bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sustaining the gains in cancer care from the oncology care model.
Authors: Csik Valerie P , Minetola Jared , Chapman Andrew E. , Flomenberg Neal 
Published: May 2019

6632 Background: The Oncology Care Model (OCM) is a 5-year demonstration project led by the Centers for Medicare and Medicaid Services (CMS) to create a framework for the future of oncology care in the United States. More than half way through the project, our large, urban NCI-designated cancer center chose to focus on and invest in resources and personnel for patient navigation and the development of clinical pathways. Although navigation has shown to reduce emergency department (ED) visits by as much as 6% per quarter compared to non-navigated patients, sustaining it is a challenge because it is a nonbillable service. Clinical pathways are a tool to reduce care variation by addressing drug expenditures, and represent an opportunity to reduce outpatient costs by as much as 35% when patients are treated on pathway.3 Many OCM practices made similar investments and all are facing the question: How will the infrastructure and efforts developed during OCM be sustainable after the demonstration project ends? Methods: An analysis of average ED cost and utilization as well as drug expenditures was conducted using OCM feedback data (Q1-Q8). Total utilization of ED visits and ED admits were used to determine a projected annualized cost which was compared to a budgeted navigation team. Similarly, projected annualized drug expenditures were compared to the annual cost of the pathways tool. Results: We found that ED visits and ED admits would need to be reduced by 11% to cover navigation costs. Similarly, a 0.7% reduction in total drug expenditures would cover the cost of clinical pathways. The OCM data represents a timeframe prior to implementation of these programs and an average increase of 1.6% per quarter for ED admits, a 0.6% decrease in ED visits and 2.7% increase in drug expenditures. This will serve as a baseline to measure progress towards our sustainability targets. Conclusions: Long term sustainability of the infrastructure developed during OCM to support cancer care transformation will be dependent on reducing high cost and highly utilized services. Aligning impact areas with resources/tools to ensure sustainability is an approach that can help define targets for OCM practices.
Identifying and predicting the most costly patients in oncology.
Authors: Waddle Mark Raymond , Stross William C , Malouff Timothy D , Kaleem Tasneem , Trifiletti Daniel Michael , Vallow Laura , White Launia , Li Zhuo , Naessens James , Spaulding Aaron , Ma Daniel , Keole Sameer R. , Miller Robert Clell 
Published: May 2019

6633 Background: Quality based payment programs in medicine are currently being introduced nationally, aimed to improve care and reduce cost. This study aimed to evaluate the top spenders (TS) after cancer diagnosis and predict TS at two separate time points using predictive analytics. Methods: Patient characteristics, cancer details, treatments, adverse events, and outcomes were collected for patients treated for cancer at Mayo Clinic from 2007 - 2017. Standardized costs over a 2 year period after first treatment were obtained from the Mayo Clinic Cost Data Warehouse with Medicare reimbursements assigned to all services and adjusted to the 2017 GDP Implicit Price Deflator for inflation. TS were identified as those with greater than 93rd percentile costs (≥$113,158) due to a sharp rise in cost at that level. Descriptive statistics and univariate analysis were used for comparison. A prediction model with a training (80%) and validation set (20%) using multivariate selection was used to predict TS and was repeated using information available at 1) the time of consultation and 2) at last follow-up. Results: A total of 80,385 patients were included and 5,626 TS were identified. Mean cost (25th, 75th percentile) overall was $44,953 ($16,776, $51,889). Prediction models at time 1 and 2 had ROC AUC statistics of 0.82 and 0.89 in training and 0.82 and 0.88 in the validation indicating good prediction of high costs. Factors most predictive of TS included need for blood transfusions within 90 days of treatment (OR 5.3), bone marrow transplant (OR 4.0), mild liver disease (OR 3.5), hemiplegia (OR 3.4), weight loss > 10% within 90 days of treatment (OR 3.3), upper GI cancer (OR 3.0), ‘other’ cancer type (OR 2.8), immunotherapy use (OR 2.7), and hospitalizations within 90 days (OR 2.4), all p < 0.001, among others. The largest costs were due to hospital services in the TS and non-TS groups, mean costs $114,258 and $13,185 respectively. Conclusions: This is the first study to predict with high accuracy the top spenders in Oncology. Patient comorbidities and toxicities were among the strongest predictors of high costs, along with certain treatments (bone marrow transplant and immunotherapy). Our findings suggest that quality payment programs should adjust for comorbidities, and that reducing toxicity may be an effective method at reducing costs.
Drug funding price negotiations: Towards achieving a balance between individual and population gains in health benefits.
Authors: Parmar Ambika , Jiao Tina , Chan Kelvin K. 
Published: May 2019

