Citations

Objectives/HypothesisCreate a competency‐based assessment tool for pediatric tracheotomy.Study DesignBlinded, modified, Delphi consensus process.MethodsUsing the REDCap database, a list of 31 potential items was circulated to 65 expert surgeons who perform pediatric tracheotomy. In the first round, items were rated as “keep” or “remove,” and comments were incorporated. In the second round, experts were asked to rate the importance of each item on a seven‐point Likert scale. Consensus criteria were determined a priori with a goal of 7 to 25 final items.ResultsThe first round achieved a response rate of 39/65 (60.0%), and returned questionnaires were 99.5% complete. All items were rated as “keep,” and 137 comments were incorporated. In the second round, 30 task‐specific and seven previously validated global rating items were distributed, and the response rate was 44/65 (67.7%), with returned questionnaires being 99.3% complete. Of the Task‐Specific Items, 13 reached consensus, 10 were near consensus, and 7 did not achieve consensus. For the 7 previously validated global rating items, 5 reached consensus and two were near consensus.ConclusionsIt is feasible to reach consensus on the important steps involved in pediatric tracheotomy using a modified Delphi consensus process. These items can now be considered to create a competency‐based assessment tool for pediatric tracheotomy. Such a tool will hopefully allow trainees to focus on the important aspects of this procedure and help teaching programs standardize how they evaluate trainees during this procedure.Level of Evidence5 Laryngoscope, 130:2700–2707, 2020

Background: Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction, the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women compared with men. Methods: In a prespecified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction), which compared sacubitril-valsartan and valsartan in patients with heart failure with preserved ejection fraction. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes. Results: Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older and had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP (N-terminal pro–B-type natriuretic peptide) levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI, 0.59–0.90) in women and 1.03 (95% CI, 0.84–1.25) in men ( P interaction = 0.017). The benefit from sacubitril-valsartan was attributable to reduction in heart failure hospitalization. The improvement in New York Heart Association class and renal function with sacubitril-valsartan was similar in women and men, whereas the improvement in Kansas City Cardiomyopathy Questionnaire clinical summary score was less in women than in men. The difference in adverse events between sacubitril-valsartan and valsartan was similar in women and men. Conclusions: As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. Whereas the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding. Clinical Trial Registration: https://www.clinicaltrials.gov . Unique identifier: NCT01920711.

Introduction: Daratumumab, a CD38-directed monoclonal antibody, in combination with lenalidomide and dexamethasone (D-Rd), recently received FDA approval for the treatment of patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem cell transplantation (ASCT). FDA approval was based on results of the prespecified interim analysis of a pivotal phase III trial (MAIA) in which D-Rd was compared to Rd among patients with NDMM who were ineligible for ASCT. In the MAIA trial, D-Rd significantly reduced the risk of progression or death compared to Rd. However, no trials have compared D-Rd to other standard-of-care (SOC) regimens. The present study compared progression-free survival (PFS) of D-Rd from the MAIA trial database to common SOC regimens from the Flatiron Health EHR Database, a de-identified nationwide US database of records primarily from community-based oncology practices. Methods: Patient-level data were obtained from the MAIA trial and the Flatiron database. Patients in the MAIA trial were enrolled between March 2015 and January 2017. To be included in MAIA, patients had to be deemed ineligible for high-dose chemotherapy with ASCT due to either age (≥65 years) or presence of comorbidities, have Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, creatinine clearance ≥30mL/min, and adequate bone marrow reserve. In the Flatiron Database, patients had to be diagnosed with MM between January 2011 and April 2019, age ≥65 years at initiation of first line treatment (LOT1), could not have received stem cell transplant as part of LOT1, and met MAIA inclusion/exclusion criteria. Regimens received by fewer than 10% of patients in Flatiron were excluded due to sample size and statistical power considerations. Bortezomib-lenalidomide-dexamethasone (VRd), bortezomib-dexamethasone (Vd), and Rd were the most commonly used regimens in non-transplant NDMM patients, representing 67% of regimens used in this setting. Multiple imputation by chained equations was used to address missing data in Flatiron. Eligible Flatiron patients treated with VRd, Vd, or Rd as LOT1 were reweighted to resemble the MAIA trial population on measured baseline characteristics using propensity-score (PS) weighting. An anchored adjusted indirect treatment comparison (ITC) was performed to compare D-Rd to VRd and D-Rd to Vd, using a stratified Cox proportional hazards regression model with Rd as the common anchor across both data sources. The model calculates hazard ratios (HRs) for direct comparisons within MAIA (D-Rd vs Rd) and within Flatiron (VRd vs. Rd, Vd vs. Rd) to estimate the HRs indirectly for D-Rd vs. VRd and D-Rd vs. Vd. Results: After application of MAIA inclusion criteria and PS-reweighting, the Flatiron VRd, Rd, and Vd patients resembled the MAIA trial population on baseline patient demographics and clinical characteristics (Table 1). D-Rd statistically significantly reduced the risk of progression or death compared to Rd (HR=0.55; 95% CI, 0.41-0.72) based on the direct comparison with D-Rd using the MAIA trial data; D-Rd statistically significantly reduced the risk of progression or death compared to VRd (HR=0.66; 95% CI, 0.46-0.95) and Vd (HR=0.47; 95% CI, 0.33-0.67) based on the anchored ITC (Figure 1). Sensitivity analyses will be performed and updated analysis using longer follow-up data from the MAIA study will be presented at the meeting. Conclusion: This analysis demonstrated that D-Rd reduced the risk of progression or death compared to other SOCs VRd and Vd for patients with NDMM who are transplant-ineligible. In the absence of head-to-head trials, this type of patient-level analysis provides important information that can help optimize treatment for patients with NDMM who are transplant-ineligible. Disclosures Durie: Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Kumar:Takeda: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Usmani:Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor. Ammann:Janssen: Employment, Equity Ownership. Lam:Janssen: Employment, Equity Ownership. Kobos:Janssen: Employment. Maiese:Janssen: Employment, Equity Ownership. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees.

