Combination of Peri- and Intratumoral Radiomic Features on Baseline CT Scans Predicts Response to Chemotherapy in Lung Adenocarcinoma.

PURPOSE: To identify the role of radiomics texture features both within and outside the nodule in predicting (a) time to progression (TTP) and overall survival (OS) as well as (b) response to chemotherapy in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Data in a total of 125 patients who had been treated with pemetrexed-based platinum doublet chemotherapy at Cleveland Clinic were retrospectively analyzed. The patients were divided randomly into two sets with the constraint that there were an equal number of responders and nonresponders in the training set. The training set comprised 53 patients with NSCLC, and the validation set comprised 72 patients. A machine learning classifier trained with radiomic texture features extracted from intra- and peritumoral regions of non-contrast-enhanced CT images was used to predict response to chemotherapy. The radiomic risk-score signature was generated by using least absolute shrinkage and selection operator with the Cox regression model; association of the radiomic signature with TTP and OS was also evaluated. RESULTS: A combination of radiomic features in conjunction with a quadratic discriminant analysis classifier yielded a mean maximum area under the receiver operating characteristic curve (AUC) of 0.82 ± 0.09 (standard deviation) in the training set and a corresponding AUC of 0.77 in the independent testing set. The radiomics signature was also significantly associated with TTP (hazard ratio [HR], 2.8; 95% confidence interval [CI]: 1.95, 4.00; P < .0001) and OS (HR, 2.35; 95% CI: 1.41, 3.94; P = .0011). Additionally, decision curve analysis demonstrated that in terms of clinical usefulness, the radiomics signature had a higher overall net benefit in prediction of high-risk patients to receive treatment than the clinicopathologic measurements. CONCLUSION: This study suggests that radiomic texture features extracted from within and around the nodule on baseline CT scans are (a) predictive of response to chemotherapy and (b) associated with TTP and OS for patients with NSCLC.© RSNA, 2019Supplemental material is available for this article.

Post-treatment changes in hematological parameters predict response to nivolumab monotherapy in non-small cell lung cancer patients.

BACKGROUND: The absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count (AMC) and neutrophil to lymphocyte ratio (NLR) are known markers of inflammation. We evaluated whether ANC, ALC, AMC and NLR, both before and after treatment with nivolumab, are indicative markers of overall survival (OS) and evaluated change in NLR as a predictive marker of response in non -small cell lung cancer (NSCLC) patients treated with nivolumab. METHODS: A total of 109 patients with advanced NSCLC treated with nivolumab were included. ANC, ALC, AMC and NLR were examined at initiation of nivolumab therapy and after two cycles. The prognostic role of ANC, ALC, AMC and NLR with OS and changes in NLR ratio were examined with Kaplan-Meier curves and proportional hazard model. RESULT: Post-treatment NLR ≥5 after two cycles of nivolumab was associated with poor OS (median OS in NLR = <5 vs NLR = ≥5 was 29.1 (16.2-40.9) vs 24.2(16.1-36.2) months respectively, p<0.001). In addition NLR increased in non-responders after two cycles of nivolumab by 6.6±21.8 as compared to responders (p = 0.027). CONCLUSIONS: Post-treatment ANC, ALC and NLR are independent prognostic factors in NSCLC patients treated with nivolumab. Changes in NLR can be an early biomarker for response in NSCLC patients treated with nivolumab.

Premature Clinical Trial Discontinuation in the Era of Immune Checkpoint Inhibitors.

