tbuckley/cabot-search huggingface dataset:
First-in-human phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of oral GNS561, a palmitoyl-protein thioesterase 1 (PPT1) inhibitor, in patients with primary and secondary liver malignancies.
Authors: James J. Harding, Ahmad Awada, Thomas Decaens, Gael Roth, Philippe Merle, Nuria Kotecki, Chantal Dreyer, Christelle Ansaldi, Madani Rachid, Soraya Mezouar, Agnes Menut, Eloine Bestion, Valerie Paradis, Philippe Halfon, Eric Raymond, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2021)

e16175 Background: GNS561 belongs to a novel generation of drug blocking cancer cell proliferation by inhibiting late-stage autophagy and dose-dependent accumulation of enlarged lysosomes by interacting with palmitoyl-protein thioesterase-1 (PPT1). Methods: This phase I, multicenter, open-label, dose-escalation trial (3+3 design) explored two dosing schedules: one single oral intake three times a week and twice daily (BID) continuous oral intake of GNS561 in patients with advanced primary and secondary liver cancers (NCT03316222). The primary objective was to determine recommended phase II dose (RP2D) and schedule for further clinical development. The secondary objectives included a preliminary evaluation of the safety, pharmacokinetic (PK), pharmacodynamics (PD), and antitumor activity of GNS561. Results: Nineteen treatment-refractory patients were enrolled and were evaluable for primary endpoint: intrahepatic cholangiocarcinoma (iCCA) (9), hepatocellular carcinoma (HCC) (7), pancreatic ductal adenocarcinoma (PDAC) (2) and colorectal cancer (CRC) (1). Median age was 60, 89% were male and 37% had received 3 or more lines as prior cancer therapies. Dose escalation ranged from 50 mg three times a week to 200 mg BID. No dose-limiting toxicity were observed. Treatment-related adverse events were grade 1-2 gastrointestinal toxicity, primarily nausea/vomiting, occurring in 8 patients (42%) and diarrhea in 4 patients (21%). Occurrence of nausea/vomiting despite antiemetic prophylaxis prevented increasing doses above 200 mg BID. GNS561 displayed favorable bioavailability with interpatient variability (CV%: 13 to 223% and 21 to 98.2% on plasma concentrations on cycle 1 day 1 and cycle 2 day 1 respectively), and dose proportional exposure in plasma. GNS561 concentrations accumulated after multiple administration (2.60 - 9.00-fold) and exhibited a long half-life. Plasma and liver concentrations at doses ranging 100-200 mg BID were comparable to therapeutic exposures in preclinical models. Five patients (3 HCC and 2 iCCA) experienced tumor stabilization according to RECIST 1.1 criteria, including a minor response (-23%). Conclusions: GNS561 RP2D single agent was set at 200 mg BID based on this favorable safety profile and plasma exposure, GNS561 will be next further evaluated in monotherapy and in combination with checkpoint inhibitors considering the autophagic activity restriction of major histocompatibility complex-1 promotion of immune invasion. Clinical trial information: NCT03316222.
Physicians to be better trained on effects of air pollution on health, says college
Authors: Abi Rimmer
Journal: BMJ (2021)

The Royal College of Physicians (RCP) will review the medical curriculum to make sure physicians better understand the effects of air pollution on health.

The announcement comes after the coroner who made the first UK ruling giving toxic air as a cause of death called on the government and doctors’ training bodies to take urgent action to cut the risk of deaths …
Binimetinib activity in <i>PIK3R1</i>-mutant patient-derived xenografts (PDX) implanted into immunodeficient mice.
Authors: Melody A. Cobleigh, Abde M. Abukhdeir
Journal: Journal of Clinical Oncology (2021)

