Integrated multi-omics evaluation of 823 tumors from advanced renal cell carcinoma (RCC) patients identifies molecular subsets associated with differential clinical outcomes to angiogenesis blockade ...alone or with a checkpoint inhibitor. Unsupervised transcriptomic analysis reveals seven molecular subsets with distinct angiogenesis, immune, cell-cycle, metabolism, and stromal programs. While sunitinib and atezolizumab + bevacizumab are effective in subsets with high angiogenesis, atezolizumab + bevacizumab improves clinical benefit in tumors with high T-effector and/or cell-cycle transcription. Somatic mutations in PBRM1 and KDM5C associate with high angiogenesis and AMPK/fatty acid oxidation gene expression, while CDKN2A/B and TP53 alterations associate with increased cell-cycle and anabolic metabolism. Sarcomatoid tumors exhibit lower prevalence of PBRM1 mutations and angiogenesis markers, frequent CDKN2A/B alterations, and increased PD-L1 expression. These findings can be applied to molecularly stratify patients, explain improved outcomes of sarcomatoid tumors to checkpoint blockade versus antiangiogenics alone, and develop personalized therapies in RCC and other indications.
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•Genomics of 823 RCC tumors, including 134 sarcomatoid tumors, reveals 7 subtypes•Subtype specific angiogenesis, immune, metabolic, stromal, and cell-cycle profiles•Differential prevalence of PBRM1, KDM5C, CDKN2A/2B, and TP53 alterations in subsets•Differential outcomes to VEGF blockade alone or in combination with anti-PD-L1
Motzer et al. perform integrative multi-omics analyses of 823 renal cancer tumors from a randomized clinical trial. A robust molecular classification scheme, based on transcriptional and gene alteration profiles and differential clinical outcomes to VEGF blockade alone or in combination with anti-PD-L1, informs personalized treatment strategies and future therapeutic development in RCC.
Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade
, this has not been comprehensively evaluated in large randomized studies. Here we ...analyzed circulating pIL-8 and IL8 gene expression in peripheral blood mononuclear cells and tumors of patients treated with atezolizumab (anti-PD-L1 monoclonal antibody) from multiple randomized trials representing 1,445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma. High levels of IL-8 in plasma, peripheral blood mononuclear cells and tumors were associated with decreased efficacy of atezolizumab in patients with mUC and metastatic renal cell carcinoma, even in tumors that were classically CD8
T cell inflamed. Low baseline pIL-8 in patients with mUC was associated with increased response to atezolizumab and chemotherapy. Patients with mUC who experienced on-treatment decreases in pIL-8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNA sequencing of the immune compartment showed that IL8 is primarily expressed in circulating and intratumoral myeloid cells and that high IL8 expression is associated with downregulation of the antigen-presentation machinery. Therapies that can reverse the impacts of IL-8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors.
Atezolizumab (anti–programmed death-ligand 1) was approved in the USA, Europe, and elsewhere for treatment-naive and platinum-treated locally advanced/metastatic urothelial carcinoma (mUC).
To report ...efficacy and safety from an atezolizumab expanded access study.
This single-arm, open-label study enrolled 218 patients at 36 US sites. Key eligibility criteria included progression during/following ≥1 platinum-based chemotherapy for mUC or in perioperative setting (progression within 12 mo) and Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2.
Patients received atezolizumab1200mg intravenously every 3 wk until loss of clinical benefit, unacceptable toxicity, consent withdrawal, decision to discontinue, death, atezolizumab commercial availability, or study closure.
Key end points reported herein included Response Evaluation Criteria in Solid Tumors v1.1 objective response rate and duration, disease control rate (DCR; response or stable disease), and safety.
All patients received prior systemic therapy (68% mUC; 27% adjuvant; and 26% neoadjuvant). At baseline, 57% of 214 treated patients had ECOG PS ≥1, 19% had hemoglobin <10g/dl, and 25% had liver metastases. Median treatment duration was 9 wk (interquartile range IQR, 6–12 wk). Median follow-up duration was 2.3 mo (IQR, 1.6–3.4 mo) overall and 2.7 mo (IQR, 2.0–3.5 mo) in patients not known to have died. Seventeen of 114 evaluable patients (15%) had objective responses (16 ongoing at study termination). DCR was 49%. Treatment-related adverse events (mostly fatigue) occurred in 98 of 214 treated patients.
