tbuckley/cabot-search huggingface dataset:
Cardiovascular adverse events in immune checkpoint inhibitor clinical trials: A U.S. Food and Drug Administration pooled analysis.
Authors: Laleh Amiri-Kordestani, Javid Moslehi, Joyce Cheng, Shenghui Tang, Robert Schroeder, Rajeshwari Sridhara, Katherine Karg, Joseph Connolly, Julia A. Beaver, Gideon Michael Blumenthal, Richard Pazdur
Journal: Journal of Clinical Oncology (2018)

3009 Background: Immune checkpoint inhibitors (ICI) have been approved for numerous cancers and have transformed patient outcomes. There is a growing recognition of immune-related adverse events (AE), including cardiovascular (CV) AE. While rare cases of fulminant myocarditis have been reported, the full extent of CV AE remains unknown. Methods: This exploratory observational study pooled data from prospective ICI trials submitted to FDA in initial or supplemental Biologics License Applications until 1/2018. To systematically categorize CV AE, we combined CV MedDRA Preferred terms with a focus on the underlying pathology. Descriptive statistics were used to characterize the incidence of CV AE by exposure to ICI and calculate relative risks (RR) between arms of interest. To account for bias with respect to duration of exposure, we based our analyses on the first 6-month treatment window. Results: Within 59 trials (N = 21,664), ICI therapy was associated with higher rates of myocarditis, vasculitis, ischemia, arrhythmia, and pericardial disease compared to non-ICI therapy. When ICIs were used in combination, CV AE increased across most categories compared to monotherapy. Five fatal cases of myocarditis were reported with ICI therapy. Conclusions: To our knowledge, this is the largest report of CV AE associated with ICI in clinical trials. Our results show that combination ICI therapy appears to be associated with an increase in observed incidence rates of CV AE relative to ICI monotherapy. CV AE for patients with/without ICI. Grouping Incidence Rates (%) Relative Risks All ICI N = 18605 Combo N = 1533 Mono N = 17072 Non-ICI N = 3059 ICI/Non-ICI Combo/Mono CHF 0.53 0.65 0.52 0.78 0.67 1.27 Arrhythmia 5.56 8.41 5.31 5.03 1.11 1.59 Myocarditis 0.03 0.13 0.02 0 * 7.42 Valvular 0.03 0.2 0.02 0.13 0.25 11.14 Vasculitis 0.04 0.07 0.04 0.03 1.32 1.59 Vascular/Thromboembolic/Bleeding 8.93 11.61 8.69 10.33 0.86 1.34 HTN 3.86 5.28 3.73 9.25 0.42 1.42 Sudden Cardiac Death 0.3 0.46 0.28 0.42 0.70 1.62 Vascular/PVD 0.27 0.52 0.25 0.56 0.48 2.12 Pericardial/Pericarditis 0.7 0.26 0.74 0.62 1.13 0.35 Ischemia 0.58 1.3 0.51 0.42 1.35 2.56 *not available due to 0 events in the Non-ICI group
Design and implementation of a risk identification tool to improve oncology patient management.
Authors: Garrett Young, Tiffany Hoy, Ashley Roper, Whitney Church, Lee Steven Schwartzberg
Journal: Journal of Clinical Oncology (2018)

e18521 Background: Methods to identify cancer patients that are likely to seek inpatient care for conditions that can be treated in the outpatient setting are not well defined. In light of the rise in value-based care programs, there is increased pressure on oncology providers to decrease costs of care while continuing to achieve high-quality outcomes. One way this can be achieved is by decreasing avoidable, high-cost utilization through population management. We sought to investigate the feasibility of creating a model to predict which patients were more likely to utilize emergency department (ED) and inpatient hospital (IP) services as well as the impact such a model may have on patient management. Methods: For a sample of 1093 patients, historical information was gathered across four domains: Cancer-specific Attributes, Comorbidity Burden, Social Factors, and Utilization History. This data set was then used to design a predictive model which assigned a numerical “acuity” score to each patient. Patients were ranked by numerical score, and their subsequent ED and IP utilization was measured. The developed model was then tested on an independent set of 591 patients to assess broader validity. After development, the predictive model was built into a tool for use in patient management by a team of nurse care managers. Results: Of the 100 highest-ranking patients in the training sample, 29% had at least one future hospitalization and 33% had at least one future ED visit, compared to 13% and 19% in the entire sample, respectively. In the validation sample, 11% of the 100 highest-ranking patients had at least one future hospitalization and 20% had at least one future ED visit, compared to 5% and 13% in the entire sample, respectively. Before model deployment, an average of 39 follow-up touchpoints were completed for high-risk patients per month. After deployment, the average rose to 160 touchpoints per month, an increase of 314%. Conclusions: Models can be developed to proactively identify cancer patients at a higher risk of utilizing ED and inpatient hospital services. Implementation of such models can also increase communication with patients and help to focus care management resources on higher-risk patients.
P01.017 Geriatric Assessments in Neuro Oncology - a viable prospect
Authors: C Lorimer, G Walsh, M MacKinnon, K Greenwood, A Corbett, K Bedborough, F Saran, A Chalmers, J Brock
Journal: Neuro-Oncology (2018)