e13062 Background: The PIK3R1 gene is genetically altered in ̃3% of breast cancers in the Western and ̃17% in the Eastern worlds. We recently reported that breast cancer cells lacking protein expression of PIK3R1 had elevated levels of activated MEK, sensitizing them to the MEK inhibitor trametinib. To better understand whether MEK inhibition is a therapeutic option for breast cancer patients with mutated PIK3R1, we tested the newer generation MEK inhibitor, binimetinib, in a PDX mouse model. Methods: Two PDx models (table) were tested in athymic nude-foxn1nu (immune-compromised) mice. Both patients had had metastatic, grade 3 breast cancer and expressed moderate RNA levels of PIK3R1. Results: Body weights of treatment arms were unchanged throughout the experiment. The TNBC PDx study was halted early at 13 days because tumors reached the predefined maximum size of 1500 mm 2 . The binimetinib treated mice experienced slowed tumor growth (522.8 +/- 172.8%) compared to the vehicle control (720.7 +/- 229.1%), (p=0.0693). In the HR+ PDx model, the combination of binimetinib plus tamoxifen resulted in a statistically significant decrease (371.5 +/- 108.1%) in tumor volume compared to tamoxifen alone (525.0 +/- 154.1%; p = 0.0302). Conclusions: Our previous and current results suggest that mutation in PIK3R1 sensitizes cells to MEK inhibitors. Binimetinib inhibited growth in both models. This inhibition was of borderline significance in the TNBC model and was statistically significant in the ER+, HER2- model. To the best of our knowledge, these results provide the first evidence of binimetinib efficacy in PIK3R1-mutant, HR+, HER2- PDX immunodeficient mice. Plans for a phase II trial in patients with PIK3R1-mutant, HR+, HER2- breast cancer are underway.[Table: see text]
Therapeutic effect of DDR pathway with different functional annotations for immune checkpoint inhibitor.
Authors: Wei Nie, Hua Zhong, Fengcai Wen, Ding Zhang, Shiqing Chen, Baohui Han
Journal: Journal of Clinical Oncology (2021)

2611 Background: DNA damage response and repair (DDR) pathway-related gene mutations have been reported to predict the efficacy of immune checkpoint inhibitor (ICI). However, therapeutic effect of DDR pathway with different functional annotations is not fully studied. Here we explore the relationship of DDR pathway with different functional annotations and clinical outcomes in public cohorts of immunotherapy and chemotherapy. Methods: Genetic testing and clinical outcomes data were obtained from the public clinical cohorts across 10 tumor types. 232 DDR pathway-related gene were assigned to eight pathway according to the literature. Nine predictive models for the mutation pathogenicity were included in the analysis, of which at least five returned positive results were defined as deleterious mutations. All annotations were according to the American College of Medical Genetics (ACMG) standards and guidelines. To explore the association between DDR pathways and ICI, DDR pathway mutation is grouped. Patients, who harbored mutations in two or more DDR pathways and meanwhile had deleterious mutation in at least one DDR pathway, were enrolled in group A. Patients, who harbored deleterious mutations in only one DDR pathway or had only uncertain significance mutations, were enrolled in group B. Patients with no DDR gene mutations were enrolled in Group C. We analyzed relation of the group and survival outcomes in four public cohorts. Results: Of 4 clinical cohort analyzed, the group A treated with ICI has the best PFS or OS outcomes. However, the comparison of group B and group C is not coincide across different cohorts. Treatment is the key factor that influents the relation of DDR pathway mutations and clinical outcomes. As shown in POPLAR/OAK cohort, patients in group C has the best PFS (p=0.0381) or OS (p=0.0350) outcome when treated with chemotherapy, but patients in group A has the best PFS (p=0.0083) or OS (p=0.0222) outcome when treated with ICI. Conclusions: When treated with ICI, patients with at least one deleterious mutation and another deleterious or uncertain significance mutation has the best PFS or OS outcomes, but not for chemotherapy. Our study suggested that DDR pathway with deleterious mutations might be a potential predictive factor for immunotherapy.[Table: see text]
Risk and Outcome of Venous and Arterial Thrombosis in Patients With Cirrhosis: A Danish Nation‐wide Cohort Study
Authors: Peter Jepsen, Elliot B. Tapper, Thomas Deleuran, Konstantin Kazankov, Gro Askgaard, Henrik Toft Sørensen, Hendrik Vilstrup, Joe West
Journal: Hepatology (2021)