The benefit/risk profile of atezolizumab was consistent with that observed in previous studies, despite pretreatment and poor prognostic factors. These results suggest a potential role for atezolizumab in a broader patient range than typically eligible for phase 1–3 studies.
In this expanded access study, atezolizumab was active and tolerable in a range of patients with platinum-treated metastatic urothelial carcinoma.
In an expanded access study in platinum-treated advanced urothelial carcinoma, the benefit/risk profile of atezolizumab was consistent with previous trials despite a broader patient range than may be typical for phase 1–3 studies.
Regional disparities in the quality of stroke care Seabury, Seth, PhD; Bognar, Katalin, PhD; Xu, Yaping, MD, MPH ...
The American journal of emergency medicine,
09/2017, Letnik:
35, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Abstract Background and purpose There is widespread geographic variation in healthcare quality, but we often lack clear strategies for improving quality in underserved areas. This study characterized ...geographic disparities in stroke care quality to assess whether improved access to neurological services has the potential to bridge the care quality gap, particularly in terms of alteplase (rt-PA) administration. Methods This was a retrospective study using quality performance data from the 2015 Hospital Compare database linked to information on certification status from the Joint Commission and information on local access to neurological services from the Area Health Resources File. We used these data to compare stroke care quality according to geographic area, certification, and neurologist access. Results Non-metropolitan hospitals performed worse than metropolitan hospitals on all assessed stroke care quality measures. The most prevalent disparity occurred in the use of rt-PA for eligible patients (52.2% versus 82.7%, respectively). Certified stroke centers in every geographic designation provided higher quality of care, whereas large variation was observed among non-certified hospitals. Regression analyses suggested that improvements in hospital certification or access to neurologists were associated with absolute improvements of 44.9% and 21.3%, respectively, in the percentage of patients receiving rt-PA. Conclusions The large quality gap in stroke care between metropolitan and non-metropolitan areas could be at least partly addressed through improved procedural efforts by stroke center certification increasing the supply of neurological services, (i.e. through training and hiring new neurologists) or by adopting decision support systems such as telemedicine.
Atezolizumab can induce sustained responses in metastatic urothelial carcinoma. We report the results of IMvigor130, a phase 3 trial that compared atezolizumab with or without platinum-based ...chemotherapy versus placebo plus platinum-based chemotherapy in first-line metastatic urothelial carcinoma.
In this multicentre, phase 3, randomised trial, untreated patients aged 18 years or older with locally advanced or metastatic urothelial carcinoma, from 221 sites in 35 countries, were randomly assigned to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Patients received 21-day cycles of gemcitabine (1000 mg/m2 body surface area, administered intravenously on days 1 and 8 of each cycle), plus either carboplatin (area under the curve of 4·5 mg/mL per min administered intravenously) or cisplatin (70 mg/m2 body surface area administered intravenously) on day 1 of each cycle with either atezolizumab (1200 mg administered intravenously on day 1 of each cycle) or placebo. Group B patients received 1200 mg atezolizumab, administered intravenously on day 1 of each 21-day cycle. The co-primary efficacy endpoints for the intention-to-treat population were investigator-assessed Response Evaluation Criteria in Solid Tumours 1.1 progression-free survival and overall survival (group A vs group C) and overall survival (group B vs group C), which was to be formally tested only if overall survival was positive for group A versus group C. The trial is registered with ClinicalTrials.gov, NCT02807636.