6641 Background: Drug price negotiation to lower cost to a cost-effectiveness threshold (λ) is a recognized approach to improve health care opportunities for the greater benefit of the population. Critics have raised concerns for this approach given the additional time required and speculated loss of quality-adjusted life-years (QALY) for patients. The current study aimed to quantify the incremental net health benefit (INHB) of publicly funded oncology drugs, if funding occurred at list prices without (w/o) negotiations. Methods: Pan-Canadian Oncology Drug Review submissions were reviewed to identify funded drugs with unique indications. For included drug indications economic guidance panel (EGP) reports were reviewed for incremental costs (ΔC) and ΔQALY from manufacturer’s base case cost-effectiveness analyses, EGP lower (LL) and upper limit (UL) re-analyzed estimates (based on list prices). Number of new cases in Ontario (most populous province in Canada) per indication (2017-18) was obtained from provincial databases. Annual QALY gain for each indication was determined by: (ΔQALY×cases). Provincial QALY gain/loss w/o price negotiations to reference λ was estimated by: (INHB= [ΔQALY− (ΔC/λ)] ×cases). Incremental net monetary benefit demonstrated annual monetary gain/loss w/o price negotiations to reference λ: (INMB= [(ΔQALY×λ) −ΔC] ×cases). Results: 34 drug indications including 4,629 new cases were identified. Annual QALY gain for funded indications using manufacturer, LL and UL estimates was 1,851, 1,617 and 1,301, respectively. At reference λ CAD$100,000/QALY, funding w/o negotiations resulted in loss of 2,176, 2,368, 2,451 QALY, representing budgetary diversions away from other health care interventions. This would result in a provincial net annual loss of 325, 751 and 1,150 QALY, respectively. INMB demonstrated provincial net monetary loss of CAD$32,472,389, $75,113,684 and $115,022,331, respectively. Conclusions: Despite an annual gain in QALY for funded drug indications, a net provincial loss in QALY w/o price negotiations was demonstrated. Thus, supportive evidence exists for drug price negotiations towards the promotion of health benefits for the population.
Cost-minimization analysis of using tumor cell-free DNA as monitoring tool in cancer immunotherapy.
Authors: Kuhlmann Alexander , Weiss Glen J. , Beck Julia , Oellerich Michael , Westphal Ronja , Schütz Ekkehard , Graf von der Schulenburg J.-Matthias 
Published: May 2019

6642 Background: Albeit showing great benefit in individual cancer patients, only the minority of patients benefit from checkpoint inhibitor immunotherapies (IMTs). Mutation load and PD-L1 staining are used for response prediction, but are imperfect predictors. A universal method to quantify tumor cell-free DNA (TcfDNA) enables the early and effective evaluation of individual IMT efficacy[1], by comparing TcfDNA to pre-therapeutic values. Here we present a health economic evaluation of test usage. Methods: This cost-minimization study determines the economic efficiency of TcfDNA-test from the perspective of the statutory health insurance in Germany. The assumption is that the effectivity of the intervention (TcfDNA monitoring) and of the comparator (no test), is comparable with regards to the patient-relevant-endpoints (morbidity, mortality, quality of life). The model simulates the course of treatment for each patient with and without TcfDNA testing, calculating the respective cost. Treatment details, outcome (RECIST) and TcfDNA results are derived from an earlier clinical trial.[1] Costs are obtained from publicly accessible data bases. Two testing strategies are explored. Strategy 1: Testing all patients only before the second cycle. Strategy 2: Same as strategy 1 plus a confirmation test before the third cycle, in patients with initial result in a defined grey zone. Results: Both testing strategies correctly classified 68% of progressive disease patients. Testing strategy-1 misclassifies about 8% of disease control patients, which would lead to discontinuation of successful therapies in those. In contrast strategy-2 correctly classifies all patients with disease control, whilst requiring only 24% more tests, since ~50% of patients are undoubtedly classified after one cycle. Assuming six cycles at average costs of 4,781 EUR in the no-test-setting, average costs savings per patient with strategy-1 are 5,735 EUR (20% of treatment costs), with strategy-2 are 2,010 EUR (7%) compared to no testing. Conclusions: TcfDNA monitoring is a cost-saving strategy. However, a confirmatory strategy is desirable to avoid early discontinuation of successful IMT. [1] Weiss GJ et al.: Clin Cancer Res: 2017;5074-81.
Three-year survival outcomes in a prospective cohort evaluating a prognostic 31-gene expression profile (31-GEP) test for cutaneous melanoma (CM).
Authors: Hsueh Eddy C. , DeBloom James R. , Cook Robert W. , McMasters Kelly 
Published: May 2019

