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An assurance calculation is a Bayesian alternative to a power calculation. One may be performed to aid the planning of a clinical trial, specifically setting the sample size or to support decisions about whether or not to perform a study. Immuno-oncology is a rapidly evolving area in the development of anticancer drugs. A common phenomenon that arises in trials of such drugs is one of delayed treatment effects, that is, there is a delay in the separation of the survival curves. To calculate assurance for a trial in which a delayed treatment effect is likely to be present, uncertainty about key parameters needs to be considered. If uncertainty is not considered, the number of patients recruited may not be enough to ensure we have adequate statistical power to detect a clinically relevant treatment effect and the risk of an unsuccessful trial is increased. We present a new elicitation technique for when a delayed treatment effect is likely and show how to compute assurance using these elicited prior distributions. We provide an example to illustrate how this can be used in practice and develop open-source software to implement our methods. Our methodology has the potential to improve the success rate and efficiency of Phase III trials in immuno-oncology and for other treatments where a delayed treatment effect is expected to occur., (© 2024 The Author(s). Statistics in Medicine published by John Wiley & Sons Ltd.)

Introduction: Real-world evidence is receiving considerable attention as a way to evaluate the efficacy and safety of medical products for substance use disorders (SUDs). However, the feasibility of using real-world data (RWD) to emulate clinical trials evaluating treatments for SUDs is uncertain. The aim of this study is to identify the number of clinical trials evaluating treatments for SUDs with reported results that could be feasibly emulated using observational data from contemporary insurance claims and/or electronic health record (EHR) data., Methods: In this cross-sectional study, all phase 2-4 trials evaluating treatments for SUDs registered on ClinicalTrials.gov with reported results were identified. Each trial was evaluated to determine if the indications, interventions, at least 80% of eligibility criteria, comparators, and primary end points could be ascertained using contemporarily available administrative claims and/or structured EHR data., Results: There were 272 SUD trials on ClinicalTrials.gov with reported results. Of these, when examining feasibility using contemporarily available administrative claims and/or structured EHR data, 262 (96.3%) had indications that were ascertainable; 194 (71.3%) had interventions that were ascertainable; 21 (7.7%) had at least 80% of eligibility criteria that were ascertainable; 17 (6.3%) had active comparators that were ascertainable; and 61 (22.4%) had primary end points that were ascertainable. In total, there were no trials for which all 5 characteristics were ascertainable using contemporarily available administrative claims and/or structured EHR data. When considering placebo comparators as ascertainable, there were 6 (2.2%) trials that had all 5 key characteristics classified as ascertainable from contemporarily available administrative claims and/or structured EHR data., Conclusions: No trials evaluating treatments for SUDs could be feasibly emulated using contemporarily available RWD, demonstrating a need for an increase in the resolution of data capture within a public health system to facilitate trial emulation., (© 2024. The Author(s).)

The failure rates of phase 3 trials are high. Incorrect sample size due to uncertainty of effect size could be a critical contributing factor. Adaptive sequential design (ASD), which may include one or more sample size re-estimations (SSR), has been a popular approach for dealing with such uncertainties. The operating characteristics (OCs) of ASD, including the unconditional power and mean sample size, can be substantially affected by many factors, including the planned sample size, the interim analysis schedule and choice of critical boundaries and rules for interim analysis. We propose a systematic, comprehensive strategy which uses iterative simulations to investigate the operating characteristics of adaptive designs and help achieve adequate unconditional power and cost-effective mean sample size if the effect size is in a pre-identified range.

Background: The last years have seen unprecedented improvement in breast cancer (BC) survival rates. However, this entirely apply to female BC patients, since gender minorities (male, transgender/gender-diverse) are neglected in BC phase III registration clinical trials., Methods: We conducted a scoping review of phase III clinical trials of agents with a current positioning within the therapeutic algorithms of BC., Results: We selected 51 phase III trials. Men enrollment was allowed in 35.3% of trials. In none of the trial inclusion/exclusion criteria referred to transgender/gender-diverse people. A numerical higher rate of enrolled men was observed in the contemporary as compared to historical group. We found a statistically significant association between the drug class and the possibility of including men: 100%, 80%, 50%, 33.3%, 25%, 10% and 9.1% of trials testing ICI/PARP-i, ADCs, PI3K/AKT/mTOR-i, anti-HER2 therapy, CDK4/6-i, ET alone, and CT alone. Overall, 77409 patients were enrolled, including 112 men (0.2%). None of the trial reported transgender/gender-diverse people proportion. Studies investigating PARP-i were significantly associated with the highest rate of enrolled men (1.42%), while the lowest rates were observed for trials of CT (0.13%), ET alone (0.10%), and CDK 4/6-I (0.08%), p < 0.001., Conclusions: We confirmed that gender minorities are severely underrepresented among BC registration trials. We observed a lower rate of men in trials envisaging endocrine manipulation or in less contemporary trials. This work sought to urge the scientific community to increase the awareness level towards the issue of gender minorities and to endorse more inclusive criteria in clinical trials., Competing Interests: Declaration of competing interest FM reports personal fees from Roche, Novartis, Pfizer, Seagen, Gilead, Astrazeneca, Lilly, Menarini all outside the submitted work (all the disclosed activities are outside the submitted work). CDA reports advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Daiichi-Sankyo, Gilead, and GSK and speaker honoraria from Roche, Lilly, Novartis, Pfizer, Seagen, GSK, GILEAD, and Daiichi-Sankyo; travel Grants from Gilead and research support (to the Institution) from Novartis, GILEAD, and Daiichi-Sankyo outside the submitted work (all the disclosed activities are outside the submitted work). RC reports fees for talk or consultation from Novartis, Lilly, MSD, Gilead, Roche, Pfizer, Veracyte, Seagen, Astra Zeneca, Daichii Sankyo, Menarini, Pierre-Fabre (all the disclosed activities are outside the submitted work). EB has received grants or contracts from Astra-Zeneca, Roche and honoraria for lectures from Merck-Sharp & Dome, Astra-Zeneca, Pfizer, Eli-Lilly, Bristol-Myers Squibb, Novartis, Takeda and Roche; he has been member of Data Safety Monitoring Board or Advisory Board of Merck-Sharp & Dome, Pfizer, Novartis, Bristol-Myers Squibb, Astra-Zeneca, and Roche (all the disclosed activities are outside the submitted work). AV reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AndromedaE20, Oncotech; support for attending meetings and/or travel: Pierre Fabre, Lilly, Gilead, Seagen, Novartis, MSD, Menarini (all the disclosed activities are outside the submitted work). LDM reports institutional grants from Eli Lilly, Novartis, Roche, Daiichi Sankyo, Seagen, Astrazeneca, Gilead, Pierre Fabre; consulting fees: Eli Lilly, Gilead, Daiichi Sankyio; payment or honoraria for lectures, presentations, speakers bureaus: Roche, Novartis, Pfizer, Eli Lilly, Astrazeneca, MSD, Seagen, Gilead, Pierre Fabre, Eisai, Exact Sciences, Ipsen, GSK, Agendia, Stemline; support for attending meetings and/or travel: Roche, Pfizer, Eisai, Daiichi Sankyo, Astrazeneca, Gilead; Participation on a Data Safety Monitoring Board or Advisory Board: Novartis, Roche, Eli Lilly, Pfizer, Daiichi Sakyo, Exact Sciences, Gilead, Pierre Fabre, Eisai, Astrazeneca, Agendia, GSK, Seagen, Olema, MSD, Stemline Menarini (all the disclosed activities are outside the submitted work). FM reports consultancy fees from Roche, Novartis, AstraZeneca, Daiichy Sankyo, SeaGen, MSD, Eli Lilly, Pfizer, and Pierre Fabre, and Travel Grants from Roche and Astra Zeneca; from May 15th, 2023, FM is Roche employee (all the disclosed activities are outside the submitted work). VG reports personal fees for advisory board membership for AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Exact Sciences, Gilead, Merck Serono, MSD, Novartis, Pfizer, Olema Oncology, Pierre Fabre; personal fees as an invited speaker for AstraZeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, GSK, Novartis, Roche and Zentiva; personal fees for expert testimony for Eli Lilly. All the remaining authors have no conflict of interest to report., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Vaccine efficacy (VE) assessed in a randomized controlled clinical trial can be affected by demographic, clinical, and other subject-specific characteristics evaluated as baseline covariates. Understanding the effect of covariates on efficacy is key to decisions by vaccine developers and public health authorities., Methods: This work evaluates the impact of including correlate of protection (CoP) data in logistic regression on its performance in identifying statistically and clinically significant covariates in settings typical for a vaccine phase 3 trial. The proposed approach uses CoP data and covariate data as predictors of clinical outcome (diseased versus non-diseased) and is compared to logistic regression (without CoP data) to relate vaccination status and covariate data to clinical outcome., Results: Clinical trial simulations, in which the true relationship between CoP data and clinical outcome probability is a sigmoid function, show that use of CoP data increases the positive predictive value for detection of a covariate effect. If the true relationship is characterized by a decreasing convex function, use of CoP data does not substantially change positive or negative predictive value. In either scenario, vaccine efficacy is estimated more precisely (i.e., confidence intervals are narrower) in covariate-defined subgroups if CoP data are used, implying that using CoP data increases the ability to determine clinical significance of baseline covariate effects on efficacy., Conclusions: This study proposes and evaluates a novel approach for assessing baseline demographic covariates potentially affecting VE. Results show that the proposed approach can sensitively and specifically identify potentially important covariates and provides a method for evaluating their likely clinical significance in terms of predicted impact on vaccine efficacy. It shows further that inclusion of CoP data can enable more precise VE estimation, thus enhancing study power and/or efficiency and providing even better information to support health policy and development decisions., (© 2024. Merck & Co., Inc., Rahway, NJ, USA and its affiliates, Institute of Computer Science of the Czech Academy of Sciences.)

