In the FLAURA trial Japanese subset, osimertinib significantly improved median PFS versus standard-of-care (gefitinib) in patients with previously untreated EGFR (exon 19 deletion or L858R) ...mutation-positive advanced or metastatic NSCLC.
Abstract
Background
The FLAURA study was a multicenter, double-blind, Phase 3 study in which patients with previously untreated epidermal growth factor receptor mutation-positive advanced non-small-cell lung carcinoma were randomized 1:1 to oral osimertinib 80 mg once daily or standard-of-care (gefitinib 250 mg or erlotinib 150 mg, once daily) to compare safety and efficacy. In the overall FLAURA study, significantly better progression-free survival was shown with osimertinib versus standard-of-care.
Methods
Selected endpoints, including progression-free survival (primary endpoint), overall survival, objective response rate, duration of response and safety were evaluated for the Japanese subset of the FLAURA study.
Results
In Japan, 120 eligible Japanese patients were randomized to osimertinib (65 patients) or gefitinib (55 patients) treatment from December 2014 to June 2017. Median progression-free survival was 19.1 (95% confidence interval, 12.6, 23.5) and 13.8 (95% confidence interval, 8.3, 16.6) months with osimertinib and gefitinib, respectively (hazard ratio, 0.61; 95% confidence interval, 0.38, 0.99). Median overall survival was not reached in either treatment arm (data were immature). In the osimertinib and gefitinib arms, objective response rate was 75.4% (49/65) and 76.4% (42/55), and median duration of response from onset was 18.4 (95% confidence interval, not calculated) and 9.5 (95% confidence interval, 6.2, 13.9) months, respectively. The incidence of adverse events was similar in the two groups. The frequency of Grade ≥3 interstitial lung disease and pneumonitis in the two groups were the same (one patient).
Conclusions
As the first-line therapy, osimertinib showed significantly improved efficacy versus gefitinib in the Japanese population of the FLAURA study. No new safety concerns were raised.
Clinical trial registration
NCT02296125 (ClinicalTrials.gov)
The reliability and reproducibility of science are under scrutiny. However, a major cause of this lack of repeatability is not being considered: the wide sample-to-sample variability in the P value. ...We explain why P is fickle to discourage the ill-informed practice of interpreting analyses based predominantly on this statistic.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
To develop an image analysis technique that distinguishes pseudoprogression from true progression by analyzing tumour heterogeneity in T2-weighted images using topological descriptors of image ...heterogeneity called Minkowski functionals (MFs).
Using a retrospective patient cohort (n = 50), and blinded to treatment response outcome, unsupervised feature estimation was performed to investigate MFs for the presence of outliers, potential confounders, and sensitivity to treatment response. The progression and pseudoprogression groups were then unblinded and supervised feature selection was performed using MFs, size and signal intensity features. A support vector machine model was obtained and evaluated using a prospective test cohort.
The model gave a classification accuracy, using a combination of MFs and size features, of more than 85% in both retrospective and prospective datasets. A different feature selection method (Random Forest) and classifier (Lasso) gave the same results. Although not apparent to the reporting radiologist, the T2-weighted hyperintensity phenotype of those patients with progression was heterogeneous, large and frond-like when compared to those with pseudoprogression.
Analysis of heterogeneity, in T2-weighted MR images, which are acquired routinely in the clinic, has the potential to detect an earlier treatment response allowing an early change in treatment strategy. Prospective validation of this technique in larger datasets is required.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Consensus is lacking regarding the androgen receptor (AR) as a prognostic marker in breast cancer. The objectives of this study were to comprehensively review the literature on AR prognostication and ...determine optimal criteria for AR as an independent predictor of breast cancer survival.
AR positivity was assessed by immunostaining in two clinically validated primary breast cancer cohorts training cohort,
= 219; validation cohort,
= 418; 77% and 79% estrogen receptor alpha (ERα) positive, respectively. The optimal AR cut-point was determined by ROC analysis in the training cohort and applied to both cohorts.