Between July 15, 2016, and July 20, 2018, we enrolled 1213 patients. 451 (37%) were randomly assigned to group A, 362 (30%) to group B, and 400 (33%) to group C. Median follow-up for survival was 11·8 months (IQR 6·1–17·2) for all patients. At the time of final progression-free survival analysis and interim overall survival analysis (May 31, 2019), median progression-free survival in the intention-to-treat population was 8·2 months (95% CI 6·5–8·3) in group A and 6·3 months (6·2–7·0) in group C (stratified hazard ratio HR 0·82, 95% CI 0·70–0·96; one-sided p=0·007). Median overall survival was 16·0 months (13·9–18·9) in group A and 13·4 months (12·0–15·2) in group C (0·83, 0·69–1·00; one-sided p=0·027). Median overall survival was 15·7 months (13·1–17·8) for group B and 13·1 months (11·7–15·1) for group C (1·02, 0·83–1·24). Adverse events that led to withdrawal of any agent occurred in 156 (34%) patients in group A, 22 (6%) patients in group B, and 132 (34%) patients in group C. 50 (11%) patients in group A, 21 (6%) patients in group B, and 27 (7%) patients in group C had adverse events that led to discontinuation of atezolizumab or placebo.
Addition of atezolizumab to platinum-based chemotherapy as first-line treatment prolonged progression-free survival in patients with metastatic urothelial carcinoma. The safety profile of the combination was consistent with that observed with the individual agents. These results support the use of atezolizumab plus platinum-based chemotherapy as a potential first-line treatment option for metastatic urothelial carcinoma.
F Hoffmann-La Roche and Genentech.
A prognostic model for overall survival of post-platinum patients with metastatic urothelial carcinoma receiving PD-1/PD-L1 inhibitors is necessary as existing models were constructed in the ...chemotherapy setting.
Patient level data were used from phase I/II trials evaluating PD-L1 inhibitors following platinum based chemotherapy for metastatic urothelial carcinoma. The derivation data set consisted of 2 phase I/II trials evaluating atezolizumab (405). Two phase I/II trials that evaluated avelumab (242) and durvalumab (198) comprised the validation data sets. Cox regression analyses evaluated the association of candidate prognostic factors with overall survival. Stepwise selection was used to select an optimal model using the derivation data set. Discrimination and calibration were assessed in the avelumab and durvalumab data sets.
The 5 prognostic factors identified in the optimal model using the atezolizumab derivation data set were ECOG-PS (1 vs 0, HR 1.80, 95% CI 1.36-2.36), liver metastasis (HR 1.55, 95% CI 1.20-2.00), platelet count (HR 2.22; 95% CI 1.54-3.18), neutrophil-to-lymphocyte ratio (HR 1.94, 95% CI 1.57-2.40) and lactate dehydrogenase (HR 1.60, 95% CI 1.28-1.99). There was robust discrimination of survival between low, intermediate and high risk groups. The c-statistic was 0.692 in the derivation and 0.671 and 0.773 in the avelumab and durvalumab validation data sets, respectively. A web based interactive tool was developed to calculate the expected survival probabilities based on risk factors.
A validated 5-factor model has satisfactory prognostic performance for survival across 3 PD-L1 inhibitors to treat metastatic urothelial carcinoma after platinum therapy and may assist in stratification, interpreting and designing trials incorporating PD-1/PD-L1 inhibitors in the post-platinum setting.
Aims: To describe healthcare utilization and cost associated with the short-term and long-term complications of cystectomy among commercially insured bladder cancer patients in the United States.
...Materials and methods: This retrospective, observational cohort study evaluated adults with bladder cancer receiving a transurethral resection of bladder tumor followed by a partial or radical cystectomy procedure using U.S. administrative claims from the 2005-2015 IBM MarketScan Commercial and Medicare Supplemental databases. Bladder cancer patients were classified into two cohorts: partial cystectomy or radical cystectomy. Cystectomy complications were identified during the cystectomy admission, short-term period, and long-term period. Complication-related utilization and cost outcomes were reported in aggregate during the cystectomy admission and per patient per month (PPPM) during the short-term and long-term follow-up periods.