Background: Older patients are underrepresented in the clinical trials that determine the standards of care for oncological treatment. We conducted a review to identify whether there have been age-restrictive inclusion criteria in clinical trials over the last twenty five years, focusing on patients with metastatic gastroesophageal cancer., Methods: A search strategy was developed encompassing Embase, PubMed and The Cochrane Library databases. Completed phase III randomised controlled trials evaluating systemic anti-cancer therapies in metastatic gastroesophageal malignancies from 1st January 1995 to 18th November 2020 were identified. These were screened for eligibility using reference management software (Covidence; Veritas Health Innovation Ltd). Data including age inclusion/exclusion criteria and median age of participants were recorded. The percentage of patients ≥ 65 enrolled was collected where available. The change over time in the proportion of studies using an upper age exclusion was estimated using a linear probability model., Results: Three hundred sixty-three phase III studies were identified and screened, with 66 trials remaining for final analysis. The majority of trials were Asian (48%; n = 32) and predominantly evaluated gastric malignancies, (86%; n = 56). The median age of participants was 62 (range 18-94). Thirty-two percent (n = 21) of studies specified an upper age limit for inclusion and over half of these were Asian studies. The median age of exclusion was 75 (range 65-80). All studies prior to 2003 used an upper age exclusion (n = 12); whereas only 9 that started in 2003 or later did (17%). Among later studies, there was a very modest downward yearly-trend in the proportion of studies using an upper age exclusion (-0.02 per year; 95%CI -0.05 to 0.01; p = 0.31). Fifty-two percent (n = 34) of studies specified the proportion of their study population who were ≥ 65 years. Older patients represented only 36% of the trial populations in these studies (range 7-60%)., Conclusions: Recent years have seen improvements in clinical trial protocols, with many no longer specifying restrictive age criteria. Reasons for poor representation of older patients are complex and ongoing efforts are needed to broaden eligibility criteria and prioritise the inclusion of older adults in clinical trials., (© 2021. The Author(s).)

Background: Studies focusing on prediction models are widespread in medicine. There is a trend in applying machine learning (ML) by medical researchers and clinicians. Over the years, multiple ML algorithms have been adapted to censored data. However, the choice of methodology should be motivated by the real-life data and their complexity. Here, the predictive performance of ML techniques is compared with statistical models in a simple clinical setting (small/moderate sample size and small number of predictors) with Monte-Carlo simulations., Methods: Synthetic data (250 or 1000 patients) were generated that closely resembled 5 prognostic factors preselected based on a European Osteosarcoma Intergroup study (MRC BO06/EORTC 80931). Comparison was performed between 2 partial logistic artificial neural networks (PLANNs) and Cox models for 20, 40, 61, and 80% censoring. Survival times were generated from a log-normal distribution. Models were contrasted in terms of the C-index, Brier score at 0-5 years, integrated Brier score (IBS) at 5 years, and miscalibration at 2 and 5 years (usually neglected). The endpoint of interest was overall survival., Results: PLANNs original/extended were tuned based on the IBS at 5 years and the C-index, achieving a slightly better performance with the IBS. Comparison with Cox models showed that PLANNs can reach similar predictive performance on simulated data for most scenarios with respect to the C-index, Brier score, or IBS. However, Cox models were frequently less miscalibrated. Performance was robust in scenario data where censored patients were removed before 2 years or curtailing at 5 years was performed (on training data)., Conclusion: Survival neural networks reached a comparable predictive performance with Cox models but were generally less well calibrated. All in all, researchers should be aware of burdensome aspects of ML techniques such as data preprocessing, tuning of hyperparameters, and computational intensity that render them disadvantageous against conventional regression models in a simple clinical setting., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2021 Georgios Kantidakis et al.)

Background: The aim of the study was to estimate the minimally important difference (MID) for interpreting group-level change over time, both within a group and between groups, for the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) scores in patients with prostate cancer., Methods: We used data from two published EORTC trials. Clinical anchors were selected by strength of correlations with QLQ-C30 scales. In addition, clinicians' input was obtained with regard to plausibility of the selected anchors. The mean change method was applied for interpreting change over time within a group of patients and linear regression models were fitted to estimate MIDs for between-group differences in change over time. Distribution-based estimates were also evaluated., Results: Two clinical anchors were eligible for MID estimation; performance status and the CTCAE diarrhoea domain. MIDs were developed for 7 scales (physical functioning, role functioning, social functioning, pain, fatigue, global quality of life, diarrhoea) and varied by scale and direction (improvement vs deterioration). Within-group MIDs ranged from 4 to 14 points for improvement and - 13 to - 5 points for deterioration and MIDs for between-group differences in change scores ranged from 3 to 13 for improvement and - 10 to - 5 for deterioration., Conclusions: Our findings aid the meaningful interpretation of changes on a set of EORTC QLQ-C30 scale scores over time, both within and between groups, and for performing more accurate sample size calculations for clinical trials in prostate cancer., (© 2021. The Author(s).)

Objective: To assess the risk of hypertension in patients with migraine who received erenumab in clinical trials and in the postmarketing setting., Background: Erenumab is a monoclonal antibody for migraine prevention that targets the calcitonin gene-related peptide (CGRP) receptor. Hypertension is a theoretical risk for inhibitors of the CGRP pathway. Although no evidence of an association between erenumab treatment and hypertension was observed during the clinical development program, adverse events (AEs) of hypertension have been identified in the postmarketing setting., Methods: Safety data from four phase 2 and phase 3 clinical trials were used to perform a pooled analysis of hypertension AEs in patients with migraine receiving erenumab. Postmarketing AEs of hypertension were identified from the Amgen Global Safety database from May 17, 2018, through January 31, 2020., Results: In the pooled analysis of clinical trials, hypertension AEs (placebo, 9/1043 [0.9%]; erenumab 70 mg, 7/893 [0.8%]; erenumab 140 mg, 1/507 [0.2%]) and percentage of patients initiating medication to treat hypertension (12/1043 [1.2%], 7/893 [0.8%], 1/507 [0.2%], respectively) were similar across treatment groups. A total of 362 AEs of hypertension were identified from the postmarketing setting, 26.2% (95/362) of which were serious, >245,000 patient-years of exposure. The exposure-adjusted incidence of hypertension was 0.144 per 100 patient-years., Conclusions: Clinical trials did not demonstrate an increased risk of hypertension with erenumab compared with placebo, and AE rates of hypertension reported with erenumab in the postmarketing setting were generally low. Additional data are needed to fully characterize the extent to which hypertension is a risk associated with erenumab., (© 2021 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Importance: The results of numerous large randomized clinical trials (RCTs) have changed clinical practice in gastric cancer (GC). However, research waste (ie, unpublished data, inadequate reporting, or avoidable design limitations) is still a major challenge for evidence-based medicine., Objectives: To determine the characteristics of GC RCTs in the past 20 years and the presence of research waste and to explore potential targets for improvement., Design, Setting, and Participants: In this cross-sectional study of GC RCTs, ClinicalTrials.gov was searched for phase 3 or 4 RCTs registered from January 2000 to December 2019 using the keyword gastric cancer. Independent investigators undertook assessments and resolved discrepancies via consensus. Data were analyzed from August through December 2020., Main Outcomes and Measures: The primary outcomes were descriptions of the characteristics of GC RCTs and the proportion of studies with signs of research waste. Research waste was defined as unpublished data, inadequate reporting, or avoidable design limitations. Publication status was determined by searching PubMed and Scopus databases. The adequacy of reporting was evaluated using the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline checklist. Avoidable design limitations were determined based on existing bias or lack of cited systematic literature reviews. In the analyses of research waste, 125 RCTs that ended after June 2016 without publication were excluded., Results: A total of 262 GC RCTs were included. The number of RCTs increased from 25 trials in 2000 to 2004 to 97 trials in 2015 to 2019, with a greater increase among RCTs of targeted therapy or immunotherapy, which increased from 0 trials in 2000 to 2004 to 36 trials in 2015 to 2019. The proportion of RCTs that were multicenter was higher in non-Asian regions than in Asian regions (50 of 71 RCTs [70.4%] vs 96 of 191 RCTs [50.3%]; P = .004). The analysis of research waste included 137 RCTs, of which 81 (59.1%) were published. Among published RCTs, 65 (80.2%) were judged to be adequately reported and 63 (77.8%) had avoidable design defects. Additionally, 119 RCTs (86.9%) had 1 or more features of research waste. Study settings that included blinding (odds ratio [OR], 0.56; 95% CI, 0.33-0.93; P = .03), a greater number of participants (ie, ≥200 participants; OR, 0.07; 95% CI, 0.01-0.51; P = .01), and external funding support (OR, 0.22; 95% CI, 0.08-0.60; P = .004) were associated with lower odds of research waste. Additionally, 35 RCTs (49.3%) were referenced in guidelines, and 18 RCTs (22.2%) had their prospective data reused., Conclusions and Relevance: To our knowledge, this study is the first to describe the characteristics of GC RCTs in the past 20 years, and it found a research waste burden, which may provide evidence for the development of rational RCTs and reduction of waste in the future.

