External control arms can validate treatment efficacy in single-arm studies.

These abstracts are presented here as prepared by the authors. The accuracy and content of each abstract remain the responsibility of the authors. In the identification number above each abstract, OPL designates an Orthopaedic Section platform presentation. J Orthop Sports Phys Ther 2015;45(1):A19–A45. doi:10.2519/jospt.2015.45.1.A19

Randomized clinical trials (RCTs) are the gold standard for delineating the effect of treatment from bias, the placebo effect, and disease course changes. As such, RCTs are expensive, require a large sample size, and take a long time to complete.1 All three of these are challenging, especially for rare diseases, like glioblastoma (GBM), where RCTs can be deemed unfeasible or unethical.2,3 A common workaround in Phase II trials is to employ a single-arm study design. In a single-arm study, the best scenario is to observe a treatment effect signal; however, this design does not allow quantification of the signal nor assessment of potential biases. Recently, external control data have garnered attention to address the noted limitations of RCTs and single-arm studies.4 External controls refer to a non-randomized control that serves as the reference for interpreting a treatment effect. External controls can also be termed synthetic, concurrent, or historical controls and are selected from data sources (eg, electronic medical records [EMRs], disease registries) external to the study of interest, commonly referred to as real-world data (RWD).5 A second source is historical trials. Several approaches employing external controls to augment controls in RCTs and single-arm studies have been suggested to delineate the treatment effect.1,6

From single-arm studies to externally controlled studies. Methodological considerations and guidelines

Soft tissue sarcomas (STS) are a highly heterogeneous group of rare malignant solid tumors. Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) comprise all STS except rhabdomyosarcoma. In patients with advanced local or metastatic disease, autologous hematopoietic stem cell transplantation (HSCT) applied after high-dose chemotherapy (HDCT) is a planned rescue therapy for HDCT-related severe hematologic toxicity. The rationale for this update is to determine whether any randomized controlled trials (RCTs) have been conducted and to clarify whether HDCT followed by autologous HSCT has a survival advantage. To assess the effectiveness and safety of HDCT followed by autologous HSCT for all stages of non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) in children and adults. For this update we modified the search strategy to improve the precision and reduce the number of irrelevant hits. All studies included in the original review were considered for re-evaluation in the update. We searched the electronic databases CENTRAL (2012, Issue 11) in The Cochrane Library , MEDLINE and EMBASE (05 December 2012) from their inception using the newly developed search strategy. Online trials registers and reference lists of systematic reviews were searched. Terms representing STS and autologous HSCT were required in the title or abstract. In studies with aggregated data, participants with NRSTS and autologous HSCT had to constitute at least 80% of the data. Single-arm studies were included in addition to studies with a control arm because the number of comparative studies was expected to be very low. Two review authors independently extracted study data. Some studies identified in the original review were re-examined and found not to meet the inclusion criteria and were excluded in this update. For studies with no comparator group, we synthesized the results for studies reporting aggregate data and conducted a pooled analysis of individual participant data using the Kaplan-Meyer method. The primary outcomes were overall survival (OS) and treatment-related mortality (TRM). The selection process was carried out from the start of the search dates for the update. We included 57 studies, from 260 full text articles screened, reporting on 275 participants that were allocated to HDCT followed by autologous HSCT. All studies were not comparable due to various subtypes. We identified a single comparative study, an RCT comparing HDCT followed by autologous HSCT versus standard chemotherapy (SDCT). The overall survival (OS) at three years was 32.7% versus 49.4% with a hazard ratio (HR) of 1.26 (95% confidence interval (CI) 0.70 to 2.29, P value 0.44) and thus not significantly different between the treatment groups. In a subgroup of patients that had a complete response before treatment, OS was higher in both treatment groups and OS at three years was 42.8% versus 83.9% with a HR of 2.92 (95% CI 1.1 to 7.6, P value 0.028) and thus was statistically significantly better in the SDCT group. We did not identify any other comparative studies. We included six single-arm studies reporting aggregate data of cases; three reported the OS at two years as 20%, 48%, and 51.4%. One other study reported the OS at three years as 40% and one further study reported a median OS of 13 months (range 3 to 19 months). In two of the single-arm studies with aggregate data, subgroup analysis showed a better OS in patients with versus without a complete response before treatment. In a survival analysis of pooled individual data of 80 participants, OS at two years was estimated as 50.6% (95% CI 38.7 to 62.5) and at three years as 36.7% (95% CI 24.4 to 49.0). Data on TRM, secondary neoplasia and severe toxicity grade 3 to 4 after transplantation were sparse. The one included RCT had a low risk of bias and the remaining 56 studies had a high risk of bias. A single RCT with a low risk of bias shows that OS after HDCT followed by autologous HSCT is not statistically significantly different from standard-dose chemotherapy. Therefore, HDCT followed by autologous HSCT for patients with NRSTS may not improve the survival of patients and should only be used within controlled trials if ever considered.