AR was an independent prognostic marker of breast cancer outcome in 22 of 46 (48%) previous studies that performed multivariate analyses. Most studies used cut-points of 1% or 10% nuclear positivity. Herein, neither 1% nor 10% cut-points were robustly prognostic. ROC analysis revealed that a higher AR cut-point (78% positivity) provided optimal sensitivity and specificity to predict breast cancer survival in the training (HR, 0.41;
= 0.015) and validation (HR, 0.50;
= 0.014) cohorts. Tenfold cross-validation confirmed the robustness of this AR cut-point. Patients with ERα-positive tumors and AR positivity ≥78% had the best survival in both cohorts (
< 0.0001). Among the combined ERα-positive cases, those with comparable or higher levels of AR (AR:ERα-positivity ratio >0.87) had the best outcomes (
< 0.0001).
This study defines an optimal AR cut-point to reliably predict breast cancer survival. Testing this cut-point in prospective cohorts is warranted for implementation of AR as a prognostic factor in the clinical management of breast cancer.
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Epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) are the standard of care for non‐small‐cell lung cancer (NSCLC) patients harboring EGFR mutations. However, almost all ...patients develop resistance after approximately 1 y of treatment, with >50% of cases due to the T790M secondary mutation of the EGFR gene. A large global Phase III study (AURA3) demonstrated that osimertinib significantly prolonged progression‐free survival (PFS) over platinum‐doublet chemotherapy in patients with T790M‐positive NSCLC who had progressed on previous EGFR‐TKI therapy. However, it is not clear whether efficacy or safety of osimertinib in Japanese patients is similar to the overall population. We report a pre‐planned subgroup analysis of pooled Phase II data from the AURA Extension and AURA2 trials to investigate the efficacy and safety of osimertinib in Japanese patients. This study included 81 Japanese patients. Patients were administered 80 mg osimertinib orally once daily until disease progression. The main endpoints were objective response rate (ORR), PFS, and safety. The ORR was 63.6% and median PFS was 13.8 mo. Overall survival rate at 36 mo was 54.0%. The most common all‐cause adverse events (AEs) were rash (grouped term; 65.4%), diarrhea (51.9%), paronychia (grouped term; 49.4%), and dry skin (grouped term; 39.5%). Most AEs were grade 1‐2. Five patients (6.2%) developed interstitial lung disease, resulting in two deaths (2.5%). Osimertinib demonstrated favorable ORR and PFS in Japanese patients, similar to the overall population. Additionally, osimertinib has good efficacy and a manageable safety profile in Japanese patients with NSCLC who had acquired resistance due to the T790M mutation.
We investigated the efficacy and safety of osimertinib and report the results of a pre‐planned subgroup analysis of pooled Phase II data from the AURA Extension and AURA2 trials in 81 Japanese patients with T790M‐positive advanced NSCLC administered 80 mg osimertinib orally once daily until disease progression. The ORR, median PFS, and overall survival rate at 36 months were 63.6%, 13.8 months, and 54.0%, respectively, and the most common all‐cause AEs were rash (65.4%), diarrhea (51.9%), paronychia (49.4%), and dry skin (39.5%), with most AEs being grade 1‐2 (although five patients developed interstitial lung disease, resulting in two deaths). Osimertinib demonstrated favorable ORR and PFS in Japanese patients, good efficacy, and a manageable safety profile in Japanese patients with NSCLC who had acquired resistance due to the T790M mutation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Study Type – Therapy (systematic review)
Level of Evidence 1a
What’s known on the subject? and What does the study add?
Ureteric stents cause significant discomfort and this is probably related to ...ureteric smooth muscle spasm and trigonal irritation. Alpha‐adrenoceptor antagonists reduce smooth muscle activity and are already widely used in medical expulsive therapy to aid passage of ureteric calculi.
This meta‐analysis incorporating five randomized controlled trials provides evidence that alpha‐adrenoceptor antagonists reduce stent‐related pain and storage symptoms as assessed by the Ureteric Stent Symptoms Questionnaire (USSQ).
OBJECTIVES
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To evaluate the efficacy of α‐blockers with respect to improving stent‐related symptoms.
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Ureteric stents remain a source of marked discomfort and their placement is often required after certain ureteroscopic procedures or in the acute setting. This analysis identifies and reviews the several studies that have investigated the role of α‐blockers after stent placement.
MATERIALS AND METHODS
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Pubmed/Medline, EMBASE, CINAHL and Cochrane Library databases were scrutinized using standard MeSH headings.