The quality and reporting of neuroendocrine tumour (NET) clinical trials has previously been found to be heterogeneous impairing trial interpretability. We aimed to perform an updated review of the quality of phase II/III clinical trials in NET to assess if trial design and reporting have improved since 2011. We performed a PubMed search for phase II/III trials evaluating systemic anticancer therapies or liver-directed therapies published between 2011 and 2018. Data collected comprised administrative data, study population characteristics, endpoints, reporting and statistical design parameters, and results. Sixty studies were included (5218 patients): 50 phase II and 10 phase III trials. Study populations were heterogeneous: 52% of trials allowed tumours from various primary sites, 28% allowed both well- and poorly-differentiated tumour morphology or did not specify, and 57% did not report proliferative indices and/or tumour grade in ≥80% of the study population. Only 36% of trials mandated radiological disease progression on participant enrolment using a validated measure. Statistical design and primary endpoint were clearly defined in 67% and 88% of trials, respectively. Toxicity (88%), radiological response rate (85%) and progression-free survival/time to progression (82%) were well reported in a majority of trials, but health-related quality of life was included in the minority. Of the randomised trials (n = 11), study populations were more homogeneous and study design was more often clearly defined; however, only 45% mandated radiological progression at baseline as measured per Response Evaluation Criteria In Solid Tumours, and reporting of health-related quality of life (55%) remained suboptimal. The design and reporting of NET clinical trials, predominantly of single-arm phase II trials, remains suboptimal and has not considerably improved over time despite the growth in our knowledge of the biology and unique characteristics of NETs. Higher quality is seen in randomised trials, although certain design and reporting elements remain inadequate in some studies. We must prioritise the design and conduct of NET clinical trials to effectively inform future research and guide practice change., (© 2021 British Society for Neuroendocrinology.)

Treatment benefit in multiple myeloma (MM) patients with high-risk cytogenetics remains suboptimal. The phase 3 ICARIA-MM trial (NCT02990338) showed that isatuximab plus pomalidomide-dexamethasone prolongs median progression-free survival (mPFS) in patients with relapsed/refractory MM (RRMM). This subgroup analysis of ICARIA-MM compared the benefit of isatuximab in high-risk [defined by the presence of del(17p), t(4;14) or t(14;16)] versus standard-risk patients. The efficacy of isatuximab in patients with gain(1q21) abnormality was also assessed in a retrospective subgroup analysis. In ICARIA-MM, 307 patients received isatuximab-pomalidomide-dexamethasone (n = 154) or pomalidomide-dexamethasone (n = 153). Isatuximab (10 mg/kg intravenously) was given weekly in the first 28-day cycle, and every other week thereafter. Standard pomalidomide-dexamethasone doses were given. Isatuximab-pomalidomide-dexamethasone improved mPFS (7·5 vs 3·7 months; HR, 0·66; 95% CI, 0·33-1·28) and overall response rate (ORR, 50·0% vs 16·7%) in high-risk patients. In patients with isolated gain(1q21), isatuximab addition improved mPFS (11·2 vs 4·6 months; HR, 0·50; 95% CI, 0·28-0·88) and ORR (53·6% vs 27·6%). More grade ≥3 adverse events occurred in high-risk patients receiving isatuximab (95·7%) versus the control group (67·6%); however, isatuximab did not increase events leading to discontinuation or treatment-related mortality. Isatuximab-pomalidomide-dexamethasone provides a consistent benefit over pomalidomide-dexamethasone treatment in RRMM patients regardless of cytogenetic risk., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Aims: To evaluate efficacy and safety of Gla-300 with Gla-100 in a patient-level meta-analysis among large East Asian patients with type 2 diabetes mellitus (T2DM)., Methods: A patient level meta-analysis of three EDITION studies with similar design and endpoints were conducted over 6-months treatment period. The analysis included 547 patients treated with Gla-300 and 348 patients treated with Gla-100., Results: Over 6-month treatment period, mean change in HbA1c was similar for Gla-300 [Least square (LS) mean, (SE): -1.13 (0.05) % and Gla-100: -1.14 (0.05) %], showing non-inferiority of Gla-300 to Gla-100 (LS mean difference: 0.02%, 95% CI: -0.08 to 0.11). Gla-300 was associated with reduced risk of hypoglycemic event (confirmed ≤ 3.9 mmol/L or severe) vs Gla-100 at any time of day or at night (00:00-05:59 h). The event rates of hypoglycemia were consistently lower with Gla-300 than Gla-100. Severe hypoglycemia was rare in both treatment groups. Weight gain was minimal in both treatment groups., Conclusion: Gla-300 provides comparable glycemic control to Gla-100 in East Asian patients with broad clinical spectrum of T2DM, with consistently less hypoglycemia at any time of the day and night., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. L.J. reports receiving consulting and lecture fees from Eli Lilly, Bristol-Myers Squibb, Novartis, Novo Nordisk, Merck, Bayer, Takeda, Sanofi, Roche and Boehringer Ingelheim and research grants from Roche and Sanofi. Y.B. reports receiving lecture fees from Eli Lilly, Bristol-Myers Squibb, Novartis, Novo Nordisk, Merck, Bayer, Sanofi, Roche and Boehringer Ingelheim. S.Y. has no conflicts of interests. Y.H., X.Z., S.S, N.C., H.Y. and M.Z. are employees of Sanofi., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The real impact of bevacizumab maintenance as single agent in metastatic colorectal cancer (mCRC) remains unclear. SAKK-41/06 and PRODIGE-9 failed to demonstrate the non-inferiority and superiority of bevacizumab versus no maintenance, respectively, while AIO-KRK-0207 showed the non-inferiority of maintenance bevacizumab versus bevacizumab and fluoropyrimidines for time to strategy failure., Methods: Bibliography electronic databases (PubMed, MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials) were searched for English published clinical trials prospectively randomizing mCRC patients to receive bevacizumab maintenance or not after first-line chemotherapy plus bevacizumab. Individual patients' data (IPD) were provided by investigators for all included trials. Primary end-points were progression-free survival (PFS) and overall survival (OS), both from the start of induction and maintenance. Univariate and multivariate analyses for PFS and OS were performed., Results: Three phase III studies - PRODIGE-9, AIO-KRK-0207 and SAKK-41/06 - were included. Considering the different timing of randomization, IPD of patients not progressed during induction and starting maintenance phase entered the analysis. 909 patients were included, 457 (50%) received bevacizumab maintenance. Median PFS from induction start was 9.6 and 8.9 months in bevacizumab group versus no maintenance group, respectively (HR 0.78; 95%CI: 0.68-0.89; p < 0.0001). Subgroups analysis for PFS showed a significant interaction according for RAS status (p = 0.048), with a maintenance benefit limited to RAS wild-type patients. No difference in terms of OS was observed., Conclusions: Despite the statistically significant PFS improvement for bevacizumab maintenance, the absolute benefit appears limited. Subgroup analysis shows a differential effect of bevacizumab maintenance in favor of RAS wild-type patients. Considering these results, maintenance therapy with fluoropyrimidine with or without bevacizumab remains the first option. Single agent bevacizumab maintenance can be considered in selected cases, such as cumulative toxicity or patient's refusal, in particular for RAS wild-type patients., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Elderly and frail patients with multiple myeloma (MM) are more vulnerable to the toxicity of combination therapies, often resulting in treatment modifications and suboptimal outcomes. The phase 3 BOSTON study showed that once-weekly selinexor and bortezomib with low-dose dexamethasone (XVd) improved PFS and ORR compared with standard twice-weekly bortezomib and moderate-dose dexamethasone (Vd) in patients with previously treated MM. This is a retrospective subgroup analysis of the multicenter, prospective, randomized BOSTON trial. Post hoc analyses were performed to compare XVd versus Vd safety and efficacy according to age and frailty status (<65 and ≥65 years, nonfrail and frail). Patients ≥65 years with XVd had higher ORR (OR 1.77, p = .024), ≥VGPR (OR, 1.68, p = .027), PFS (HR 0.55, p = .002), and improved OS (HR 0.63, p = .030), compared with Vd. In frail patients, XVd was associated with a trend towards better PFS (HR 0.69, p = .08) and OS (HR 0.62, p = .062). Significant improvements were also observed in patients <65 (ORR and TTNT) and nonfrail patients (PFS, ORR, ≥VGPR, and TTNT). Patients treated with XVd had a lower incidence of grade ≥ 2 peripheral neuropathy in ≥65 year-old (22% vs. 37%; p = .0060) and frail patients (15% vs. 44%; p = .0002). Grade ≥3 TEAEs were not observed more often in older compared to younger patients, nor in frail compared to nonfrail patients. XVd is safe and effective in patients <65 and ≥65 and in nonfrail and frail patients with previously treated MM., (© 2021 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Objectives: We aimed at describing and assessing the quality of reporting in all published prospective trials about radiosurgery (SRS) and stereotactic body radiotherapy (SBRT)., Methods: The Medline database was searched for. The reporting of study design, patients' and radiotherapy characteristics, previous and concurrent cancer treatments, acute and late toxicities and assessment of quality of life were collected., Results: 114 articles - published between 1989 and 2019 - were analysed. 21 trials were randomised (18.4%). Randomisation information was unavailable in 59.6% of the publications. Data about randomisation, ITT analysis and whether the study was multicentre or not, had been significantly less reported during the 2010-2019 publication period than before (respectively 29.4% vs 57.4% ( p < 0.001), 20.6% vs 57.4% ( p < 0.001), 48.5% vs 68.1% ( p < 0.001). 89.5% of the articles reported the number of included patients. Information about radiation total dose was available in 86% of cases and dose per fraction in 78.1%. Regarding the method of dose prescription, the prescription isodose was the most reported information (58.8%). The reporting of radiotherapy characteristics did not improve during the 2010 s-2019s. Acute and late high-grade toxicity was reported in 37.7 and 30.7%, respectively. Their reporting decreased in recent period, especially for all-grade late toxicities ( p = 0.044)., Conclusion: It seems necessary to meet stricter specifications to improve the quality of reporting., Advances in Knowledge: Our work results in one of the rare analyses of radiosurgery and SBRT publications. Literature must include necessary information to first, ensure treatments can be compared and reproduced and secondly, to permit to decide on new standards of care.