An ageing population brings new challenges for oncologists in the management of older cancer patients. There is increasing use of a geriatric assessment (GA) to evaluate fitness for treatment and identify geriatric syndromes. GAs can predict for chemotherapy toxicity and overall survival however there is a paucity of data within the neuro oncology cohort. A criticism of GAs is that they are time and resource consuming. We conducted a feasibility study to assess whether a GA could be performed by members of the usual clinical staff in a UK NHS neuro oncology outpatient setting. Patients aged ≥ 65 with a new diagnosis of GBM were prospectively recruited from neuro-oncology outpatient clinics across 3 UK centres. A modified GA was performed by the clinical nurse specialists and demographic, imaging and toxicity data collected. Feasibility was assessed primarily by recruitment rate. Secondary outcomes of completion rate, acceptability to staff and patients and overall survival were measured. After completion of the study, face to face semi-structured interviews with the nurses were performed; these were interpreted qualitatively using thematic analysis. Recruitment to the study completed within the 1 year study time. 22 women and 28 men were enrolled with a mean age of 71 (65–86). Median overall survival was 8.2 months. 41 patients received active treatment (17 palliative radiotherapy, 19 chemo radiation and 5 temozolomide alone). Of the 35 patients who were tested, 31% showed MGMT promoter methylation; no IDH mutations were detected. All centres achieved recruitment rates above the target of 80% (mean 92%, 95% CI 86%-96%). Mean assessment completion rate was 94% (95% CI 92–95%). The nurses reported that completing the assessment was manageable and that, in some cases, underlying patient factors were identified that led to changes in treatment plans. Univariable regression analysis showed the MoCA (HR 2.78, p=0.02), IADLs (HR 2.88, p=0.03), baseline mobility (HR 12.1 p=0.002), ECOG PS (HR 29.2 p=0.003) and level of anxiety (HR 3.5 p=0.001) were related to overall survival, alongside treatment received. Multivariate Cox regression modelling confirmed the MoCA score to be a significant independent predictive factor for overall survival. ASCO and SIOG promote the use of a GA in the management of older cancer patients and it is becoming widely used within other tumour groups. However, to the authors’ knowledge, this is the first study of a GA within the neuro oncology patient cohort, a group with its own particular symptom burden. We have shown that performing a GA is feasible within the confines of a busy UK outpatient clinic and that, within the accepted limits of the study size, the results can help predict overall survival irrespective of treatment received. Wider use of a neurologically focussed GA should now be explored with greater patient numbers.
Improving Depression Outcome by Patient-Centered Medical Management
Authors: A. John Rush, Michael E. Thase
Journal: American Journal of Psychiatry (2018)