Introduction : Daratumumab (DARA) is a human CD38 antibody approved in combination with standard-of-care (SoC) regimens in pts with NDMM who are TIE. DARA-based treatments showed significantly improved progression-free survival (PFS) in pts with TIE NDMM in ongoing phase 3 studies ALCYONE (DARA + bortezomib/melphalan/prednisone [D-VMP] vs VMP) and MAIA (DARA + lenalidomide/dexamethasone [D-Rd] vs Rd continuous). An NMA allows estimation of the relative efficacy of regimens not compared in head-to-head trials. A previous NMA examined D-VMP and D-Rd vs comparators (Facon T et al., EHA 2019), excluding the SWOG S0777 study (bortezomib/lenalidomide/dexamethasone [VRd]; Durie BG, et al. Lancet 2017) as it enrolled both transplant-eligible (TE) and TIE pts, and data for pts who are TIE only (~50% [aged ≥65 y and frail]) were unavailable. In this NMA, D-Rd and D-VMP had the highest probabilities of being more effective than reference treatment Rd continuous in terms of PFS. Recently, VRd received EMA approval for treatment of TIE NDMM based on SWOG S0777, but results specific to TIE pts are still unavailable. Recent NMAs of TIE pts (Blommestein HM et al., Haematologica, 2019; Weisel et al., EHA 2019; Cao Y et al., Clin Lymphoma Myeloma Leuk, 2019) have included data from the the intent-to-treat (ITT) population of SWOG S0777, though its inclusion violates the similarity assumption. Here, we present a sensitivity analysis of the previously-conducted NMA including all pts who received VRd in SWOG S0777 for a comprehensive view of the comparative effectiveness of DARA-based treatments in TIE NDMM. Methods: VRd was included as part of a sensitivity analysis of the previous NMA based on the ITT population, reporting PFS and overall survival (OS). The Guyot method was used to estimate OS hazard ratios (HRs) for pts aged ≥65 y (proxy for TIE) from SWOG S0777 (Durie BG et al., ASH 2018). Median follow-up in ALCYONE and MAIA was 27.8 months and 28.0 months, respectively. Based on a systematic literature review conducted through January 2019, both PFS and OS were extracted and synthesized in Bayesian NMAs. Choice of fixed- or random-effects (FE or RE) model was based on lowest deviance information criterion (DIC) and/or presence of heterogeneity in the network. Rd continuous was selected as reference, as it was commonly included in guidelines across regions. For PFS and OS, HR <1 indicates the comparison is not in favor of Rd continuous. In addition to the previous NMA, we also report an NMA sensitivity analysis including only comparators approved by the EMA that are relevant for the European, Middle East and/or Africa (EMEA) region (EMEA NMA). Results: Global NMA: RE model was used for both PFS and OS. Compared with Rd continuous, the PFS HR for VRd in the sensitivity analysis was 0.74 (95% credible interval [CrI], 0.42-1.30), which was similar to SWOG S0777 (0.71; [96% Wald confidence interval [CI], 0.56-0.91]) and higher than HRs for D-Rd (0.55; 95% CrI, 0.31-0.97) and D-VMP (0.58; 95% CrI, 0.20-1.62; Table). For OS, the SWOG S0777 HR estimated by Guyot algorithm for pts aged ≥65 y was 0.80 (95% CI, 0.56-1.16). Compared with Rd continuous, the OS HR for VRd in the sensitivity analysis was 0.80 (95% CrI, 0.51-1.26), which was similar to SWOG S0777 and higher than D-Rd (0.78; 95% CrI, 0.51-1.18). EMEA NMA: FE model was used for both PFS and OS. Compared with Rd continuous, the PFS HR for VRd in the sensitivity analysis was 0.74 (95% CrI, 0.60-0.92), which was higher than HRs of D-Rd (0.55; 95% CrI, 0.43-0.71) and D-VMP (0.64; 95% CrI, 0.41-1.02). Compared with Rd continuous, the OS HR for VRd in the sensitivity analysis was 0.80 (95% CrI, 0.55-1.17), which was higher than for D-Rd (0.78; 95% CrI, 0.56-1.09). These results are consistent with the Global NMA, but differ slightly as the EMEA NMA has fewer evidence-loops (only EMEA SoC regimens were included). Conclusions: This study demonstrated favorable efficacy outcomes for DARA-based regimens vs other relevant frontline options, such as VRd, for pts with NDMM who are TIE. Limitations of the sensitivity analysis include lack of comparative trial data and demographic differences between pts from SWOG S0777 and trials of frontline MM treatments for pts who are TIE included in our network. The majority of SWOG S0777 pts are TE (<65 y), who often have better prognoses than TIE pts (≥65 y), and thus violates the similarity assumption of NMAs. However, DARA-based regimens still showed a comparative clinical advantage. Disclosures Facon: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Usmani:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor; Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant; Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau. Dimopoulos:Sanofi Oncology: Research Funding. Kumar:Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. Mateos:Adaptive: Honoraria; EDO: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Cavo:Janssen, Celgene, Amgen, Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Amgen, BMS, Abbvie, Takeda: Honoraria; Janssen, Celgene: Other: Travel Accommodations; Janssen, Celgene: Speakers Bureau. Heeg:Ingress-Health: Employment. Van Beekhuizen:Ingress-health: Consultancy. Pisini:Janssen: Employment, Equity Ownership. Nair:Janssen: Employment, Equity Ownership. Lam:Janssen: Employment, Equity Ownership. Slavcev:Janssen: Employment, Equity Ownership. He:Janssen: Employment, Equity Ownership.