BACKGROUND: Clinical trial completion is critical for new cancer therapies. Premature trial termination or withdrawal is common and impairs progress. We assessed factors of early terminated/withdrawn oncology trials focusing on trials with immune checkpoint inhibitors (ICI), hypothesizing that the latter may be associated with lower rates of premature discontinuation. MATERIALS AND METHODS: We reviewed all adult, intervention, oncology trials registered in ClinicalTrials.gov (November 16, 2011, to April 16, 2015) to identify all terminated/withdrawn trials and reasons for termination. Logistics regression model was used to identify factors associated with early termination/withdrawal. Discontinuation rate was compared in trials with and without ICI. RESULTS: We identified 12,875 trials (35% industry funded, 12% federal funded), of which 8.5% were prematurely terminated (5%) or withdrawn (3.5%); the main reasons were poor accrual (33%) and logistical (24%). ICI trials (n = 350) had a nonsignificant lower rate of termination or withdrawal compared with all other oncology trials (5.4% vs. 8.5%; p = .9) and were less likely to discontinue due to poor accrual (nonsignificant difference: 21% vs. 33%; p = .4). ICI trials were also less likely to discontinue compared with all other oncology drug trials (e.g., chemotherapy, targeted inhibitors, antiangiogenesis, biologics; 5.4% vs. 7.9%, respectively, nonsignificant difference). The 4-year cumulative incidence of failing to complete for reasons unrelated to toxicity or efficacy was 18% (95% confidence interval 16%-20%). There was no association between annual incidence across different tumor types or accrual goal and rate of trial termination. CONCLUSION: Poor accrual represents the main cause of early cancer trial termination. Premature termination/withdrawal rate was not significantly lower in ICI compared with other trials. Clinical trial completion remains a high priority and can be influenced by provider and patient factors. IMPLICATIONS FOR PRACTICE: Clinical trial completion is critical for new cancer therapies. Premature trial termination or withdrawal is common and impairs progress. This study assessed factors of early terminated/withdrawn oncology trials, focusing on trials with immune checkpoint inhibitors (ICI), and found that poor accrual represents the main cause of early cancer trial termination. Premature termination/withdrawal rate was not significantly lower in immune checkpoint inhibitor trials compared to other trials. The discussion herein is focused on measures taken by the National Cancer Institute and other institutions to improve clinical trial accrual and prevent premature clinical trial discontinuation.

Dabrafenib in combination with trametinib in the treatment of patients with BRAF V600-positive advanced or metastatic non-small cell lung cancer: clinical evidence and experience.

Mutations in the BRAF oncogene are found in 2-4% of all non-small cell lung cancer (NSCLC) patients. The most common activating mutation present within the BRAF oncogene is associated with valine substitution for glutamate at position 600 (V600E) within the BRAF kinase. BRAF-targeted therapies are effective in patients with melanoma and NSCLC harboring BRAF V600E mutation. In both melanoma and NSCLC, dual inhibition of both BRAF and the downstream mitogen-activated protein kinase (MEK) improves response rates compared with BRAF inhibition alone. BRAF-MEK combination therapy (dabrafenib plus trametinib) demonstrated tolerability and efficacy in a recent phase II clinical trial and was approved by the European Medicines Agency and United States Food and Drug Administration for patients with stage IV NSCLC harboring BRAF V600E mutation. Here, in this review, we outline the preclinical and clinical data for BRAF and MEK inhibitor combination treatment for NSCLC patients with BRAF V600E mutation.

Safety and Efficacy of PD-1/PD-L1 Inhibitors in Treatment-Naive and Chemotherapy-Refractory Patients With Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis.

INTRODUCTION: Programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors show significant clinical activity in non-small-cell lung carcinoma (NSCLC). However, there is a relative lack of data on comparative efficacy of these drugs in the first-line setting versus chemotherapy-treated patients. We compared the efficacy and toxicity of these drugs in these 2 distinct groups of patients. MATERIALS AND METHODS: Electronic databases (PubMed-Medline, EMBASE, Scopus) and major conference proceedings were systematically searched for all phase I to III clinical trials in NSCLC using PD-1/PD-L1 inhibitors. Objective response rate (ORR) and progression-free survival (PFS) data were collected and combined using DerSimonian and Laird random effects model meta-analysis. The I2 statistic was used to assess heterogeneity. RESULTS: Seventeen distinct trials (8 with treatment-naive patients [n = 937]; 14 with chemotherapy-treated patients [n = 3620]; 5 with separate treatment-naive and previously treated arms) were included. Treatment-naive patients had a statistically significant higher ORR (30.2%; 95% confidence interval [CI], 22.70-38.2) than patients previously treated with chemotherapy (ORR, 20.1%; 95% CI, 17.5-22.9; P = .02). No significant differences in PFS were observed between the 2 groups. Treatment-naive patients had statistically significant higher rates of all grade pneumonitis compared with previously treated patients (4.9%; 95% CI, 3.4-6.7 vs. 3.0%; 95% CI, 2.0-4.1; P = .04); however, no significant differences in any other immune-related adverse events were observed. CONCLUSION: PD-1/PD-L1 inhibitor therapy for advanced NSCLC has a significantly higher ORR and a higher rate of immune-mediated pneumonitis when used in the first-line setting compared with chemotherapy treated patients.