Specific challenges that profoundly affect the outcome of treatment for depression include 1) patient engagement and retention in care and optimization of treatment adherence, 2) optimization of symptom and side effect control by medication adjustments using measurement-based care procedures, 3) restoration of daily functioning and quality of life, and 4) prevention or at least mitigation of symptomatic relapse or recurrence. According to data from the Sequenced Treatment Alternatives to Relieve Depression study, some 10%-15% of patients will not return for treatment after an initial thorough evaluation visit; an additional 20%-35% will not complete the first acute-phase treatment step, and another 20%-50% will not complete 6 months of continuation treatment. Among patients who stay in treatment, over 50% exhibit poor adherence. Thus, most patients do not overcome the first two challenges. There are no systematic, widely agreed-upon psychosocial approaches to any of these four major challenges. The authors propose "patient-centered medical management" to address each of the four challenges, using psychoeducational, behavioral, cognitive, interpersonal, and dynamic models and methods. A renewed emphasis on the development and testing of systematic approaches to overcoming these common clinical challenges could enhance the chances of patient recovery and care system cost efficiencies. [AJP AT 175: Remembering Our Past As We Envision Our Future July 1933: Psychotherapeutics at Stockbridge Horace K. Richardson: "Frequently, in the simpler situations, very few interviews are required in order that he [the patient] discover for himself what part of the adaptive machinery is at fault, and for him to develop a technique of handling the maladjustment on a more satisfactory level in the future." (Am J Psychiatry 1933; 90:45-56 )].
Results of GROC-rev salvage regimen: Gemcitabine, rituximab, and oxaliplatin chemotherapy with revlimid for relapsed/refractory aggressive non-Hodgkin lymphoma (NHL).
Authors: Fernando Cabanillas, Idalia Liboy, Alexis Cruz, Pedro Gil Solivan, Noridza Rivera, Wandaly Ibis Pardo, Mirelis Acosta
Journal: Journal of Clinical Oncology (2017)

7556 Background: Currently there is no optimal salvage regimen for relapsed/refractory NHL (R/R NHL). Prognosis of pts who fail to achieve CR to salvage therapy is dismal. We sought to improve the CR rate by adding Lenalidomide (L) to GROC (ASCO #8530, 2008). Methods: Primary endpoint was rate of conversion to CR after switch to L for pts whose best response to GROC was &lt;CR. Secondary endpoint was progression free survival (PFS) of all pts as well as those who achieve &lt;CR on chemotherapy and were crossed over to L.Pts who failed to achieve at least PR after GROC x2 and those who didn’t achieve CR after GROC x6, were crossed over to L 25 mg x 3 weeks q 28 days. CRs were maintained on L x 2 yrs. Results: 34 pts were enrolled of which 32 are evaluable. Median age: 61 and 56% males. Histologies included DLBCL (81%), PTCL (9%), follicular grade 3-B (9%). Stage was III-IV in 75% and median IPI=2. Best overall response rate (ORR) at any point during treatment= 19/32 (59%) and CR 13/32 (41%). ORR before crossover to L=13/32 (41%) and CR= 8/32 (25%). There were 24 who failed to achieve CR on GROC (19 who didn’t respond at all and 5 whose maximum response was PR). Of these, 21 crossed over to L and 7 (33%) responded (CR in 5, PR in 2). The fact that 5 pts attained a CR to L thus improving the CR rate from 25% to 41% after exhibiting refractoriness to GROC is noteworthy. Of the 7 responders to L, all are alive and only 1 relapsed. At 2 yrs., overall survival (OS) was 48% and PFS 35%. This compares favorably with our previous GROC study without L in which 2 yr. OS= 33% and PFS 29%. In total, 11 pts were eligible for ASCT after chemo plus L and 8 were transplanted (3 refused). Of these eight, 6 remain in CR at 11, 18, 21, 22, 52, 74 mos. At 2 yrs, PFS for transplanted pts is 73% and for those whose response to GROC before crossover to L was &lt;CR, it is 27 mos. Toxic events included 2 neutropenic fevers, 1 MDS (34 mos. after ASCT) and 1 AML (11 mos. after ASCT). Both of these remain continuously in CR after allo SCT. Conclusions: 2 yrOS=48% and PFS=35% with GROC-Rev are the best observed with any salvage regimen we have tested. L is active as a single agent in 29% of cases whose best response to GROC was &lt;CR. A larger study is desirable to confirm these data. Clinical trial information: NCT01307592.
Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting in lung cancer patients receiving carboplatin-based therapies.
Authors: Cindy Weinstein, Karin Jordan, Stuart Green, Saleem A. Khanani, Elizabeth Beckford-Brathwaite, Waldimir Vallejos, Annpey Pong, Stephen Joseph Noga, Bernardo Rapoport
Journal: Journal of Clinical Oncology (2017)