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non–clear cell renal cell carcinoma, and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize the NCCN Kidney Cancer Panel discussions for the 2020 update to the guidelines regarding initial management and first-line systemic therapy options for patients with advanced clear cell renal cell carcinoma.

Abstract Background: Each additional line of therapy is associated with lower rates of deeper responses, shorter durations of treatment-free intervals, and increased rates of toxicities/comorbidities in patients with multiple myeloma (MM; Yong K, et al. Br J Haematol 2016. 175[2]:252-264), all of which are factors that contribute to treatment discontinuation. In order to characterize the newly diagnosed MM (NDMM) patient population in the United States not treated with a stem-cell transplant based on the number of subsequent lines of therapy (LOT) received, we examined baseline patient characteristics and pre-existing comorbidities, frontline treatment patterns, and attrition rates for these patients according to whether subsequent LOT was received or not received. Methods: NDMM patients were identified from 3 US patient-level data sources: the Surveillance, Epidemiology, and End Results (SEER)-Medicare Linked database (from January 2007 through December 2014), the OPTUM™ Commercial Claims database (from January 2000 through March 2017), and the OPTUM™ Electronic Medical Records (EMR) database (from January 2007 through March 2016). Patients included in the assessment had 1) an index diagnosis of MM on or after 1 January 2007, 2) known gender, 3) medical prescription coverage in place at diagnosis, 4) a 1-year look-back period prior to the index diagnosis, 5) no prior malignancies in the 1-year period prior to index diagnosis, and 6) received ≥1 LOT. The analysis was limited to patients who did not receive stem cell transplantation at any time during their follow-up. Descriptive and logistic regression analyses were conducted to characterize and compare patients who received or did not receive a subsequent LOT. Results: The analysis included a total of 7,724 patients (1 LOT only: n = 3,906; 2+ LOT: n = 3,818). A summary of baseline patient characteristics and pre-existing comorbidities by LOT is summarized in Table 1. Patients who received a subsequent LOT vs those that did not were significantly younger (median age 72.0 vs 74.0 years; P <0.0001) and had significantly lower mean Charleston Comorbidity Index (CCI) score due to lower occurrence of renal, cardiac, and hepatic comorbidities (Table 1). Older age at diagnosis and presence of renal, congestive heart failure (CHF), hepatic, and pulmonary comorbidities were associated with higher attrition. The regimens used in frontline treatment included bortezomib/dexamethasone (26%), lenalidomide/dexamethasone (21%), bortezomib/lenalidomide/dexamethasone (11%), a bortezomib/alkylator ± steroid combination (6%), bortezomib monotherapy (10%), lenalidomide monotherapy (6%), thalidomide monotherapy (4%), and other (17%). The proportions of patients progressing to each subsequent line of therapy are shown in Table 2. In total, 49% of patients went on to receive a second line of therapy, and 55% of patients receiving a second line of therapy went on to receive a third line of therapy. The incidence of patients not receiving subsequent lines of therapy due to death or being lost to follow up by LOT is summarized in Table 2. Conclusions: A majority of non-transplant patients with NDMM in the study did not progress to subsequent lines of therapy, with attrition as high as 50% per line of therapy and only <8% of patients reaching LOT 5. This high level of attrition is associated with older age and poor comorbidity status of non-transplant patients with NDMM. Therefore, utilizing the most optimal regimens upfront (rather than reserving them for later lines) is warranted. Disclosures Fonseca: Mayo Clinic: Employment; Amgen: Consultancy. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Mehra:Janssen Global Services, LLC: Employment. Slavcev:Janssen Global Services, LLC: Employment. Ukropec:Janssen Scientific Affairs, LLC: Employment. Lam:Janssen Global Services, LLC: Employment. Potluri:SmartAnalyst Inc.: Employment.