Incidence of Pneumonitis With Use of Programmed Death 1 and Programmed Death-Ligand 1 Inhibitors in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Trials.

BACKGROUND: Programmed death 1 (PD-1) programmed death-ligand 1 (PD-L1) inhibitors show significant clinical activity in non-small cell lung carcinoma (NSCLC). However, they are often associated with potentially fatal immune-mediated pneumonitis. Preliminary reports of trials suggest a difference in the rate of pneumonitis with PD-1 and PD-L1 inhibitors. We sought to determine the overall incidence of pneumonitis and differences according to type of inhibitors and prior chemotherapy use. METHODS: MEDLINE, Embase, and Scopus databases were searched up to November 2016. Rates of pneumonitis of any grade and grade ≥ 3 from all clinical trials investigating nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab as single agents in NSCLC were collected. The incidence of pneumonitis across trials was calculated using DerSimonian-Laird random effects models. We compared incidences between PD-1 and PD-L1 inhibitors and between treatment naive and previously treated patients. RESULTS: Nineteen trials (12 with PD-1 inhibitors [n = 3,232] and 7 with PD-L1 inhibitors [n = 1,806]) were identified. PD-1 inhibitors were found to have statistically significant higher incidence of any grade pneumonitis compared with PD-L1 inhibitors (3.6%; 95% CI, 2.4%-4.9% vs 1.3%; 95% CI, 0.8%-1.9%, respectively; P = .001). PD-1 inhibitors were also associated with higher incidence of grade 3 or 4 pneumonitis (1.1%; 95% CI, 0.6%-1.7% vs 0.4%; 95% CI, 0%-0.8%; P = .02). Treatment naive patients had higher incidence of grade 1 through 4 pneumonitis compared with previously treated patients (4.3%; 95% CI, 2.4%-6.3% vs 2.8%; 95% CI, 1.7%- 4%; P = .03). CONCLUSIONS: There was a higher incidence of pneumonitis with use of PD-1 inhibitors compared with PD-L1 inhibitors. Higher rate of pneumonitis was more common in treatment naive patients.

Reporting Compliance of Stroke Trials: Cross-Sectional Analysis.

BACKGROUND: The FDA mandates timely reporting of all clinical trials conducted in the United States. However, often the results are not reported in a timely manner, resulting in wastage of finite resources. We assessed the reporting of results of completed stroke trials and compared the reporting trends between U.S. and non-U.S. stroke trials. METHODS: We assessed consecutive clinical stroke trials registered as completed in ClinicalTrials.gov between January 1, 2008 and January 1, 2015. Descriptive data collected included study phase, study type, participant age, number of enrolled patients, study locations, start and primary completion dates, result availability, time to reporting (months), sponsorship, funding sources, and publication status. We also performed manual search for stroke trials in Pubmed, Web of Science, and Google scholar. RESULTS: Out of a total 140 completed trials, 39 trials (35,359 patients) involved at least 1 U.S. center and 101 trials (58,542 patients) were conducted in non-U.S. centers. Of the trials involving at least a single U.S. center, 31 of 39 (79%) reported their results, whereas only 6 of 31 (19%) reported their results within 1 year. Of the trials conducted at non-U.S. centers, 72 of 101 (71%) reported their results, whereas results for 24 of 72 (33%) trials were available within a year of completion. The time to reporting of results was significantly lower for all the included clinical trials in the 2012-2014 period (P < .001, Cohen's d = .726) as compared to the 2008-2011 period. CONCLUSION: Only one-fifth of completed stroke trials involving at least a single U.S. center report their results within 1 year. Additionally, every fifth completed trial involving stroke patients at U.S. centers remain unreported.