Purpose: When treating cancer, both quantity and quality of life are valuable, though oncology trials have long placed greater emphasis on the former. The goal of this work was to evaluate how patient-reported outcomes (PROs) have been incorporated into radiation therapy trials within the National Clinical Trials Network over the last 2 decades to measure quality of life and to assess how PRO data have been disseminated in publications upon trial conclusion., Methods and Materials: This cross-sectional study analyzed the frequency of use of PROs in National Clinical Trials Network cooperative group radiation therapy phase 2 and 3 clinical trials over the past 2 decades. A literature review was performed to determine the publication outcomes of PRO data, including only trials that used PROs in their design and were mature enough to have published results., Results: Fifty-seven (56.4%) of the 101 trials included in this study included PROs in their design. Brain and head and neck trials demonstrated the largest proportional incorporation of PROs (81.8% and 76.9%, respectively), and thoracic and breast trials used the fewest (18.8% and 37.5%, respectively). The EQ-5D family of questionnaires was the most commonly used PROs, used in 22.8% of trials included. The literature review demonstrated a pattern of increased publication of PRO data alongside survival endpoints in manuscripts derived from these trials over time., Conclusions: Though there is room for improvement, the field of radiation oncology has embraced the incorporation of PROs into multicenter, high-impact clinical trials over the past 2 decades and has increased its publication of this data alongside survival data from these trials., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In elderly patients (pts) with aggressive B cell lymphoma (aNHL), curative treatment often cannot be administered because of comorbidities and tolerability. We analyzed the influence of age in pts > 60 years receiving the R-CHOP-14 regimen within different prospective DSHNHL trials. Of the RICOVER-60 trial and CHOP-R-ESC trials, 1171 aNHL pts were included in this retrospective analysis of age-dependent event-free survival (EFS), progression-free survival (PFS), and overall survival (OS). All patients received prophylactic G-CSF, and anti-infective prophylaxis with amphotericin B mouth wash and oral fluorchinolone was optional. In the CHOP-R-ESC trials, prophylaxis was augmented to include mandatory continuous orally administered aciclovir and a pneumocystis prophylaxis with cotrimoxazole as well as oral fluorchinolones during neutropenia. The patient population was separated into 4 age groups (61-65 years, 66-70 years, 71-75 years, and 76-80 years). The results from the RICOVER-60 trial were subsequently confirmed in the following CHOP-R-ESC trials by a multivariate analysis adjusted for IPI factors and gender. Significant differences (p < 0.001) in EFS, PFS, and OS were seen between age groups (RICOVER-60). Hematotoxicity, infections, and TRM increased with age. TRM was significantly elevated in the age group 76-80 years. Therefore, this analysis shows that an age above 75 years defines an especially vulnerable patient population when being treated with chemoimmunotherapy for aNHL. Prophylactic anti-infective drugs are essential and clinically effective in reducing morbidity when treating elderly aNHL pts.

Background: The Fragility Indexquantifies the reliability of positive trials by estimating the number of events, which would change statistically significant results to non-significant results., Methods: We identified randomized trials supporting drug approvals by the US FDA between 2009 and 2019 in lung, breast, prostate, and colon cancers and in melanoma. We reconstructed survival tablesand calculated the number of events, which would result in a non-significant result for the primary endpoint. The FI was then compared to the number of patients in each trial who withdrew consent or were lost to follow-up. Regression analyses were used to explore associations between RCT characteristics and FI and trials in which FI was lower or equal to number of participants who withdrew consent or were lost to follow-up., Results: Among 81 RCTs, the median FI was 28. The median number of patients who withdrew consent or were lost to follow up was 27. FI was equal or lower than the number of patients who withdrew consent or were lost to follow-up in 47 trials (58%). There was a modest increase in FI over time (p = 0.02). Trials with overall survival as the primary endpoint (p = 0.006) and those in the palliative setting (p < 0.001) had lower FI. There was no association with trial sample size or duration of follow-up., Findings: Statistical significance of RCTs in common solid tumours can be reversed often with a small number of additional events. Post-approval RCTs or real-world data analyses should be performed to ensure results of registration trials are robust., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