Many studies show that camrelizumab combination therapy can significantly improve progression-free survival (PFS) and overall survival (OS) in non-small cell lung cancer (NSCLC). However, the time of camrelizumab to market is short, and there is no systematic evaluation of camrelizumab-based comprehensive treatment of NSCLC. To systematically evaluate the efficacy and safety of camrelizumab in comprehensively treating NSCLC. A systematic review and meta-analysis. Databases, including PubMed, Web of Science, Embase, and Cochrane, were searched by computer before August 2023 based on Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, and reports on the efficacy and safety of camrelizumab-based treatment for NSCLC were collected, and RevMan 5.4 software was employed for meta-analysis finally. Totally, 5 RCTs, 2 cohort studies, and 12 single-arm studies were included. The meta-analysis results revealed that, compared with the treatment without camrelizumab, the camrelizumab-based combination treatment considerably extended the OS (hazard ratio (HR) = 0.60, 95% confidence interval (CI): (0.44-0.82), p < 0.01), PFS (HR = 0.42, 95% CI: (0.28-0.63), p < 0.01), and event-free survival (EFS) (HR = 0.55, 95% CI: (0.44-0.68), p < 0.01). The median objective response rate in single-arm studies was 41% (95% CI: 28%-53%), and the disease control rate was 84% (95% CI: 78%-89%). Furthermore, in terms of the occurrence of grades 3-5 adverse events, the incidence of neutropenia was lower in the camrelizumab combination group than in the control group, while the incidence of leukopenia and rash was higher than in the combination group, and no significant difference was revealed in the incidence of other adverse events. Among single-arm studies, the incidence of grades 3-5 adverse events did not exceed 10%. Treatment combined with camrelizumab can effectively prolong OS, PFS, and EFS in NSCLC patients with good safety, camrelizumab combined with chemotherapy is an effective treatment option for NSCLC patients.

errata

The hazards of randomized phase II trials

To date, an empirical evaluation of the quality of control arms in randomized clinical trials (RCTs) leading to anticancer drug approvals by the US Food and Drug Administration (FDA) has not been undertaken. We sought to estimate the percentage of RCTs that used a control arm deemed suboptimal and led to FDA approval of anticancer drugs from January 1, 2013, to July 31, 2018. This quality improvement study included 143 anticancer drug approvals granted by the FDA from January 1, 2013, to July 31, 2018. All approvals based on single-arm studies (48 approvals) were excluded. Approvals based on RCTs were further investigated and each trial was analyzed for design, time of patient accrual, control arm, and primary end point. Standard-of-care therapy was determined by evaluating the literature and published guidelines 1 year prior to the start of trial enrollment. The percentage of approvals based on RCTs that used suboptimal control arms was then calculated. The quality of the control arm was deemed suboptimal if the choice of control agent was restricted to exclude a recommended agent, the control arm was specified but the recommended agent was unspecified, and if prior RCT data had demonstrated that the control agent was inferior to an available alternative. Estimated percentage of RCTs that used suboptimal control arms that led to FDA approval of anticancer agents between January 1, 2013, to July 31, 2018. A total of 145 studies that led to 143 drug approvals between January 1, 2013, and July 31, 2018, were included. Of these studies, 48 single-arm studies were excluded. The remaining 97 studies led to 95 drug approvals. Of these 95 approvals, 16 (17%) were based on RCTs with suboptimal control arms; 15 were international trials, and 1 was conducted in the United States. The type of approval was regular in 15 trials and accelerated in 1 trial. When categorized by the nature of suboptimal control, 4 (25%) trials omitted active treatment in control arm by limiting investigator's choice, 11 (63%) trials omitted active treatment in the control arm by using a control agent known to be inferior to other available agents or not allowing combinations, and 1 (13%) trial used a previously used treatment in the control arm with a known lack of benefit associated with reexposure. Although anticancer drug approvals are increasing, a proportion of these drugs are reaching the market without proven superiority to what is considered the standard of care at the time of patient enrollment in pivotal trials. The choice of control arm should be optimized to ensure that new anticancer agents being marketed are truly superior to what most clinicians would prescribe outside a clinical trial setting.