e21685 Background: Chemotherapy-induced nausea and vomiting (CINV) is a distressing symptom of cancer treatment; in lung cancer, carboplatin is commonly used. In a post hoc analysis, we explored prevention of CINV in lung cancer patients with a single-day triple-antiemetic fosaprepitant (FA) regimen compared with a standard 3-day control regimen. Methods: This was a phase 3, global, randomized, double-blind, parallel-group study in adults scheduled to receive an intravenous (IV) dose of ≥1 moderately emetogenic chemotherapy (MEC) on treatment day 1 (NCT01594749). Subjects were randomly assigned 1:1 to a control or FA regimen. The control regimen consisted of 8 mg oral ondansetron, 20 mg dexamethasone, and IV saline as placebo before the first dose of MEC on day 1, and 8 mg oral ondansetron 8 hours after the first dose and every 12 hours on days 2 and 3. The FA regimen consisted of the same dose of oral ondansetron on day 1, along with 12 mg dexamethasone and a single dose of 150 mg IV FA before the first dose of MEC on day 1, with no additional prophylactic antiemetic beyond day 1. The primary end point was complete response (CR; no vomiting or rescue medication) in the delayed phase (25-120 hours). Results: Overall, 1000 subjects were included in the intention-to-treat population (FA: n = 502; control: n = 498). The primary end point was met ( P &lt; 0.001; FA vs control). In a subset of 254 subjects with lung cancer (71% male), 129 in FA regimen and 125 in control regimen, most (98%) received carboplatin-based chemotherapy. CR in the delayed phase was achieved by 80.6% in the FA group and 74.4% in the control group (difference, 6.2%). More subjects had no vomiting episodes in the FA (85.3%) vs control (78.4%) groups within the delayed phase (difference, 6.9%), and overall time-to-first vomiting episode was longer for subjects in the FA group. Adverse events (AEs) were similar between groups: overall AEs occurred in 57.7% and 54.8%, and serious AEs occurred in 12.3% and 12.1% in the FA and control groups, respectively. No serious AEs were considered related to study medication. Conclusions: A single-day IV FA regimen is effective for preventing CINV in patients with lung cancer receiving carboplatin. Clinical trial information: NCT01594749.
Baseline demographics and disparities in cancer registration trials: An analysis of U.S. Food and Drug Administration approved drugs in 2015 and 2016.
Authors: Rohan Maniar, Angela Green, Peter Bach, Sham Mailankody
Journal: Journal of Clinical Oncology (2018)

e18623 Background: Clinical trials play a fundamental role in the advancement of cancer care, yet specific groups remain under-represented in oncology clinical trials. We analyzed the age, race, performance status, and geographic enrollment data of cancer patients in registration trials for new drug approvals or indications by the US Food and Drug Administration (FDA) from 2015-2016. Methods: Demographic data from cancer patients enrolled in registration trials during 2015 and 2016 were analyzed. Distributions by age (65-74yo and ≥ 75yo), race (categories), performance status (ECOG ≥ 2, ECOG ≥ 3), and geographic enrollment (US/Canada, Europe, Rest of the World) were described and compared to Centers for Disease Control and Prevention (CDC) data for the general cancer population. Results: A total of 45 approved drugs investigated in 53 trials were evaluated, including 22,789 patients. Age was reported on 7850 patients, with 2524/7580 (33.3%) 65-74yo and 981/7580 (12.9%) ≥ 75yo. The race distribution for enrolled patients were 15018/18897 (79.5%) for Caucasians, 356/18897 (1.9%) for Black/AA, 2302/18897 (12.2%) for Asians and 505/18897 (2.7%) for Others. 461/19729 (2.3%) and 5/19729 (0.025%) of patients enrolled in registration trials had an ECOG ≥2 and ECOG ≥3, respectively. Portions of geographic enrollment were 3518/13192 (26.6%), 7263/13192 (55.0%), and 2379/13192 (18.0%) for US/Canada, Europe and the Rest of the World, respectively. Conclusions: These data suggest that older adults ≥75yo, blacks, and patients with co-morbid conditions are under-represented in contemporary registration clinical trials. Thus, results of recent cancer clinical trials leading to FDA drug approvals may not be generalizable to the broader cancer population in the US. Improvements in the trial enrollment process are needed to address these disparities and may be facilitated through effective health policy. Table: Comparison of age and race among clinical trial participants and all US cancer patients Registration Trials (2015-2016) CDC US Cancer Statistics (2014) 65-74yo 33.3% 28.2% ≥ 75yo 12.9% 26.5% Caucasian 79.5% 83.4% Black/AA 1.9% 10.8% Asian 12.2% 3.1% Other 2.7% 0.5%
Immune-related adverse events and survival in elderly patients with melanoma treated with ipilimumab.
Authors: Idrees Mian, Ming Yang, Hui Zhao, Mohsin Shah, Adi Diab, Vickie Shannon, Anisha Patel, Rodabe Navroze Amaria, Sharon Hermes Giordano, Maria E. Suarez-Almazor
Journal: Journal of Clinical Oncology (2016)