This study examined the outcomes of recent confirmatory randomized controlled trials (RCTs) in phase III that were initiated between 2005 and 2017 for oncologic drugs in the United States and identified several factors that were associated with the success of RCTs. Our regression analysis showed that studies with progression-free survival or response rate as primary end point were more likely to succeed than studies with overall survival (odds ratio (OR) = 2.94 and 6.23, respectively). The status of development was also linked with success rates. Studies for non-lead indication tended to have lower success rates than studies for lead indication (OR = 0.68). Studies for first-line therapy were observed to have low success rates compared with studies for post second-line therapies (OR = 0.37). Studies for which strong prior evidence was not listed in their publication tended to be more successful than studies that followed rigorous RCTs or single arm studies for the indication. These results suggest that historical success rates may reflect not only the important features of trials, which can be observed directly from study design and results, but also the background status of trials in clinical development pathways., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Mathematical models combined with new imaging technologies could improve clinical oncology studies. To improve detection of therapeutic effect in patients with cancer, we assessed volumetric measurement of target lesions to estimate the rates of exponential tumor growth and regression as treatment is administered., Experimental Design: Two completed phase III trials were studied (988 patients) of aflibercept or panitumumab added to standard chemotherapy for advanced colorectal cancer. Retrospectively, radiologists performed semiautomated measurements of all metastatic lesions on CT images. Using exponential growth modeling, tumor regression ( d ) and growth ( g ) rates were estimated for each patient's unidimensional and volumetric measurements., Results: Exponential growth modeling of volumetric measurements detected different empiric mechanisms of effect for each drug: panitumumab marginally augmented the decay rate [tumor half-life; d [IQR]: 36.5 days (56.3, 29.0)] of chemotherapy [ d : 44.5 days (67.2, 32.1), two-sided Wilcoxon P = 0.016], whereas aflibercept more significantly slowed the growth rate [doubling time; g = 300.8 days (154.0, 572.3)] compared with chemotherapy alone [ g = 155.9 days (82.2, 347.0), P ≤ 0.0001]. An association of g with overall survival (OS) was observed. Simulating clinical trials using volumetric or unidimensional tumor measurements, fewer patients were required to detect a treatment effect using a volumetric measurement-based strategy (32-60 patients) than for unidimensional measurement-based strategies (124-184 patients)., Conclusions: Combined tumor volume measurement and estimation of tumor regression and growth rate has potential to enhance assessment of treatment effects in clinical studies of colorectal cancer that would not be achieved with conventional, RECIST-based unidimensional measurements., (©2020 American Association for Cancer Research.)

Background: The National Cancer Institute Moonshot research initiative calls for improvements in the analysis and reporting of treatment toxicity to advise key stakeholders on treatment tolerability and inform regulatory and clinical decision making. This study illustrates alternative approaches to toxicity evaluation using the National Surgical Adjuvant Breast and Bowel Project R-04 clinical trial as an example., Methods: National Surgical Adjuvant Breast and Bowel Project R-04 was a neoadjuvant chemoradiation trial in stage II-III rectal cancer patients. A 2 x 2 factorial design was used to evaluate whether the addition of oxaliplatin (Oxa) to 5-fluorouracil (5FU) or capecitabine (Cape) with radiation therapy improved local-regional tumor control. The toxicity index (TI), which accounts for the frequency and severity of toxicities, was compared across treatments using multivariable probabilistic index models, where Pr A < B indicates the probability that higher values of TI were observed for A when compared with B. Baseline age, sex, performance status, body mass index, surgery type, and stage were evaluated as independent risk factors., Results: A total of 4560 toxicities from 1558 patients were analyzed. Results from adjusted probabilistic index models indicate that oxaliplatin-containing regimens had statistically significant (P < .001) probability (Pr) for higher TI compared with regimens without oxaliplatin (Pr 5FU < 5FU + Oxa = 0.619, 95% confidence interval [CI] = 0.560 to 0.674; Pr 5FU < Cape + Oxa = 0.627, 95% CI = 0.568 to 0.682; Pr Cape < 5FU + Oxa = 0.587, 95% 0.527 to 0.644; and Pr Cape < Cape + Oxa = 0.596, 95% 0.536 to 0.653). When compared with other existing toxicity analysis methods, TI provided greater power to detect differences between treatments., Conclusions: This article uses standard data collected in a cancer clinical trial to introduce descriptive and analytic methods that account for the additional burden of multiple toxicities. These methods may provide a more accurate description of a patient's treatment experience that could lead to individualized dosing for better toxicity control. Future research will evaluate the generalizability of these findings in trials with similar drugs., (© The Author(s) 2020. Published by Oxford University Press.)

Background: More than 95% of recent cancer randomized controlled trials used the log-rank test to detect a treatment difference making it the predominant tool for comparing two survival functions. As with other tests, the log-rank test has both advantages and disadvantages. One advantage is that it offers the highest power against proportional hazards differences, which may be a major reason why alternative methods have rarely been employed in practice. The performance of statistical tests has traditionally been investigated both theoretically and numerically for several patterns of difference between two survival functions. However, to the best of our knowledge, there has been no attempt to compare the performance of various statistical tests using empirical data from past oncology randomized controlled trials. So, it is unknown whether the log-rank test offers a meaningful power advantage over alternative testing methods in contemporary cancer randomized controlled trials. Focusing on recently reported phase III cancer randomized controlled trials, we assessed whether the log-rank test gave meaningfully greater power when compared with five alternative testing methods: generalized Wilcoxon, test based on maximum of test statistics from multiple weighted log-rank tests, difference in t -year event rate, and difference in restricted mean survival time with fixed and adaptive τ ., Methods: Using manuscripts from cancer randomized controlled trials recently published in high-tier clinical journals, we reconstructed patient-level data for overall survival (69 trials) and progression-free survival (54 trials). For each trial endpoint, we estimated the empirical power of each test. Empirical power was measured as the proportion of trials for which a test would have identified a significant result ( p value < .05)., Results: For overall survival, t -year event rate offered the lowest (30.4%) empirical power and restricted mean survival time with fixed τ offered the highest (43.5%). The empirical power of the other types of tests was almost identical (36.2%-37.7%). For progression-free survival, the tests we investigated offered numerically equivalent empirical power (55.6%-61.1%). No single test consistently outperformed any other test., Conclusion: The empirical power assessment with the past cancer randomized controlled trials provided new insights on the performance of statistical tests. Although the log-rank test has been used in almost all trials, our study suggests that the log-rank test is not the only option from an empirical power perspective. Near universal use of the log-rank test is not supported by a meaningful difference in empirical power. Clinical trial investigators could consider alternative methods, beyond the log-rank test, for their primary analysis when designing a cancer randomized controlled trial. Factors other than power (e.g. interpretability of the estimated treatment effect) should garner greater consideration when selecting statistical tests for cancer randomized controlled trials.

Aim: Evidence-based medicine uses high-quality methods, such as randomization and blinding prcedures, to support and inform clinical practice. The investigation of trials registered in clinical research databases may help understand the main characteristics of studies conducted in countries, such as Brazil. This study aimed to investigate the characteristics of Brazilian clinical trials registered in ClinicalTrials.gov in the last decade., Methods: Cross-sectional study performed in ClinicalTrials.gov database with clinical studies registered in Brazil between 2010 and 2020. A search was conducted in the database considering this period using filters for country (Brazil), start date (01 January 2010) and end date (date of the search: 07 May 2020). Descriptive statistics were used to characterize the studies. All analyses were conducted on Stata 14.2., Results: In total, 5368 studies were retrieved, which were mostly randomized (93.2%), blinded (63.2%), Phase III (48.7%) interventional studies (89.9%) with small sample sizes (57.2%) conducted with adults (93.0%) using drugs (42.7%) with a treatment purpose (77.3%), with funding from institutions other than the industry, the NIH, and the US Federal (71.3%)., Conclusions: The majority of Brazilian clinical studies used blinding and randomization procedures in the last 10 years. However, the predominance of trials with small sample sizes and with a focus on adult patients indicate the need of larger studies conducted with the pediatric population., (© 2020 Chinese Cochrane Center, West China Hospital of Sichuan University and John Wiley & Sons Australia, Ltd.)

In clinical development, there is a trade-off between investment and level of confidence in the potential of the drug before going into phase III. Reduced investment requires the use of short-term endpoints. On new compounds, only limited information about the relationship between treatment effects of short- and long-term endpoints is usually available. Therefore, decision-making solely based on short-term endpoints does not seem desirable. Our goal is to plan an efficient development program, which uses short- and long-term endpoints data for decision-making. We found that with limited prior information and restrictions on maximum sample size, decision-making after phase II cannot be substantially improved. We follow the concept of a "phase 2+" design where after a go-to-phase-III-decision, further follow-up data from phase II are employed to make interim decisions on phase III. The program will be stopped early when additional phase II and/or available phase III data lead to a low probability of success (PoS). We utilize information from a multi-categorical short-term endpoint (response status) and a long-term endpoint (overall survival (OS)) to determine the PoS in phase III with OS as the primary endpoint. Optimal combinations of decision boundaries and time points are demonstrated in a simulation study. Our results show that the proposed second look using additional follow-up data from phase II/III improves PoS estimates compared to the first look, especially when prior data about the control arm is available. The proposed planning strategy allows a customized compromise between the quality of decision-making and program duration., (© 2020 John Wiley & Sons Ltd.)