Quality of Control Arms in Randomized Trials of Chronic Lymphocytic Leukemia Enrolling in the USA: A Systematic Review

2500 Background: Temozolomide (TMZ) is an oral alkylating agent that penetrates the blood-brain barrier with moderate toxicity, and has shown anti-tumor activity in primary central nervous system lymphoma (PCNSL) in single arm studies. Our goal was to determine whether the addition of concomitant and adjuvant TMZ chemotherapy to standard treatment of high-dose methotrexate (HD-MTX) and whole brain radiotherapy (WBRT) for PCNSL improves survival in a randomized controlled trial. Methods: We did an open-label, randomized phase III trial at 30 hospitals in Japan enrolling immunocompetent patients (pts) aged 20-70 years with histologically confirmed newly diagnosed PCNSL. Pts enrolled at step 1 registration received HD-MTX (MTX; 3.5 g/m2 at day 1, 15, 29). Pts who received at least 1 cycle of HD-MTX were randomly assigned (1:1) at step 2 registration to receive WBRT (30 Gy) ± 10 Gy boost (control arm: A) or WBRT ± boost with concomitant TMZ (75 mg/m2 daily) and adjuvant TMZ (150-200 mg/m2 daily for 5 days every 28 days) for two years after initiation of HD-MTX or until tumor progression (experimental arm: B). Randomization was adjusted by institution, PS (0-1 / 2-3), age (≤60/≥61 years), presence or absence of intraparenchymal tumor after HD-MTX. The primary endpoint was overall survival (OS). The planned sample size was 130 pts in total, to provide an 80% power to detect a 0.52 hazard ratio (65% vs 80% in 2y-OS) for arm B to A and a one-sided alpha of 5%. Results: Between September 29, 2014 and October 15, 2018, 134 pts were enrolled, of whom 122 were randomly assigned and analyzed; 62 to arm A and 60 to arm B. At the planned interim analysis, the 2-y OS was 86.8% (95% CI: 72.5-94.0) in arm A and 71.4% (56.0-82.2) in arm B. The hazard ratio was 2.18 (95% CI: 0.95 to 4.98) with predictive probability for showing the superiority of arm B at the final analysis was calculated to be 1.3%. The study was terminated due to futility. The 2-y progression-free survival was 60.6% (43.6-73.8) in arm A and 49.9% (34.4-63.5) in arm B with a hazard ratio of 1.54 (0.88 to 2.70). The most common grade 3 and 4 toxicities were lymphopenia, observed in 7 (11.5%) pts during WBRT in arm A, 18 (30%) pts during WBRT + concomitant TMZ and 18 (37.5%) pts during adjuvant TMZ in arm B. Conclusions: This study failed to demonstrate the benefit of the addition of TMZ to WBRT and adjuvant TMZ in newly diagnosed PCNSL. Possible biomarkers including methylation status of the MGMT promoter in the tumors will be analyzed. Clinical trial information: jRCTs031180207 .