Background and Aims Cirrhosis affects hemostasis, but its effects across the spectrum of thromboses remain poorly understood. We examined risks and outcomes of venous and arterial thrombosis. Approach and Results We used nation‐wide Danish health care registries to identify outpatients with cirrhosis and a sex‐ and age‐matched comparison cohort without cirrhosis from the general population. Patients with cirrhosis and comparators were followed until they had a venous thromboembolism (VTE), acute myocardial infarction (AMI), or ischemic stroke (IS) or died. We computed absolute risks and HRs of thrombosis and compared outcomes after thrombosis. We included 5,854 patients with cirrhosis (median Model for End‐Stage Liver Disease score, 9; interquartile range, 7‐13), and their risk of any of the thrombotic events was 0.8% after 1 year and 6.3% after 10 years. They were more likely than the 23,870 matched comparators to have a VTE (adjusted hazard ratio [aHR], 2.0; 95% CI, 1.5‐2.6) or IS (aHR, 1.7; 95% CI, 1.3‐2.3), but not AMI (aHR, 0.7; 95% CI, 0.5‐0.9). Among patients with cirrhosis, decompensation increased the risk of AMI, but not the other thromboses. Following thrombosis, patients with cirrhosis had higher 90‐day mortality than comparators (after VTE: 17% vs. 7%; after AMI: 27% vs. 5%; after IS: 10% vs. 7%) and were less likely to receive antithrombotic treatment. Conclusions Patients with cirrhosis had an increased risk of VTE and IS, but not AMI. Among patients with cirrhosis, decompensation increased the risk of AMI, exclusively. Mortality after thrombosis was higher in patients with cirrhosis than in other patients. These findings are relevant for decisions about antithrombotic prophylaxis in patients with cirrhosis.
A successful model of biosimilar adoption in a community oncology practice.
Authors: Lalan S. Wilfong, Neal Dave, Jody S. Garey, Sara Toth, Jim R. Schwartz, Lance Ortega, Chris Sellers, Barry Don Brooks
Journal: Journal of Clinical Oncology (2021)

6514 Background: The emergence of biosimilars creates an opportunity for more cost-effective treatment. Utilization of biologics in cancer care has increased and accounts for 70% of oncologic drug spending growth from 2010 to 2015. Biosimilars can play a vital role in controlling this rapid rise in cost. Practices focused on Value Based Care arrangements, such as the Oncology Care Model, can reduce total cost of care by increasing utilization of biosimilars. The process of interchange is complicated by the designation of each biosimilar which prevents simple interchange. Communication with physicians and the healthcare team along with patient education and consent must be performed. We describe a successful model for therapeutic interchange of brand drugs to biosimilars. Methods: Texas Oncology elected to increase utilization of biosimilars in 2020. We collaborated with McKesson Specialty Health to create educational materials for patients and clinical staff. Communication was sent to all personnel about the therapeutic interchange process. A central pharmacy team reviewed all new orders and substituted a biosimilar for brand, unless a payer insisted on origin drug or a biosimilar not in the practice formulary. Additionally, a report was generated weekly of all existing patients who would benefit from switching. The pharmacists, upon consultation with the physician, then substituted a biosimilar for brand drug. Patients were then educated and re-consented. We started with rituximab in 07/2020 followed by bevacizumab in 09/2020 then trastuzumab in 10/2020. Results: The table below shows our conversion rate for all administrations. We were able to increase utilization of biosimilars from January of 2020 to December of 2020 from 5% to 80% for Rituximab, 9% to 88% for bevacizumab and 8% to 74% for trastuzumab. Based on average ASP for a 70 kg patient, the potential savings per administration is $550 for bevacizumab, $850 for trastuzumab, and $1400 for rituximab. In one month alone, this project dramatically reduced cost by $4 million or 21% by conversion to these three biosimilars. Additional savings can be realized with the use of biosimilar multi-dose vials vs single dose vials. Conclusions: Our comprehensive team approach successfully deploys therapeutic interchange of biosimilars for brand drugs in a community oncology practice which leads to substantial cost savings. This has real implications in controlling the total cost of care.[Table: see text]
Stress as a predictor of tumor growth and development of metastases.
Authors: Tristen Peyser, David A. Geller, Lauren Terhorst, Michael Antoni, Yoram Vodovotz, Leslie Hausmann, Donna Olejniczak, Aarshati Amin, Gauri J. Kiefer, Carol Lynn Hecht, Jessica Miceli, Albert Tong, Jonas T. Johnson, Marci Lee Nilsen, Dan Paul Zandberg, Vincent Edgar Reyes, Jennifer Steel
Journal: Journal of Clinical Oncology (2021)