Abstract Objective: To fully contextualize the benefit of novel agents such as daratumumab (DARA) monotherapy for the treatment of patients with heavily pre-treated and highly refractory multiple myeloma (MM), it is critical to understand the real-world outcomes of this patient population on current standard of care (SOC) therapies. The objective of this study was to perform adjusted comparisons to determine the comparative effectiveness of DARA monotherapy versus real-world SOC therapies. Methods: Data for patients treated with DARA 16 mg/kg monotherapy were available from clinical trials MMY2002 (n=106) and GEN501 (n=42), while patients treated with SOC therapies were derived from the International Myeloma Foundation (IMF) chart review of patients with MM who had ≥3 prior lines of therapy and were double refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) (n=543) (Kumar et al., ASH 2016; submitted). The pooled DARA studies demonstrated a median overall survival (OS) of 20.1 months versus 13.0 months for SOC based on the IMF cohort (Usmani et al., Blood 2016; Kumar et al., ASH 2016; submitted). The relative treatment effect of DARA versus SOC was estimated using two adjusted comparison methodologies, propensity score matching (PSM) and multivariate Cox regression analyses. Both methodologies utilized individual patient data to compare OS. Modeled covariates for the PSM were age, gender, prior lines of therapy, albumin, and refractory status to bortezomib (BOR), carfilzomib (CAR), lenalidomide (LEN), and pomalidomide (POM). PSM was performed using caliper matching with a caliper width 25% of the standard deviation of the logit-transformed propensity score, using sampling without replacement. For the regression analysis, the covariates included in the multivariate proportional hazards regression model were age, gender, prior lines of therapy, albumin, beta-2 microglobulin, prior exposure to POM and CAR, and PI/IMiD refractory status. Clustering of observations at the treatment-line level within patients was controlled for using the robust sandwich estimate for the covariance matrix, making confidence intervals (CIs) more conservative. For both PSM and regression, statistical significance testing was performed using a two-tailed p-value of <0.05, and all comparisons between treatment groups were reported with hazard ratios (HRs) and 95% CIs. Results: Prior to PSM, imbalances between the DARA and SOC groups were significant for prior lines of therapy and proportions of patients refractory to POM, CAR, BOR, and LEN. After PSM, the DARA and SOC groups were well balanced for all covariates included in propensity score calculations. After PSM, comparisons found significant improvement in favor of DARA relative to SOC for OS (HR=0.44 [95% CI 0.31-0.63]) (Figure 1). Regression analyses revealed consistent results. After adjustment for differences in all covariates included in regression between the DARA and SOC groups, results showed significant improvement in favor of DARA compared with SOC for OS (HR=0.43 [95% CI 0.32-0.59]) (Figure 2). Conclusions: Findings from both PSM and regression analyses were consistent and suggest that DARA is associated with significant gains in OS compared with SOC therapies for patients with heavily pre-treated and highly refractory MM. References: 1. Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A et al. (2016) Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood 128 (1): 37-44. 2. Kumar SK, et al. (2016) Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. The 58th Annual Meeting of the American Society of Hematology: submitted. Disclosures Kumar: Celgene: Consultancy, Research Funding; Noxxon: Consultancy, Honoraria; Janssen: Research Funding; AbbVie: Research Funding; BMS: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Consultancy, Honoraria. Durie:Amgen: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Su:Janssen: Research Funding. Diels:Johnson & Johnson: Employment, Equity Ownership. Hutton:Essai Canada: Consultancy; Cornerstone Research Group: Consultancy; Janssen: Research Funding. Lam:Janssen: Employment. Tetsuro:Johnson & Johnson: Equity Ownership; Janssen: Employment.