A case of crizotinib-induced esophageal ulcers.

We report a case of crizotinib-induced esophageal ulcers in a 45-year-old woman with metastatic anaplastic lymphoma kinase-positive non-small-cell lung cancer after 10 weeks of therapy. Endoscopic and pathologic findings were consistent with active inflammation with mid-esophageal ulceration and consistent with drug-induced esophagitis. Crizotinib was held and had a complete clinical and radiographic resolution of her symptoms. Patient was started on treatment with another anaplastic lymphoma kinase-targeted agent alectinib and has been tolerating it well without evidence of recurrence of esophagitis.

Programmed Cell Death 1 (PD-1) Ligand (PD-L1) Expression in Solid Tumors As a Predictive Biomarker of Benefit From PD-1/PD-L1 Axis Inhibitors: A Systematic Review and Meta-Analysis.

PURPOSE: Drugs targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway show significant clinical activity across several tumor types. However, a majority of patients do not respond to these agents. Use of biomarker assays to predict response to these agents is an active area of research; however, the predictive value of PD-L1 immunohistochemistry (IHC) assays is largely inconsistent across clinical trials. In this meta-analysis of clinical trials of PD-1/PD-L1-targeted agents, we evaluate the predictive value of a tumor and tumor-infiltrating immune cell PD-L1 IHC assay as a biomarker for objective response to PD-1/PD-L1 inhibitors. METHODS: We searched databases (PubMed, Medline, ASCO abstracts, European Society for Medical Oncology abstracts, and Scopus) up until December 2016 for clinical trials using PD-1/PD-L1 inhibitors with reported PD-L1 biomarker data. Objective response rates (primary end point) from all phase I to III trials investigating nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab in advanced solid tumors were collected. Odds ratios (ORs) for response in PD-L1-positive patients compared with PD-L1-negative patients were calculated using the DerSimonian-Laird random effects model to combine trials. We performed meta-analysis as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Forty-one distinct trials with 6,664 patients were identified. PD-L1 expression was predictive of favorable response across all tumor types (OR, 2.26; 95% CI, 1.85 to 2.75; P < .001), with the significantly largest effect observed in non-small-cell lung cancer (OR, 2.51; 95% CI, 1.99 to 3.17; P < .001). A subgroup analysis across all non-small-cell lung cancer trials using nivolumab and Dako clone 28-8 (Dako, Carpinteria, CA) IHC antibody assay yielded a significantly higher objective response rate in patients with tumor PD-L1 expression even at the minimum cutoff value of 1% (OR, 2.17; 95% CI, 1.03 to 4.57). CONCLUSION: Our meta-analysis shows that tumor and tumor-infiltrating immune cell PD-L1 overexpression based on IHC is associated with significantly higher response rates to PD-1/PD-L1 axis inhibitors across a range of malignant solid tumors.

Interaction of incidental microbleeds and prior use of antithrombotics with early hemorrhagic transformation: Causative or protective?

BACKGROUND: Gradient echo (GRE) sequence of magnetic resonance imaging (MRI) is a sensitive tool to detect hemorrhagic transformation (HT) and old cerebral microbleeds (CMBs). Presence of CMBs and prior use of antithrombotics pose a risk of HT in ischemic stroke. We evaluated the association of CMBs and antithrombotic use with resultant HT in acute ischemic stroke (AIS). METHODS: This retrospective study included AIS patients admitted to our center between January 2009 and August 2010 who underwent GRE-weighted MRI within 48 h of admission. Demographic and clinical data including diabetes mellitus, hypertension, hyperlipidemia, prior intake of antiplatelets/anticoagulants/statins, and presence of CMBs at admission were collected and compared between patients who developed HT and those who did not. We did a multivariate analysis using logistic regression to assess the effect of CMBs and prior use of antithrombotic agents on the risk of development for early HT in ischemic stroke. RESULTS: Of 529 AIS patients, 81 (15%) were found to have HT during the initial hospital course. CMBs were found in only 9 of 81 patients (11%) with HT and in 40 out of remaining 448 patients (9%) who did not develop HT. The presence of CMBs was not associated with increased risk of HT (P = 0.53). However, prior use of antiplatelets (33% vs. 47% in the patients without HT, P = 0.02) was associated with decreased risk of HT in ischemic stroke. CONCLUSION: Presence of incidental CMBs was not associated with increased risk for early HT of an ischemic stroke. Interestingly, the prior intake of antiplatelets was found to be protective against HT of ischemic stroke.

