in 8 pts at data cut-off. Safety findings showed 50% of pts experienced treatment-related AEs. 25% of pts experienced treatment-related Grade ≥3 AEs, which were thrombocytopenia and fatigue (7.1% each), and anemia, diarrhea, and platelet count decreased (3.6% each). SAEs were observed in 25% of pts; none of the SAEs was attributable to AZD5153 alone. Dose-limiting toxicities of thrombocytopenia (1 pt) and diarrhea with herpetic rash leading to discontinuation (1 pt) occurred at 20 mg BID. 53.6% of pts discontinued due to disease progression. Total median treatment duration was 1.3 mo (range up to 8.9 mos). Dose proportional increase in C max and AUC were observed across the dose range tested. T max ranged from 0.5 to 3 h and t 1/2 was 6 h. Dose-dependent changes in expression of target genes (eg, HEXIM1, HIST2H2BF, CD274, and CCR2) and platelet counts were observed in the peripheral blood. Conclusions: AZD5153 monotherapy is safe and tolerated at doses up to 30 mg QD and 15 mg BID. Linear increase in PK was observed. Additional safety and efficacy updates will be reported at the annual meeting. Clinical trial information: NCT03205176.
Access to clinical trials, multidisciplinary environment, and health care providers by facility type and outcomes of patients with newly diagnosed glioblastoma using SEER-Medicare dataset.
Authors: Ping Zhu, Xianglin L. Du, Yoshua Esquenazi, Jay-Jiguang Zhu
Journal: Journal of Clinical Oncology (2019)

e13576 Background: Prior studies demonstrated the superior outcomes among glioblastomas patients treated at academic facilities (ACs) verses non-academic facilities (non-AC). However, the factors contributed to the survival benefit observed at ACs remain unknown. Methods: Eligible GBM patients between 2004 and 2014 were derived from the SEER-Medicare database. Patients were categorized by treatment facility status (AC versus non-AC). Outcomes include overall survival (OS) and the receipt of surgery and adjuvant therapies. Kaplan-Meier and Cox proportional hazard model were applied for survival analysis, and multivariable binary/multinomial logistic regression models were performed to compare differences in treatments received and hospital characteristics by facility type. Results: A total of 3263 patients treated at 562 facilities were included. Significantly superior survival was observed at ACs [Hazard ratio (HR): 0.92, 95% CI: 0.85-0.99, P = 0.024], prior to and after adjusting all covariates. Radiation and chemotherapy were utilized more frequently at ACs. For the access to clinical trials, ACs were more likely to be NCI designated cancer center, Radiation Therapy Oncology Group (RTOG), and American College of Surgeons Oncology Group (ACSOG) compared to non-ACs (all P &lt; 0.001). For multidisciplinary resources, ACs had higher probability to provide health care services in emergency, intensive care, inpatient care, nuclear medicine, operative room, and radiation treatment than non-ACs (all P &lt; 0.01). Further, there were more sufficient health care provider resources (number of full-time registered nurses, physicians, and total beds) at ACs over non-ACs (all P &lt; 0.001). Conclusions: This study identified factors that contributed to the superior outcomes when GBM patients are treated at ACs. An increased likelihood of undergoing adjuvant therapies, access to clinical trials, multidisciplinary environment, and available health care provider resources in ACs are important contributors to the improved GBM outcomes.
The utility of circulating tumor DNA analysis to identify BRAF mutations in malignant melanoma.
Authors: Eric Kirby, Philip D. Leming
Journal: Journal of Clinical Oncology (2019)

e14539 Background: Circulating tumor DNA provides an opportunity to assess the genetic profile of a patient’s tumor without performing a tissue biopsy. The Guardant360 assay is one platform available to perform genetic sequencing of circulating tumor DNA from a blood sample. This can allow for assessing the BRAF mutation status of patients with malignant melanoma from a liquid biopsy. Methods: Retrospective chart review was done of patients with malignant melanoma with a positive BRAF V600 mutation based on a tissue biopsy. The BRAF V600 mutation status of these patents as determined by a Guardant360 assay, which was not necessarily done at the same time as the tissue biopsy, was gathered. The status of each patient’s malignancy at the time of each liquid biopsy was assessed and divided into three categories, which included active distant metastatic disease, active locoregional disease, and no evidence of active disease. Results: 51 total patients with a positive BRAF V600 mutation based on tissue biopsy were included in this analysis. Some patients had multiple Guardant360 assays which were done at different timepoints, which made for 83 total liquid biopsies. Out of 30 liquid biopsies done when the patient had evidence of active distant metastatic disease, 21 (70%) were positive for a BRAF V600 mutation. Out of 13 liquid biopsies done when the patient had evidence of active locoregional disease, 2 (15.4%) were positive for a BRAF V600 mutation. Out of 40 liquid biopsies done when the patient had no evidence of active disease, 3 (7.5%) were positive for a BRAF V600 mutation. Conclusions: The Guardant360 assay in detecting a BRAF V600 mutation had it’s highest sensitivity in the setting of active distant metastatic disease. This assay can allow for sparing patients more invasive tissue biopsies when the suspicion for metastatic melanoma is high and the BRAF mutation status is unknown.
Disparities in the occurrence of late effects following treatment among adolescent and young adult melanoma survivors.
Authors: Alicia Gingrich, Melanie Goldfarb, Candice Sauder, Qian Li, Theodore Wun, Theresa Keegan
Journal: Journal of Clinical Oncology (2019)

9580 Background: Melanoma is the third most common cancer in the adolescent and young adult (AYA) population and the incidence worldwide is increasing. However, no studies have addressed the occurrence of late effect medical conditions following melanoma treatment in these young survivors. Methods: All patients ages 15-39 diagnosed with cutaneous melanoma from the 1996-2012 and surviving ≥ 2 years were obtained from the California Cancer Registry and linked to statewide hospitalization data. The influence of age at diagnosis, sex, race/ethnicity, neighborhood socioeconomic status (SES), and health insurance on the development of late effects by system was evaluated using multivariable Cox proportional hazards regression models. Results: Of 8,524 patients, 35.6% were male, 83.1% non-Hispanic white, 82.1% had private health insurance, 60.3% were considered high SES, and 70.7% had no documented co-morbidities at diagnosis. After controlling for competing factors, males had an increased risk of developing late effects across all systems, including cardiac [HR:2.13, 95%CI 1.87-2.42], neurologic (HR:2.24, CI 1.92-2.63), lymphedema (HR:2.22, CI 1.89-2.62), bleeding events (HR:2.35, CI 2.00-2.77), major infection/sepsis (HR:2.23, CI 1.95-2.56), and second cancers [HR:1.66, CI 1.47-1.89]. In addition, patients with public or no insurance (vs. private) had a greater risk of developing all studied late effects, including lymphedema (HR:2.48, CI 2.04-3.01), respiratory illness (HR:2.21, CI 1.85-2.64) renal dysfunction (HR:2.31, CI 1.90-2.81), and subsequent cancers (HR:1.82, CI 1.54-2.16). AYA patients residing in low SES neighborhoods had a similar increased risk of developing late effects. However, neither age nor race/ethnicity had an impact on the occurrence of late effects. Conclusions: Of AYA melanoma survivors, males, those with public or no health insurance, and those living in low SES neighborhoods had a much greater likelihood of developing of late effects. Strategies to improve surveillance and secondary prevention of these late effects is needed among AYA melanoma survivors, particularly for this demographic.