The main objective of a confirmatory multiregional clinical trial (MRCT) is to demonstrate the overall efficacy of test drugs in all participating regions as well as to evaluate the possibility of extrapolating the overall results to each region. With the emergence of the demands of biosimilar drugs development, some guidelines recommended using equivalence design to demonstrate the comparability of efficacy between biosimilar and reference drugs. Previous discussions about assessing regional consistency in MRCT are mainly focused on superiority or non-inferiority designs, while the extensions to equivalence designs were limited. In this work, we proposed a flexible regional consistency criterion for the MRCT with equivalence design. Based on this criterion, sample size determination and sample allocation were also discussed., (© 2020 John Wiley & Sons Ltd.)

Objective: Clinical trials are increasingly globalized, and adverse event (AE) rates and treatment responses may differ by geographical region. This study assessed regional differences in AE reporting rates and ACR response rates (ACR20/50) in patients with RA who received placebo/standard-of-care treatment in clinical trials., Methods: Patients from the placebo arms of 7 RA trials in the TransCelerate Biopharma Inc database were grouped into 5 geographical regions (Asia, Latin America, Russian Federation and Eastern Europe [RFEE], USA, and Western Europe). Differences in demographics, AE reporting rates and ACR response were evaluated using descriptive statistics and omnibus tests for significance; pairwise comparisons were made between regions, with false discovery rate correction for multiple comparisons., Results: Among 970 patients included, week 12 AE rates were significantly lower in the RFEE than in Asia, Latin America and the USA (22% vs 51%, 49% and 53%, respectively; P < 0.05 after false discovery rate correction). Similar differences in AE rates across geographical regions were seen at week 52. Among 747 patients with ACR data, the lowest response rates were observed in the USA (ACR20, 22%) and RFEE (ACR50, 3%); the highest response rates were seen in Western Europe (ACR20, 43%) and Latin America (ACR50, 15%). Only the differences in ACR50 response between the RFEE and Latin America remained significant after false discovery rate correction., Conclusion: These placebo/standard-of-care arm data revealed significant regional differences in AE reporting rates and ACR50 response rates. Regional distribution of patients should be considered when conducting RA clinical trials, particularly during recruitment., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Evidence from randomized controlled trials available for timely health technology assessments of new pharmacological treatments and regulatory decision making may not be generalizable to local patient populations, often resulting in decisions being made under uncertainty. In recent years, several reweighting approaches have been explored to address this important question of generalizability to a target population. We present a case study of the Innovative Medicines Initiative to illustrate the inverse propensity score reweighting methodology, which may allow us to estimate the expected treatment benefit if a clinical trial had been run in a broader real-world target population. We learned that identifying treatment effect modifiers, understanding and managing differences between patient characteristic data sets, and balancing the closeness of trial and target patient populations with effective sample size are key to successfully using this methodology and potentially mitigating some of this uncertainty around local decision making., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Rituximab monotherapy is widely used for follicular lymphoma. However, there are no established predictors for response or response duration. We analyzed the long-term prognostic relevance of pre-treatment absolute blood counts of lymphocytes with subsets and monocytes in 265 follicular lymphoma patients, uniformly treated with rituximab without chemotherapy, in two Nordic Lymphoma Group trials. There were 265 previously untreated, stage II-IV follicular lymphoma patients with a median follow-up of over 10 years. Absolute B cell counts ≥ median (0.09 × 10 9 /L) were an independent predictor for shorter time to next treatment or death (multivariable analysis P = 0.010). In univariate analysis, absolute monocyte counts ≥ median (0.5 × 10 9 /L) did not correlate with time to next treatment or death, but with inferior overall survival (P = 0.034). Absolute T cell or T cell subset counts were not predictive for outcome. High absolute B cell counts, possibly reflecting circulating lymphoma cells, have an unfavorable impact on time to next treatment or death in patients treated with rituximab without chemotherapy.

Background: The dynamic effects of immune checkpoint inhibitors (ICIs) are a challenge when designing and analysing data in non-proportional hazards (PH) scenarios. Herein, we present the risk of making type II errors, affecting pharmacotherapeutic development when methods that assume constant effects are applied., Patients and Methods: Individual patient data from six clinical trials (KEYNOTE-062/061, IMvigor211, CA184-143 y CheckMate-057/037) were extracted. The most relevant time-varying effects were examined using the Royston-Parmar spline model (RPSM), time-driven analyses and weighted log-rank and Renyi tests., Results: The RPSM yields an appropriate fit in non-PH contexts, enabling dynamic descriptions of the hazard rate, and time-varying differences of overall survival (OS)/progression-free survival. In the KEYNOTE-061, CheckMate-057 and 037 trials, 12-, 18-, and 24-month OS rates were higher with immunotherapy (differences of some 10%) (P-value <0.05). In KEYNOTE-062, CA184-043 and IMvigor-211 trials, OS rate differences were significant for past 20 months. Flemming-Harrington and Renyi tests with late weighting (e.g. with ρ-value = 0 and γ-value = 1) captured the existence of significant differences on all curves. The Cox models and log-rank tests were inefficient at detecting the effect., Conclusion: This analysis highlights the risk of declaring studies with ICIs negative, despite associating substantial OS benefits. Effort and consensus are needed with respect to methodology to design and evaluate trials with ICIs in non-PH settings., Competing Interests: Conflict of interest statement A.S-.A. reports collaborating professionally with Roche Pharma S.A. E.C. reports receiving travel grants from AstraZeneca, Spain, BMS, MSD and Roche, Spain and serving a consulting/advisory role for AstraZeneca, BMS, MSD and Roche, all outside of the scope of this work. F.A.M. reports no conflict of interest. P.J-.F. reports receiving travel grants from Ipsen and serving a consulting/advisory role for Roche, Celgene, Bristol, MSD, Mylan, Rovi and LeoPharma, all outside of the scope of this work. A.C-.B. reports receiving travel grants from Ipsen, Spain, Roche, Spain and Novartis, Spain and serving a consulting/advisory role for Roche, Merck, Rovi, LeoPharma, Pfizer and Esteve, all outside of the scope of this work., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Sarcomatoid renal cell carcinoma (sRCC) represents a rare form of renal cell carcinoma marked by an aggressive biology, poor prognosis and little benefit from anti-angiogenic targeted therapy. More promising results come from the recent therapeutic strategy based on immune checkpoint inhibitor (ICI) combinations., Materials and Methods: For this meta-analysis, we searched MEDLINE/PubMed, the Cochrane Library and American Society of Medical Oncology (ASCO) Meeting abstracts for phase II or III randomised clinical trials. Data extraction was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis statement. The hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) with the relative 95% confidence intervals were extracted from studies. Summary HRs were calculated using random- or fixed-effects models, depending on the heterogeneity of the included studies., Results: Four studies were selected for final analysis, including 467 patients (226 treated in with ICI combinations and 241 received sunitinib in the control arms). ICI-based combinations were associated with an improved PFS and OS compared with sunitinib, with a reduction of more than 40% of progression (HR = 0.56; p < 0.0001) and mortality (HR = 0.56; p = 0.001) risk. Moreover, ICI-based combinations are associated with a objective response rate (ORR) of more than 50% (versus 20% with sunitinib), corresponding to a doubled risk of achieving an ORR compared with controls (relative risk [RR] = 2.15; p < 0.00001). Finally, immunotherapy significantly increased the possibility to obtain complete responses (RR = 8.15, p = 0.0002) with an incidence of 11%., Conclusion: Our data support the efficacy of ICI-based combinations for sRCC therapy, redefining the first-line treatment., Competing Interests: Conflict of interest statement R.I. reports serving as a consultant or playing an advisory role for Pfizer, Janssen, Sanofi, IPSEN, MSD and Novartis and receiving travel accommodations from Pfizer, Janssen and Ipsen. C.C. reports serving as a consultant of IPSEN and Merk. E.B. reports receiving funds from the Italian Association for Cancer Research AIRC-IG20583, the International Association for Lung Cancer (IASLC), the LILT (Lega Italiana per la Lotta contro i Tumori) and Fondazione Cariverona; receiving fee for speak’ and travel’ from MSD, AstraZeneca, Pfizer, Helsinn, Eli-Lilly, BMS, Novartis and Roche; receiving consultant fee from Roche and Pfizer and receiving institutional research grants from Astra-Zeneca and Roche. S.B. reports serving as a consultant or playing an advisory role for Pfizer, BMS, MSD, Roche, Astellas, Janssen, Ipsen, Bayer, Merck and AstraZeneca and reports receiving travel accommodations from Pfizer, BMS, Roche, Astellas, Janssen, Ipsen, AstraZeneca and Exelixis. G.P. reports serving as a consultant or playing an advisory role for AstraZeneca, Bayer, BMS, Ipsen, MSD, Novartis and Pfizer. C.P. reports serving a consultant and speaker for EUSA, Bristol-Myers Squibb, MSD, Pfizer, Ipsen, Eisai, AstraZeneca, Janssen, Novartis and General Electrics and reports receiving honoraria from Roche. G.T. reports serving a consultant or playing an advisory role for BMS and Novartis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The use of overall survival (OS) as the gold standard primary end-point (PEP) in metastatic oncologic randomised controlled trials (RCTs) has declined in favour of progression-free survival (PFS) without a complete understanding of the degree to which PFS reliably predicts for OS., Methods: Using ClinicalTrials.gov, we identified 1239 phase III oncologic RCTs, 260 of which were metastatic solid tumour trials with a superiority-design investigating a therapeutic intervention by using either a PFS or OS PEP. Each individual trial was reviewed to quantify RCT design factors and disease-related outcomes., Results: A total of 172,133 patients were enrolled from the year 1999 to 2015 in RCTs that used PFS (56.2%, 146/260) or OS (43.8%, 114/260) as the PEP. PFS trials were more likely to restrict patient eligibility by using molecular criteria (15.1% versus 4.4%, p = 0.005) use targeted therapy (80.1% versus 67.5%, p = 0.048), accrue fewer patients (median 495 versus 619, p = 0.03), and successfully meet the trial PEP (66.9% versus 33.3%, p < 0.0001). On multiple binary logistic regression analysis, factors that predicted for PFS or OS PEP trial success included choice of PFS PEP (p < 0.0001), molecular profile restriction (p = 0.02) and single agent therapy (p = 0.02). Notably, there was only a 38% (31/82) conversion rate of positive PFS-to-OS benefit; lack of industry sponsorship predicted for PFS-to-OS signal conversion (80.0% without industry sponsorship versus 35.1% with industry sponsorship, p = 0.045)., Conclusions: A PFS PEP has suboptimal positive predictive value for OS among phase III metastatic solid tumour RCTs. Regulatory agency decisions should be judicious in using PFS results as the primary basis for approval., Competing Interests: Conflict of interest statement The authors report no financial disclosures or conflicts of interests related to this work. Dr. Jagsi reports stock ownership and an advisory role in Equity Quotient; personal fees from Amgen and Vizient; grants from the National Institutes of Health, the Doris Duke Foundation, the Greenwall Foundation, and Blue Cross Blue Shield of Michigan. Dr. Das reports personal fees from Adlai Nortye. Dr. Fuller reports honoraria from the University of Texas Health Science Center San Antonio and Elekta AB; royalties from Demos Medical Publishing; travel expenses/accommodations from Oregon Health & Science University, Great Baltimore Medical Center, University of Illinois Chicago, Elekta AB, the Translational Research Institute of Australia; grants from the National Science Foundation and National Institutes of Health. Dr. Thomas reports receiving a stipend as deputy editor of JAMA Oncology. Dr. V. Subbiah reports funding for clinical trials from Roche/Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint medicines, Loxo Oncology, Medimmune, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, Turning point therapeutics, Boston Pharmaceuticals; for travel from Novartis, Pharmamar, ASCO, ESMO, Helsinn, Incyte; for consultancy from Helsinn, LOXO Oncology/Eli Lilly, R-Pharma US, INCYTE, QED pharma, Medimmune, Novartis; and for other duties from Medscape., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory approval is approximately 57%, suggesting that a considerable number of treatments with phase 2 trial results deemed sufficiently successful to progress to phase 3 do not yield positive phase 3 results. Deficiencies in the quality of clinical trial conduct could account for some of this failure. An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting was convened to identify potential areas for improvement in trial conduct in order to improve assay sensitivity (ie, ability of trials to detect a true treatment effect). We present recommendations based on presentations and discussions at the meeting, literature reviews, and iterative revisions of this article. The recommendations relate to the following areas: 1) study design (ie, to promote feasibility), 2) site selection and staff training, 3) participant selection and training, 4) treatment adherence, 5) data collection, and 6) data and study monitoring. Implementation of these recommendations may improve the quality of clinical trial data and thus the validity and assay sensitivity of clinical trials. Future research regarding the effects of these strategies will help identify the most efficient use of resources for conducting high quality clinical trials. PERSPECTIVE: Every effort should be made to optimize the quality of clinical trial data. This manuscript discusses considerations to improve conduct of pain clinical trials based on research in multiple medical fields and the expert consensus of pain researchers and stakeholders from academia, regulatory agencies, and industry., (Copyright © 2020. Published by Elsevier Inc.)