e24124 Background: The aims of this study were to examine; the predictors of perceived stress; and the associations between perceived stress and tumor growth and development of metastases as well as the mediational role of inflammatory biomarkers. Methods: This study is prospective in design. A battery of questionnaires, including a sociodemographic characteristic and the Perceived Stress Scale, was collected at baseline from patients diagnosed with solid tumors at various stages of treatment. Disease progression was measured over a 12-month period. Poverty threshold was determined using the U.S. Department of Health &amp; Human Services 2020 poverty guidelines. Computerized tomography and Magnetic Resonance Imaging scans were assessed for disease progression between baseline and 12 months using Response Evaluation Criteria in Solid Tumors. Blood was collected and serum levels of IL-2, IL-1a, IL-1b, TNF-a, IL-6, and IL-8 were assessed. The predictors of stress include sociodemographic and disease specific characteristics. Primary outcomes were tumor growth and development of metastases. Descriptive statistics, correlations, and ordinal and linear regression were performed to assess the aims. Results: Of 159 patients diagnosed with cancer, 47.8% were male, mean age was 62.97 (SD = 10.35), 89.3% were Caucasian, and 13.8% met poverty guidelines. Significant predictors of stress were age (b=-.151, p=0.029, 95% C.I.=-2.86-.016) and income below the poverty threshold (b= 5.615, p=0.007, 95% C.I.=1.596-9.635). Gender was the only sociodemographic and disease specific factor significantly associated with disease progression. After adjusting for gender, greater perceived stress was associated with tumor growth and development of metastases (p =0.029), accounting for 33.3% of the variance. Circulating cytokines were significantly related to disease progression [IL-1a, p=0.020; IL-1b, p=0.011; IL-6, p&lt;0.001; and IL-8, p&lt;0.001] but not stress [IL-1a, p=0.369; IL-1b p=0.292; IL-2, p=0.470; IL6 p=0.406; and IL8, p=0.401]. Conclusions: Future research should evaluate inflammation in the tumor microenvironment as well as neutrophils and tumor suppressor genes as potential mediators between stress and disease progression.
Checkpoint inhibition in immunosuppressed or immunocompromised patients with advanced cutaneous squamous cell carcinoma (CSCC): Data from prospective CemiplimAb-rwlc Survivorship and Epidemiology (C.A.S.E.) study.
Authors: Guilherme Rabinowits, Soo J Park, David M. Ellison, Francis P. Worden, Rhonda W. Gentry, John Strasswimmer, Suraj S. Venna, Michael Robert Migden, Sunandana Chandra, Emily S. Ruiz, Nikita Mehta, Haixin Raymond Zhang, Jennifer McGinniss, Jigar Desai
Journal: Journal of Clinical Oncology (2021)