Incidence of Thromboembolic Complications Within 30 Days of Electrical Cardioversion Performed Within 48 Hours of Atrial Fibrillation Onset.

OBJECTIVES: This study sought to compare the risk of thromboembolism after cardioversion within 48 h of atrial fibrillation (AF) onset in patients therapeutically versus not therapeutically anticoagulated. BACKGROUND: Although guidelines do not mandate anticoagulation for cardioversion within 48 h of AF onset, risk of thromboembolism in this group has been understudied. METHODS: Patients undergoing cardioversion within 48 h after AF onset were identified from a prospectively collected database and retrospectively reviewed to determine anticoagulation status and major thromboembolic events within 30 days of cardioversion. RESULTS: Among 567 cardioversions in 484 patients without therapeutic anticoagulation (mean CHA2DS2-VASc score, 2.3 ± 1.7), 6 had neurological events (1.06%), all in patients on aspirin alone. Among 898 cardioversions in 709 patients on therapeutic anticoagulation (mean CHA2DS2-VASc score, 2.6 ± 1.7; p = 0.017), 2 neurological events occurred (0.22%; OR: 4.8; p = 0.03), both off anticoagulation at the time of stroke. No thromboembolic events occurred in patients with CHA2DS2-VASc score <2 (p = 0.06) or in patients with postoperative AF. CONCLUSIONS: In patients with acute-onset AF, odds of thromboembolic complications were almost 5 times higher in patients without therapeutic anticoagulation at the time of cardioversion. However, no events occurred in post-operative patients and in those with CHA2DS2-VASc scores of <2, supporting the utility of accurate assessment of AF onset and risk stratification in determining the need for anticoagulation for cardioversion of AF <48 h in duration.

Dose-Response Relationship Between Physical Activity and Risk of Heart Failure: A Meta-Analysis.

BACKGROUND: Prior studies have reported an inverse association between physical activity (PA) and risk of heart failure (HF). However, a comprehensive assessment of the quantitative dose-response association between PA and HF risk has not been reported previously. METHODS AND RESULTS: Prospective cohort studies with participants >18 years of age that reported association of baseline PA levels and incident HF were included. Categorical dose-response relationships between PA and HF risk were assessed with random-effects models. Generalized least-squares regression models were used to assess the quantitative relationship between PA (metabolic equivalent [MET]-min/wk) and HF risk across studies reporting quantitative PA estimates. Twelve prospective cohort studies with 20 203 HF events among 370 460 participants (53.5% women; median follow-up, 13 years) were included. The highest levels of PA were associated with significantly reduced risk of HF (pooled hazard ratio for highest versus lowest PA, 0.70; 95% confidence interval, 0.67-0.73). Compared with participants reporting no leisure-time PA, those who engaged in guideline-recommended minimum levels of PA (500 MET-min/wk; 2008 US federal guidelines) had modest reductions in HF risk (pooled hazard ratio, 0.90; 95% confidence interval, 0.87-0.92). In contrast, a substantial risk reduction was observed among individuals who engaged in PA at twice (hazard ratio for 1000 MET-min/wk, 0.81; 95% confidence interval, 0.77-0.86) and 4 times (hazard ratio for 2000 MET-min/wk, 0.65; 95% confidence interval, 0.58-0.73) the minimum guideline-recommended levels. CONCLUSIONS: There is an inverse dose-response relationship between PA and HF risk. Doses of PA in excess of the guideline-recommended minimum PA levels may be required for more substantial reductions in HF risk.