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Randomized or controlled trials comparing α‐blockers with control or standard therapy were included.
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In all studies, patients completed the Ureteral Stent Symptom Questionnaire (USSQ).
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The study data were independently reviewed by two assessors.
RESULTS
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In total, five studies of varying quality were identified, including 461 patients receiving either tamsulosin or alfuzosin, or control.
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On meta‐analysis, all five studies showed a reduction in USSQ urinary symptom score and body pain scores. There was mean reduction of 8.4 (95% CI, 5.6–11.1) in the urinary symptom score and 7.2 (95% CI, 2.5–11.8) in the body pain score.
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In three studies, the numbers of patients experiencing stent related pain were stated: 45% (51/114) of patients receiving an α‐blocker experienced painful episodes within the follow‐up period defined for that study compared to 76% (88/116) in the control groups, which is equivalent to a relative risk of pain of 0.59 (95% confidence interval, 0.47–0.71).
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There were also reductions in other aspects of the USSQ, such as the general health score and sexual matters score, although these were not statistically significant or uniformly reported.
CONCLUSION
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There is evidence that α‐blockers provide an improvement in discomfort after placement of a ureteric stent.
Full text
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Retinoic acid receptor-alpha (RAR alpha) is a known estrogen target gene in breast cancer cells. The consequence of RAR alpha induction by estrogen was previously unknown. We now show that RAR alpha ...is required for efficient estrogen receptor-alpha (ER)-mediated transcription and cell proliferation. RAR alpha can interact with ER-binding sites, but this occurs in an ER-dependent manner, providing a novel role for RAR alpha that is independent of its classic role. We show, on a genome-wide scale, that RAR alpha and ER can co-occupy regulatory regions together within the chromatin. This transcriptionally active co-occupancy and dependency occurs when exposed to the predominant breast cancer hormone, estrogen--an interaction that is promoted by the estrogen-ER induction of RAR alpha. These findings implicate RAR alpha as an essential component of the ER complex, potentially by maintaining ER-cofactor interactions, and suggest that different nuclear receptors can cooperate for effective transcriptional activity in breast cancer cells.
Although aberrant methylation of key genes in the progression of colorectal neoplasia has been reported, no model-based analysis of the incremental changes through the intermediate adenoma stage has ...been described. In addition, the biological drivers for these methylation changes have yet to be defined. Linear mixed-effects modelling was used in this study to understand the onset and patterns of the methylation changes of SFRP2, IGF2 DMR0, H19, LINE-1 and a CpG island methylator phenotype (CIMP) marker panel, and they were correlated with DNA methyltransferase 3B (DNMT3B) levels of expression in a sample set representative of colorectal neoplastic progression.
Methylation of the above CpG islands was measured using quantitative pyrosequencing assays in 261 tissue samples. This included a prospective collection of 44 colectomy specimens with concurrent normal mucosa, adenoma and invasive cancer tissues. Tissue microarrays from a subset of 64 cases were used for immunohistochemical analysis of DNMT3B expression.
It is shown that the onset and pattern of methylation changes during colorectal neoplastic progression are locus dependent. The CIMP marker RUNX3 was the earliest CpG island showing significant change, followed by the CIMP markers NEUROG1 and CACNA1G at the hyperplastic polyp stage. SFRP2 and IGF2 DMR0 showed significant methylation changes at the adenomatous polyp stage, followed by the CIMP markers CDKN2A and hMLH1 at the adenocarcinoma stage. DNMT3B levels of immunohistochemical expression increased significantly (p < 0.001) from normal to hyperplastic and from adenomatous polyps to carcinoma samples. DNMT3B expression correlated positively with SFRP2 methylation (r = 0.42, p < 0.001, 95% CI 0.25 to 0.56), but correlated negatively with IGF2 DMR0 methylation (r = 0.26, p = 0.01, 95% CI -0.45 to -0.05). A subset of the CIMP panel (NEUROG1, CACNA1G and CDKN2A) positively correlated with DNMT3B levels of expression (p < 0.05).
Hierarchical epigenetic alterations occur at transition points during colorectal neoplastic progression. These cumulative changes are closely correlated with a gain of DNMT3B expression, suggesting a causal relationship.
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