9547 Background: Immunosuppressed and/or immunocompromised patients are at increased risk for solid tumors and cutaneous malignancies. Limited data exist on the safety and effectiveness of immune checkpoint inhibitors (ICIs) in these patients because they are frequently excluded from clinical trials. Here, we describe the safety and effectiveness results from the initial cohort of immunosuppressed and/or immunocompromised patients with advanced CSCC enrolled in the C.A.S.E. study (NCT03836105). Methods: C.A.S.E. is a prospective, real-world, multi-center, longitudinal study evaluating the effectiveness, safety, quality of life, and survivorship in patients with advanced CSCC treated with cemiplimab. Patients received cemiplimab 350 mg intravenously every 3 weeks per routine standard of care. Patient demographics, disease characteristics, immunosuppression, and relevant medical history were collected. Immunosuppressive regimens varied amongst patients. Investigator assessment of objective response rate (ORR), safety, and tolerability was conducted. Data from 26 immunosuppressed and/or immunocompromised patients with advanced CSCC treated with cemiplimab are presented. Recruitment is ongoing. Results: As of November 17, 2020, 121 patients were enrolled in the C.A.S.E. study, of which 26 patients (median age: 74 years [IQR: 71-84]; 85% male; 89% Caucasian) were designated as immunocompromised or immunosuppressed due to a history of solid organ transplant (n = 6), autoimmune disorder (n = 11), or hematologic malignancy (n = 9). Median duration of cemiplimab exposure was 14 months (IQR: 9.1–42, range: 0, 67). Among 19 immunocompromised or immunosuppressed patients who enrolled in C.A.S.E. prior to their third dose of cemiplimab, ORR per investigator assessment was 47% (95% CI: 24–71); 1 (5%) patient had complete response; 8 (42%) had partial response. One patient had a treatment-related serious adverse reaction of organ transplant rejection. One (3.8%) patient discontinued treatment due to increased alanine aminotransferase (not treatment-related). Immune-related AEs (irAEs) occurred in 23% of patients. No treatment-related AEs led to death. Conclusions: The safety, tolerability, and effectiveness of cemiplimab in this initial cohort of immunosuppressed and/or immunocompromised patients with advanced CSCC appear to be consistent with those observed in clinical trials that excluded these patients. Further follow-up and additional data would add to our general understanding of safety and effectiveness of anti-PD1 therapy in immunocompromised and/or immunosuppressed patient populations overall. Clinical trial information: NCT03836105.
Association Between Glucagon-Like Peptide 1 Receptor Agonist and Sodium–Glucose Cotransporter 2 Inhibitor Use and COVID-19 Outcomes
Authors: Anna R. Kahkoska, Trine Julie Abrahamsen, G. Caleb Alexander, Tellen D. Bennett, Christopher G. Chute, Melissa A. Haendel, Klara R. Klein, Hemalkumar Mehta, Joshua D. Miller, Richard A. Moffitt, Til Stürmer, Kajsa Kvist, John B. Buse, Tim Q. Duong
Journal: Diabetes Care (2021)