The mean and median ages of diagnosis of multiple myeloma range from 70 to 73 years old, with 63% of patients being over the age of 65. Phase 3 clinical trials are designed to study efficacy in the target disease population and are meant to have the most representative subject pool. The purpose of this review is to identify the age demographic of subjects participating in interventional phase 3 clinical trials that aim to treat multiple myeloma and to determine if they encompass the true age demographic of the disease. To complete this review, a search of phase 3 multiple myeloma research trials with reported results was conducted on clinicaltrials.gov, a national, publicly available resource listing clinical trials. Reported mean or median ages of subjects were identified for each trial, and adjusted averages of these values were calculated. Data from 81 clinical trials were assessed, with 42 trials reporting an average mean age of 65.78 years and 15 trials reporting an average median age of 63.29 years. Based on these results, it was determined that the clinical trials reported in this study enrolled patients that were younger than the true age demographic of the disease. There is an unmet need in research in the older population of patients with multiple myeloma, and this may hinder the generalizability and utility of clinical trial results.

Bortezomib-induced peripheral neuropathy (BIPN) is a common toxicity associated with the treatment of multiple myeloma (MM), typically requiring dose reduction, delay, or cessation of treatment protocol. This systematic review aimed to investigate risk factors, trends, and variability associated with the development of BIPN. Searches were undertaken using Medline, PubMed, Cochrane Central Register of Controlled Trials, Embase, Scopus, and Web of Science. Additional studies were identified by investigating authors' bibliographic references cited by original and review articles. Articles that reported on neuropathy in phase III randomised control trials involving bortezomib in any treatment arm for the treatment of MM were included in this review. A total of 43 full text articles met criteria, which examined 23 phase III trials (N = 8218). Overall incidence of neuropathy ranged from 8.4% to 80.5% (median = 37.8%) and severe neuropathy (grade 3-4) ranged from 1% to 33.2% (median = 8%). Similar reports of neuropathy of any grade and severe neuropathy were observed between the newly diagnosed and relapsed cohort. Bortezomib regimens with reduced dose intensity were associated with reduced neuropathy incidence. Increased cumulative dosing levels, intravenous compared with subcutaneous administration and combination therapy with thalidomide were associated with higher rates of BIPN. This analysis revealed that BIPN is a significant toxicity. More sensitive measures are required to capture the incidence and severity of BIPN. Better understanding of risk factors and reversibility profiles will minimise the number of cancer survivors living with residual treatment side effects., (© 2019 John Wiley & Sons Ltd.)

For patients with untreated hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) with multi-organ dysfunction (MOD), mortality is >80%. We conducted a pooled analysis of three studies that assessed Day 100 survival in relationship to MOD severity, with dialysis and/or ventilator dependence representing the most severe organ dysfunction. All patients in the analysis were diagnosed using Baltimore criteria/biopsy. This analysis of patients with VOD/SOS and MOD after haematopoietic cell transplantation (HCT; n = 651) demonstrated higher Day 100 survival rates amongst defibrotide-treated patients with VOD/SOS with less versus more severe forms of MOD. Even patients with severe forms of MOD post-HCT benefitted from defibrotide., (© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: Neutropenia is the most common toxicity of CDK4/6 inhibitors, causing frequent dose interruptions. However, CDK4/6 inhibitor-induced neutropenia shows a benign clinical course in contrast to that caused by chemotherapy. Here, we investigated the safety of a new dose scheme for palbociclib, which avoids dose delays or reductions due to afebrile grade 3 neutropenia., Methods: A consecutive cohort of ER( +)/HER2( -) advanced breast cancer patients who received palbociclib between 2017 and 2018 was analyzed. The patients were classified into Group 1 (patients who maintained palbociclib dose with afebrile grade 3 neutropenia), Group 2 (patients who experienced any dose modification with afebrile grade 3 neutropenia), and Group 3 (patients without afebrile grade 3 neutropenia). The primary endpoint was febrile neutropenia incidence; other toxicities were compared with those of the PALOMA-2 trial., Results: Among the 107 patients, 54.2%, 22.4%, and 23.4% were classified into Groups 1, 2, and 3, respectively. There was no febrile neutropenia in Groups 1 and 2 during palbociclib treatment. Group 1 showed higher incidence of thrombocytopenia (all-grade, 32.8%; grade 3-4, 8.6%) than Group 2 and the PALOMA-2 data, but there was no bleeding related to thrombocytopenia. Group 1 showed higher incidence of all-grade non-hematologic adverse events than Group 2; only one grade 3 non-hematologic toxicity was observed in Group 1. There were no treatment-related hospitalizations or deaths in Group 1., Conclusions: Thus, omitting palbociclib dose modification with afebrile grade 3 neutropenia is safe and tolerable without febrile neutropenia events. This scheme could be useful to avoid unnecessary reductions in palbociclib doses in future practice.