3047 Background: Immune-related adverse events (irAE) encompass wide-ranging toxicities in patients (pts) taking Ipilimumab. Experienced by many pts on Ipilimumab, they occasionally result in death. As irAE could be indicative of an enhanced immune response to therapy, pts developing these events potentially experience improved therapeutic response and survival. We evaluated the toxicity patterns of irAE in older pts with melanoma receiving Ipilimumab, and the association of irAE with their overall survival (OS). Methods: We identified melanoma pts 65 years or older, treated with Ipilimumab using the Surveillance Epidemiology and End Results (SEER) and Texas Cancer Registry (TCR) linked with Medicare data between 3/2011 and 12/2013. We defined 44 types of irAE based on 228 ICD-9 diagnosis codes; irAE had to occur within 3 months of last treatment and include one or more diagnosis codes, which could not be present within a 6-month window before treatment. We classified pts with irAE as severe if they had a related hospitalization or death within 2 weeks of the claim. We used log rank and multivariable Cox regression to analyze OS. Results: We identified 858 pts with mean age at diagnosis 69.1 years and mean age at treatment 74.8 years. More than half of pts (63.3%) had a Charlson Comorbidity Index of 0. Pts received a median of 3 treatment courses. 510 (60%) pts experienced irAE with 178 pts (20.7%) experiencing severe irAE. The most frequent irAE were colitis (17.5%), hypothyroidism (10.5%), dermatitis (5.4%) and hypophysitis (3.7%). Those with non-severe irAE had improved OS compared with no irAE or severe irAE with median survival years being 1.1, 0.9, and 0.6, respectively (p < 0.001). In the multivariable analysis, severe irAE pts were 28% more likely to die compared to pts with no irAE (p = 0.04). Conclusions: In this retrospective study our findings suggest that the incidence of irAE occurs in elderly melanoma pts at comparable rates to all melanoma pts treated with Ipilimumab. Hypothyroidism occurred more frequently than what has been reported in clinical trials. Pts with non-severe irAE had improved OS compared to pts with no irAE. Pts with severe irAE appeared to have the highest risk of death.
Evaluation of an intratumorally administered slow release docetaxel formulation in combination with systemic anti-PD-1 treatment in a preclinical model.
Authors: Martin Johansson, Stefan Gruden, Niklas Axén
Journal: Journal of Clinical Oncology (2018)

e24214 Background: A number of trials investigating the combination of immune checkpoint inhibitors and chemotherapy have been conducted in different types of cancer. The rational for this is that certain chemotherapy agents can induce immunogenic cell death whereby damage-associated molecular pattern molecules are released, inducing systemic immunity and thus potentiating the effect of immunotherapy. However, systemic chemotherapies can also be immunosuppressive, as evidenced by neutropenia and killing of circulating lymphocytes, thereby negating the effects of immunotherapy. To overcome this we envisaged the use of a combination of intratumoral administration of docetaxel, a widely used microtubule stabilizing chemotherapy agent,with an immune checkpoint inhibitor. To effectively and safely administer docetaxel intratumorally, we have developed a controlled release formulation based on NanoZolid, a clinically proven and tested drug delivery technology. Methods: To assess the in vivo anti-tumor efficacy of a NanoZolid formulation of docetaxel as monotherapy and in combination with a PD-1 immune checkpoint inhibitor, a syngeneic murine breast cancer model was utilized where EMT6/P cells were implanted subcutaneously in both flanks of CD2F1 mice. Treatment started upon randomization (tumor volume 100-300 mm3). Body weight measurements and tumor volume determination were performed three times per week. Results: Intratumorally administered Nanozolid-docetaxel was well tolerated and significantly increased the efficacy of aPD-1 treatment compared to aPD-1 monotherapy as measured by reduced tumor growth. In contrast, tumors grew faster in animals that received systemic docetaxel in combination with aPD-1 treatment compared to PD-1 monotherapy. Conclusions: Our results suggest that local delivery of docetaxel enhances the efficacy of systemic immunotherapy without causing any additional side-effects and that a combination of checkpoint inhibition and local docetaxel treatment can be an effective new treatment modality. A clinical trial with NanoZolid-docetaxel for the local treatment of NSCLC will be initiated in 2018.