9519 Background: A 31-GEP test is a validated prognostic tool for predicting the risk of metastasis in CM, classifying patients (pts) as Class 1 (low risk) or Class 2 (high risk). Here we report updated survival analysis from two clinical registry studies (NCT02355574/NCT02355587) designed to prospectively evaluate outcomes in patients for whom the GEP test was part of their clinical care. Methods: Eleven US dermatologic and surgical centers participated using IRB-approved protocols. Participants were CM pts ≥16 years old who had successful 31-GEP test results. Recurrence-free (RFS), distant metastasis-free (DMFS) and overall survival (OS) were assessed using Kaplan-Meier and Cox regression analysis. Results: At data censoring, 340 pts were accrued who had completed at least one follow-up visit. Median age was 58 years (range 18-87), 53.5% were male, median Breslow thickness was 1.2mm (range 0.2-12mm), 18.2% (62/340) were ulcerated, and 11.2% (38/340) had a positive sentinel lymph node (SLN). Median follow-up was 3.2 years for pts without an event. Six percent (16/265) of Class 1 pts had a recurrence compared to 33% (25/75) of Class 2 pts (p < 0.001). Three-year RFS was 96%, 91%, 80%, and 62% for Class 1A, 1B, 2A, and 2B, respectively (p < 0.001). Three-year DMFS was 97%, 93%, 84%, and 80% for Class 1A, 1B, 2A, and 2B, respectively (p < 0.001). Three-year OS was 98%, 90%, 96%, and 74% for Class 1A, 1B, 2A, and 2B, respectively (p < 0.001). Class 2 was an independent predictor of RFS and OS in multivariate analysis (respective HRs: 2.28 and 3.70, p < 0.05). Conclusions: Consistent with results from previous studies, this analysis demonstrates that the GEP test complements conventional staging and improves the ability to identify high-risk CM pts. These results support use of the test for guiding decisions related to follow-up, surveillance, and treatment in CM pts. Clinical trial information: NCT02355574/NCT02355587.
The anti–PD-1 antibody spartalizumab (S) in combination with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600–mutant melanoma: Updated efficacy and safety from parts 1 and 2 of COMBI-i.
Authors: Long Georgina V. , Lebbe Celeste , Atkinson Victoria , Mandalà Mario , Nathan Paul D. , Arance Fernandez ANA Maria , Richtig Erika , Yamazaki Naoya , Robert Caroline , Schadendorf Dirk , Tawbi Hussein Abdul-Hassan , Ascierto Paolo Antonio , Ribas Antoni , Flaherty Keith , Lee Dung-Yang , Masood Aisha , Gasal Eduard , Dummer Reinhard 
Published: May 2019