A clinical trial often has primary and secondary endpoints and comparisons of high and low doses of a study drug to a control. Multiplicity is not only caused by the multiple comparisons of study drugs versus the control, but also from the hierarchical structure of the hypotheses. Closed test procedures were proposed as general methods to address multiplicity. Two commonly used tests for intersection hypotheses in closed test procedures are the Simes test and the average method. When the treatment effect of a less efficacious dose is not much smaller than the treatment effect of a more efficacious dose for a specific endpoint, the average method has better power than the Simes test for the comparison of two doses versus control. Accordingly, for inferences for primary and secondary endpoints, the matched parallel gatekeeping procedure based on the Simes test for testing intersection hypotheses is extended here to allow the average method for such testing. This procedure is further extended to clinical trials with more than two endpoints as well as to clinical trials with more than two active doses and a control.

Genetic parameters are established prognostic factors in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy, but are less well studied with novel compounds. We assessed immunoglobulin heavy variable chain (IGHV) mutation status, common genomic aberrations, and gene mutations in 421 untreated patients within the CLL14 trial (NCT02242942), comparing obinutuzumab+chlorambucil (GClb) vs obinutuzumab+venetoclax (VenG). The incidences of genomic aberrations considering the hierarchical model were del(17p) 7%, del(11q) 18%, +12 18%, and del(13q) 35%, whereas IGHV was unmutated in 60% of patients. NOTCH1 mutations were most common (23%), followed by SF3B1 (16%), ATM (13%), and TP53 (10%). Although the overall response rate (ORR) for GClb was lower in patients with del(17p), del(11q), mutated TP53, ATM, and BIRC3, none of these parameters reduced complete remission (CR) rate and ORR with VenG. At a median follow-up of 28 months, del(17p) and mutated TP53 were the only abnormalities with an effect on progression-free survival (PFS) for both treatment groups: GClb (hazard ratio [HR], 4.6 [P < .01]; HR, 2.7 [P < .01], respectively) and VenG (HR, 4.4 [P < .01]; HR, 3.1 [P < .01], respectively). No other factors affected outcome with VenG, whereas for GClb del(11q), BIRC3, NOTCH1, and unmutated IGHV were associated with shorter PFS. Multivariable analysis identified del(17p), del(11q), unmutated IGHV, and mutated TP53, BIRC3, and SF3B1 as independent prognostic factors for PFS with GClb, whereas for VenG, only del(17p) was significant. VenG was superior to GClb across most genetic subgroups. Patients with adverse genetic markers had the strongest benefit from VenG, particularly subjects with unmutated IGHV, which was identified as a predictive factor in a multivariable treatment-interaction analysis., (© 2020 by The American Society of Hematology.)

Bortezomib is a first-in-class proteasome inhibitor, approved for the treatment of multiple myeloma. The originally approved dosing schedule of bortezomib results in significant toxicities that require dose interruptions and discontinuations. Consequentially, less frequent dosing has been explored to optimise bortezomib's benefit-risk profile. Here, we performed exposure-response analysis to compare the efficacy of the original bortezomib dosing regimen with less frequent dosing of bortezomib over nine 6-week treatment cycles using data from the VISTA clinical trial and the control arm of the ALCYONE clinical trial. The relationship between cumulative bortezomib dose and clinical response was evaluated with a univariate logit model. The median cumulative bortezomib dose was higher in ALCYONE versus VISTA (42·2 vs. 38·5 mg/m 2 ) and ALCYONE patients stayed on treatment longer (mean: 7·2 vs. 5·8 cycles). For all endpoints and regimens, probability of clinical response correlated with cumulative bortezomib dose. Similar to results observed for VISTA, overall survival was longer in ALCYONE patients with ≥ 39·0 versus < 39·0 mg/m 2 cumulative dose (hazard ratio, 0·119; P < 0·0001). Less frequent bortezomib dosing results in comparable efficacy, and a higher cumulative dose than the originally approved bortezomib dosing schedule, which may be in part be due to reduced toxicity and fewer dose reductions/interruptions., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

As a result of the successful completion of their respective phase III studies compared with vitamin K antagonists (VKAs), four direct oral anticoagulants (DOACs) have been approved for the treatment and secondary prevention of venous thromboembolism (VTE). These DOACs-apixaban, dabigatran, edoxaban, and rivaroxaban-have subsequently seen a steady uptake among clinicians since their approval. Despite the suitability of DOACs for a broad range of patients, they are not appropriate in certain situations, whereas in others they require additional considerations such as dose reductions. Subanalyses of phase III trials and studies on specific VTE patient populations have been conducted to evaluate the safety and efficacy of the DOACs in a broad range of settings, such as patients with renal impairment, patients with cancer, patients of childbearing potential, patients with multiple comorbidities and pediatric patients. Furthermore, many recent guidance documents from important hematological societies and other specialists have incorporated several of these developments. These documents also identify the patients for whom DOACs are not suitable and where traditional anticoagulation options such as heparins or VKAs should be considered instead. This review provides an overview of key VTE patient subgroups, the clinical evidence supporting the use of anticoagulation in these patients, and a discussion of the most appropriate approaches to their management, including considerations such as dosing, acute and extended treatment durations, and DOAC selection., Competing Interests: C.E.K. reports personal fees from Bayer Health Care, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, and Pfizer Pharma during the conduct of the study; personal fees from Amgen and Sanofi-Aventis outside the submitted work. S.M. reports grants and personal fees from Aspen, Bayer, BMS/Pfizer, Boehringer Ingelheim, Daiichi Sankyo, GSK, Portola, Sanquin, and Sanofi during the conduct of the study., (Georg Thieme Verlag KG Stuttgart · New York.)

Traditionally, a clinical trial is conducted comparing treatment to standard care for all patients. However, it could be inefficient given patients' heterogeneous responses to treatments, and rapid advances in the molecular understanding of diseases have made biomarker-based clinical trials increasingly popular. We propose a new targeted clinical trial design, termed as Max-Impact design, which selects the appropriate subpopulation for a clinical trial and aims to optimize population impact once the trial is completed. The proposed design not only gains insights on the patients who would be included in the trial but also considers the benefit to the excluded patients. We develop novel algorithms to construct enrollment rules for optimizing population impact, which are fairly general and can be applied to various types of outcomes. Simulation studies and a data example from the SWOG Cancer Research Network demonstrate the competitive performance of our proposed method compared to traditional untargeted and targeted designs., (© 2019 The International Biometric Society.)

The purpose of the research is to develop a statistical decision support algorithm for patients who may benefit from Adjuvant Cisplatin/Vinorelbine (ACT) and improve their survival rates. Genome-wide microarray data are used to identify feasible sets of genes and probe sets that constitute the gene signature. The data are available at the National Center for Biotechnology Information Gene Expression Omnibus (GSE14814). Preliminary studies have shown that high-risk patients who received ACT resulted in an improved prognosis. However, low-risk patients showed no benefit from ACT, and the treatment was possibly detrimental to the patient. Studies using tree-based ensemble statistical learning algorithms have shown that genomic markers could potentially identify a patient's risk factor and likelihood to benefit from ACT; however, it was noted that tree-based ensemble statistical learning algorithms do not provide an estimate of the strength of the treatment effect, nor is it possible to clearly identify subgroups of patients with similar responses to ACT treatment. Building on this idea, Accelerated Failure Time models are used to predict the probability of benefit from receiving chemotherapy or surgery only and provide a treatment recommendation for a new patient. We showed that regardless of whether the model recommended chemotherapy or surgery only, patients who followed the predicted treatment recommendation had significantly longer survival times than patients who did not. The proposed approach provides the likelihood of benefit for each treatment based on a small number of genomic biomarkers.