OBJECTIVE To determine the respective associations of premorbid glucagon-like peptide-1 receptor agonist (GLP1-RA) and sodium–glucose cotransporter 2 inhibitor (SGLT2i) use, compared with premorbid dipeptidyl peptidase 4 inhibitor (DPP4i) use, with severity of outcomes in the setting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. RESEARCH DESIGN AND METHODS We analyzed observational data from SARS-CoV-2–positive adults in the National COVID Cohort Collaborative (N3C), a multicenter, longitudinal U.S. cohort (January 2018–February 2021), with a prescription for GLP1-RA, SGLT2i, or DPP4i within 24 months of positive SARS-CoV-2 PCR test. The primary outcome was 60-day mortality, measured from positive SARS-CoV-2 test date. Secondary outcomes were total mortality during the observation period and emergency room visits, hospitalization, and mechanical ventilation within 14 days. Associations were quantified with odds ratios (ORs) estimated with targeted maximum likelihood estimation using a super learner approach, accounting for baseline characteristics. RESULTS The study included 12,446 individuals (53.4% female, 62.5% White, mean ± SD age 58.6 ± 13.1 years). The 60-day mortality was 3.11% (387 of 12,446), with 2.06% (138 of 6,692) for GLP1-RA use, 2.32% (85 of 3,665) for SGLT2i use, and 5.67% (199 of 3,511) for DPP4i use. Both GLP1-RA and SGLT2i use were associated with lower 60-day mortality compared with DPP4i use (OR 0.54 [95% CI 0.37–0.80] and 0.66 [0.50–0.86], respectively). Use of both medications was also associated with decreased total mortality, emergency room visits, and hospitalizations. CONCLUSIONS Among SARS-CoV-2–positive adults, premorbid GLP1-RA and SGLT2i use, compared with DPP4i use, was associated with lower odds of mortality and other adverse outcomes, although DPP4i users were older and generally sicker.
Everolimus combined with endocrine therapy in advanced HR-positive, HER2-negative Chinese breast cancer patients: A retrospective study.
Authors: Xia-Bo Shen, Guang-Liang Li, Ya-Bing Zheng, Zhan-Hong Chen, Wen-Ming Cao, Xi-Ying Shao, Xiao-Jia Wang
Journal: Journal of Clinical Oncology (2021)

e13023 Background: The Food and Drug Administration (FDA) approves the combination of everolimus and exemestane for the treatment of advanced breast cancer patients who are hormone-receptor (HR) positive but human epidermal growth factor receptor-2 (HER2) negative. However, there is little real-world data on the everolimus in Chinese breast cancer patients. Endocrine therapy is the main treatment for advanced HR-positive, HER2-negative breast cancer patients which includes aromatase inhibitor (AI) or fulvestrant. Drug resistance and subsequent treatment after endocrine therapy are some of the most clinical concerns. CDK4/6 inhibitors and HDAC inhibitors are poorly available due to high price, and combined everolimus therapy can be a non-ignorable choice for advanced HR-positive, HER2-negative breast cancer patients. Methods: We retrospectively collected the treatment information of advanced breast cancer patients treated with everolimus from 2013 to 2020 in Zhejiang Cancer Hospital. Kaplan–Meier analysis and Cox regression methods were used to calculate and compare the progression-free survival (PFS). Results: The study finally enrolled 84 patients meeting the requirement, and patients were postmenopausal or premenopausal while received ovarian function suppression. And 54 patients were in the everolimus+AI group, 30 patients were in the everolimus+fulvestrant group. The median PFS in all 84 patients was 6.87 months, and the median overall survival (OS) was 28.87 months. The DCR in all 84 patients was 76.2%, and the most common grade 3-4 adverse event is stomatitis which is similar to other previous studies. Subgroup analyses were further performed based on everolimus combined with AI/fulvestrant. Patients were well-balanced in clinical characteristics in the two groups. Everolimus combined with fulvestrant group showed no superior to everolimus combined with AI group, 5.77 vs. 7.97 months (HR, 1.56; 95% CI, 0.92-2.65, P = 0.0735). Subgroup analyses showed everolimus combined with AI groups was superior to Everolimus combined with fulvestrant groups in some subgroups: postmenopausal group (HR, 0.50; 95% CI, 0.26-0.98); without bone metastasis group (HR, 0.22; 95% CI, 0.06-0.80); lung or pleura metastasis group (HR, 0.35; 95% CI, 0.16-0.77); visceral disease group (HR, 0.37; 95% CI, 0.20-0.69); previous therapy lines ≥ 4 group (HR, 0.44; 95% CI, 0.22-0.87). Conclusions: Everolimus combined with fulvestrant is not superior to everolimus combined with AI in HR-positive, HER2-negative breast cancer patients. For postmenopausal patients, patients without bone metastasis, and patients with visceral disease, everolimus combined with AI is a better choice.