9531 Background: Checkpoint inhibitors and targeted therapies have improved outcomes in pts with BRAF V600–mutant advanced melanoma; however, many pts progress and new treatment (tx) strategies are needed. BRAF inhibition increases T-cell infiltration, melanoma antigen expression, and PD-1/PD-L1 expression, which may lead to synergistic activity with anti–PD-1 therapy. Methods: COMBI-i is investigating first-line S 400 mg Q4W + D 150 mg BID + T 2 mg QD in pts with unresectable or metastatic BRAF V600–mutant melanoma (NCT02967692). Here we report pooled efficacy and safety data from parts 1 (run-in cohort) and 2 (biomarker cohort). Response was assessed per RECIST v1.1. Results: 36 pts were enrolled (part 1: n = 9; part 2: n = 27); 18 (50%) had stage IV M1c and 15 (42%) had elevated LDH levels. At the data cutoff (median follow-up, 15.2 mo), tx was ongoing in 17 pts (47%). The confirmed objective response rate (ORR) by investigator assessment was 75% (n = 27), with 33% complete responses (CRs; n = 12). Medians for duration of response (DOR; 7/27 pts with events), progression-free survival (PFS; 13/36 pts with events), and overall survival (OS; 7/36 pts with events) were not reached. 12-mo DOR rate was 71.4% (95% CI, 49%-85%). 12-mo PFS and OS rates were 65.3% (95% CI, 47%-79%) and 85.9% (95% CI, 69%-94%), respectively. In pts with high baseline LDH: ORR was 67%, with 3 CRs (20%), median PFS was 10.7 mo (events in 10/15 pts [67%]), and median OS was not reached, with events in 6/15 pts (40%). All pts had ≥ 1 AE; 27 (75%) had grade ≥ 3 AEs. 6 pts (17%) had AEs leading to discontinuation of all 3 study drugs. Any-grade AEs in ≥ 40% of pts included pyrexia, chills, fatigue, cough, and arthralgia. Grade ≥ 3 AEs in > 3 pts were neutropenia, pyrexia, and increased lipase. One pt died of cardiac arrest that was not considered related to study tx. Conclusions: S+D+T showed promising and durable ORR (75%) with CR in 33% of pts. With > 15 mo of follow-up, median PFS was not reached. The safety profile was manageable reflecting individual toxicities of D, T, and S. The global, placebo-controlled, randomized phase 3 (part 3) of COMBI-i is ongoing. Clinical trial information: NCT02967692.
Plasma concentrations of dabrafenib and trametinib (PCD/T) monitoring in advanced BRAFV600mut melanoma patients.
Authors: Funck-Brentano Elisa , Raynal Margot , Alvarez Jean-Claude , Beauchet Alain , Funck-Brentano Christian , Saiag Philippe 
Published: May 2019

9541 Background: Dabrafenib (D) and trametinib (T) are highly ative in BRAFV600mut melanoma pts. One previous study suggested high PCD to be associated with adverse effects (AE) but not with tumor response. We investigated the relationship between PCD/T and tumor control or AE. Methods: PCD/T were evaluated with high-performance liquid chromatography/mass spectrometry in D+T-treated metastatic melanoma patients. We analyzed results at steady state (≥2 d for D, 24 d for T after introduction or dose modification) and far from peak concentrations (8 to 14.5 h for D and 20-28 h for T). We collected data of tumor assessments (RECIST 1.1) prospectively stored in our database and AE (CTCAE 4.0) blinded to PCD/T results. Each AE was associated with the closest sample harvested to the beginning of AE, or in the absence of AE with the highest PCD/T level for each patient. Results: We analyzed 75 D and 58 T assays from 36 pts (19M/17F), treated with D+T for metastatic melanoma (Stage IV: N = 35), mostly in first line (69.4%). Initial D dose was 300 mg/d and 2 mg/d for T, reduced in 10 patients (27.7%) for AE: to 30% of D (N = 8) and 25% of T (N = 8). High interindividual variability of PCD (range: 4-945ng/mL, median 70.0) and of PCT (5-25ng/mL, median 8.6) was observed. No differences between mean PCD/T at the time of evaluations showing progressive disease (PD) compared to those without PD pts (146.6±111.6 and 9.3±2.1) and pts with complete (N = 11), partial (N = 1) or stable response (N = 1) (160.6±127.9, P = 0.81 and 10.6ng/mL±2.6, P = 0.29) were observed. No significant relationship was shown between PCD/T and body mass index (r = 0.22 and -0.31), age (p = 0.19 and 0.26), or between PCD/T and D (p = 0.11) or T (p = 0.17) doses, neither between elevated mean PCD/T and any most common AE. Conclusions: This study shows a high interindividual variability but failed to show a relationship between PCD or T and tumor response nor AE. One limit is we did not explore PC of D active metabolites (hydroxy-and desmethylD). It has been shown that there is an auto-induction of D; T inhibits P-gp, a D substrate, suggesting synergistic pharmacological interactions. Thus, D pharmacokinetic seems to be too complex to be easily monitored.
Identification of a gene expression signature predictive of clinical benefit in patients with advanced mucosal melanoma (MCM) treated with immune checkpoint blockade.
Authors: Rapisuwon Suthee , Shoushtari Alexander Noor , Gottesdiener Lee S. , Johnson Douglas Buckner , Wang Daniel Ying , Graham Garrett Thomas , Goerlitz David , Berry Deborah , Atkins Michael B. 
Published: May 2019