Results: Of 5136 patients who received a cystectomy, 488 (9.5%) received partial cystectomy and 4648 (90.5%) received radical cystectomy. The mean (SD) costs of complications during the cystectomy admission were $11,728 ($43,380) for radical cystectomy and $4657 ($25,668) for partial cystectomy. In the short-term period, PPPM complication-related healthcare costs were $638 $3793 for partial cystectomy and $2681 $14,705 for radical cystectomy. In the long-term period, PPPM complication-related healthcare costs were $544 $2580 for partial cystectomy and $1619 $7874 for radical cystectomy.
Conclusions: Cystectomy-related complications, especially with radical cystectomy, present a substantial financial burden to patients and payers immediately after surgery as well as in the long term. Targeted interventions which improve clinical outcomes but reduce substantial costs associated with cystectomy for bladder cancer are needed.
Men with metastatic castration-resistant prostate cancer (mCRPC) have limited treatment options after progressing on hormonal therapy and chemotherapy. Here, we evaluate the safety and efficacy of ...atezolizumab (anti-PD-L1) + radium-223 dichloride (radium-223) in men with mCRPC.
This phase Ib study evaluated atezolizumab + radium-223 in men with mCRPC and bone and lymph node and/or visceral metastases that progressed after androgen pathway inhibitor treatment. Following safety assessment of concurrent dosing, 45 men were randomized 1:1:1 to concurrent or one of two staggered dosing schedules with either agent introduced one cycle before the other. This was followed by a safety-efficacy expansion cohort (randomized 1:1:1). The primary endpoints were safety and objective response rate (ORR) by RECIST 1.1. Secondary endpoints included radiographic progression-free survival (rPFS), PSA responses, and overall survival (OS).
As of October 4, 2019, 44 of 45 men were evaluable. All 44 had ≥1 all-cause adverse event (AE); 23 (52.3%) had a grade 3/4 AE. Fifteen (34.1%) grade 3/4 and 3 (6.8%) grade 5 AEs were related to atezolizumab; none were related to radium-223. Confirmed ORR was 6.8% 95% confidence interval (CI), 1.4-18.7, median rPFS was 3.0 months (95% CI, 2.8-4.6), median PSA progression was 3.0 months (95% CI, 2.8-3.3), and median OS was 16.3 months (95% CI, 10.9-22.3).
This phase Ib study demonstrated that atezolizumab + radium-223, regardless of administration schedule, had greater toxicity than either drug alone, with no clear evidence of additional clinical benefit for patients with mCRPC and bone and lymph node and/or visceral metastases.
Despite the availability of results from multiple newer clinical trials and changing healthcare costs, the cost-effectiveness of recombinant tissue-type plasminogen activator (r-tPA) for treatment of ...acute ischemic stroke within 0 to 3 hours of symptom onset was last evaluated in 1998 for the United States Using current evidence, we evaluate the long-term cost-effectiveness of r-tPA administered 0 to 3 hours after acute ischemic stroke onset versus no r-tPA.
A disease-based decision model to project lifetime outcomes of patients after acute ischemic stroke by r-tPA treatment status from the US payer perspective was developed. Model inputs were derived from a recent meta-analysis of r-tPA trials, cohort studies, and health state preference studies. Cost data, inflated to 2013 dollars, were based on drug wholesale acquisition cost and the literature. To compare r-tPA to no r-tPA, we calculated incremental total direct costs, incremental quality-adjusted life years, and incremental cost-effectiveness ratios. We performed 1-way and probabilistic sensitivity analyses to evaluate uncertainty in the results.
r-tPA resulted in a gain of 0.39 quality-adjusted life years (95% confidence range, 0.16-0.66) on average per patient and a lifetime cost-saving of $25,000 (95% confidence range, -$42,500 to -$11,000) compared with no r-tPA. In probabilistic sensitivity analyses, r-tPA was dominant compared with no r-tPA in ≈100% of simulations. The model was sensitive to inputs for r-tPA efficacy, healthcare costs for disabled patients, mortality rates for disabled and nondisabled patients, and quality of life estimates.
Our analysis supports earlier economic evaluations that r-tPA is a cost-effective method to treat stroke. Appropriate use of r-tPA should be prioritized nationally.
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