9546 Background: MCM is a rare melanoma subtype (only 1% of melanomas in the US). MCM has a lower tumor mutational burden than cutaneous melanoma (CM). While some patients (pts) with MCM respond to immune checkpoint inhibitor (ICI) therapy, predictive markers of response have not been established. We analyzed a cohort of MCM from pts treated with ICI to identify gene expression signatures associated with tumor response and clinical outcome. Methods: Fifty-eight MCM specimens were collected from 3 institutions. RNA was extracted from FFPE tissue slides and analyzed by NanoString 770 Immune Profiling Panel. Gene expression profiles were linked to anatomical location and disease outcome after ICI therapy: response as defined by RECIST v1.1 and median overall survival (mOS). Results: Fifty-one pts were treated with ICI - anti-CTLA-4 (n = 9), anti-PD1 (n = 38), or both (n = 5) ) and had tumor response evaluation. Three were without response data, 2 were without disease recurrence after surgery, 2 did not receive ICI. Among 51 pts with response data, seven were without long-term follow-up (1CR, 2PR, 3SD). The overall response rate (ORR) was 40.3%, similar to the prior study (Shoushtari et al, Cancer 2016). A signature involving differential expression of 87 immunoregulatory genes correlated with tumor response: ORR: 75% (12/16) signature high vs. 33.3% (7/21) signature low (p = 0.02, high vs. low) vs. 14.3% (2/14) signature average (p < 0.01; high vs. average). mOS for the whole population was 12.4 months. Pts with increased gene signature expression had superior mOS: signature-high: Not reached, signature-low: 8.2 months, (HR: 0.2; 95%CI: 0.07-0.55, p < 0.01). Transcript pathway analysis of the gene signature showed association with chemokine receptors, interleukin-10 signaling, and Treg development. Conclusions: We have identified a gene expression signature that involves chemokine receptors, IL-10 signaling, and Treg development gene sets, that appears to predict for tumor response and mOS in pts with advanced MCM treated with ICI. Further validation of these gene signatures is underway.
Clinical features and response to immune checkpoint inhibitors (ICIs) in pregnancy-associated melanoma (PAM).
Authors: Wang Daniel Ying , Owen Carina N. , Palmieri David James , Cohen Justine Vanessa , Eroglu Zeynep , Long Georgina V. , Sullivan Ryan J. , Balko Justin M. , Carlino Matteo S. , Menzies Alexander M. , Johnson Douglas Buckner 
Published: May 2019

9564 Background: Melanoma is one of the most common malignancies diagnosed during pregnancy. Little is known about the clinical outcomes of PAM, in particular, response to ICIs. We performed a retrospective study to assess this issue. Methods: A multicenter retrospective study was performed at 4 large melanoma centers. Patients (pts) with PAM treated with ICIs were identified and examined. Clinical data and molecular data (RNA sequencing, IHC) were explored. PAM was defined as development of advanced melanoma during pregnancy or within 2 years post-partum. Results: 19 pts with PAM were treated with ICIs. Median follow-up was 11.7 months (range 1.4 – 41.9 months). Median age was 29 years (range 16-36). Most pts had a cutaneous primary (N = 17, 89%) including the extremity (N = 8) or trunk (N = 7), and 5% were occult. 11 pts (58%) had a BRAF V600E mutation and 6 (32%) pts received BRAF/MEK targeted therapy. Most pts had prior primary melanoma (N = 12, 63%) and presented with advanced melanoma in the post-partum setting (N = 11, 58%). At advanced presentation, 6 (32%) pts were stage III/M1a and 13 (68%) pts were stage M1b/c/d; 7 (41%) pts had elevated LDH and 13 (68%) had visceral involvement. Among 11 patients treated with combination ipilimumab + anti-PD-1 therapy, 7 (64%) had objective responses (OR) with a 1-year progression free survival (PFS) of 40% and 1-year overall survival (OS) of 100%. By contrast, ICI monotherapy (3 with anti-PD-1/L1 and 4 with ipilimumab) was associated with poorer outcomes (OR in 25% and 33% for ipilimumab and anti-PD-1/L1, respectively). Molecular features (RNA sequencing, immunohistochemistry) will be presented. Conclusions: Patients with PAM represent a unique population and may particularly benefit with combination ICI therapy compared with ICI monotherapy (in a limited sample size). Molecular underpinnings of PAM biology are still being elucidated.