Evaluating Front Line Treatment Regimens for Waldenstrom Macroglobulinaemia: A Systematic Review and Meta-Analysis

Lazertinib is a third-generation tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR-TKI) that selectively inhibit common EGFR mutation and T790M mutation in non-small-cell lung cancer (NSCLC) patients. No previous studies have compared lazertinib to platinum-based chemotherapy. We have compared lazertinib with platinum-based chemotherapy in EGFR-mutated NSCLC patients after previous EGFR-TKI therapy. We retrospectively compared 200 patients from LASER201, LASER301, and LASER-PMS studies to 334 patients who were treated with platinum-based chemotherapy after previous EGFR-TKI from the Samsung Medical Center. After propensity score matching (PSM), we selected 156 patients from each group. The primary outcome was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), and time to treatment discontinuation (TTD) as secondary outcomes. The median follow-up of PFS was 15.61 months in the lazertinib group and 21.67 months in the external control group. The PFS was significantly longer in patients who were treated with lazertinib than those treated with platinum-based chemotherapy (10.97 months vs. 5.10 months; adjusted hazard ratio (HR) 0.40; 95% confidence interval (CI), 0.29-0.55; p < 0.01) after PSM. Lazertinib showed superior OS (32.23 months vs. 18.73 months; adjusted HR 0.45; 95% CI, 0.29-0.69; p < 0.001), ORR (64.1% vs. 47.4%), and TTD (11.66 months vs. 6.73 months; adjusted HR 0.54; 95% CI, 0.39-0.75; p < 0.001) compared to platinum-based chemotherapy. Based on this retrospective, external control study, lazertinib has demonstrated significantly better efficacy compared with platinum-based chemotherapy. The external controls provide important context to evaluate efficacy in single-arm studies.

Thalidomide in beta-thalassemia – a systematic review and meta-analysis

e16071 Background: The current standard of care for unresectable, locally advanced or metastatic HER2 positive gastric, esophageal and gastroesophageal junction adenocarcinomas is the combination of the anti HER 2 antibody trastuzumab and cytotoxic chemotherapy. In recent years, the addition of immune checkpoint inhibitors to this combination has been studied to determine if it can improve clinical outcomes for this disease. This systematic review and meta-analysis evaluated high-quality data from clinical trials to determine the role and efficacy of this triple combination treatment. Methods: A systematic search of English-language articles on PubMed, Cochrane and Google scholar was done to identify randomized trials (RCTs) investigating the use of triple combination treatment of anti-Her 2 antibody, chemotherapy and immune checkpoint inhibitor in the treatment of unresectable, locally advanced, or metastatic HER2 overexpression positive gastric, esophageal and gastroesophageal junction adenocarcinoma. Quality of the studies was assessed using the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2). Inverse variance was the statistical method used with random effects as the analysis model in the production of the Forest plot and calculation of risk ratio (RR) at 95% confidence intervals (CI). Results: Four (4) RCTs (N = 866) were included for quality assessment and data extraction. Two (2) of these RCTs (N = 80) were single arm studies which both showed favorable outcomes in terms of objective response rate and progression free survival. The two (2) other RCTS (N = 786), each had two arms (triple regimen versus comparator) and were used in the meta-analysis. Risk of bias was low and heterogeneity was low (I2 below 50%). Pooled results showed that in patients given triple combination regimen, there is statistically significant improvement in progression free survival (RR 1.55 95% CI 1.20-2.00, p 0.0007). There is also an increase in overall response rate in favor of the triple combination regimen, albeit not statistically significant (RR 1.31 95% CI 0.99-1.74, p = 0.06). Conclusions: The addition of an immune checkpoint inhibitor to the current standard of care of anti Her 2 antibody and chemotherapy provides meaningful results in terms of tumor response and progression free survival in Her 2 positive locally advanced or metastatic gastric and esophageal adenocarcinomas. More robust trials, and data on overall survival supporting the use of this triple regimen may help re-shape the current standard of care for this disease.

Introduction: Exocrine pancreatic insufficiency (EPI) is caused by multiple clinical conditions such as cystic fibrosis and chronic pancreatitis (CP). Standard management of EPI includes pancreatic enzyme replacement therapy (PERT) along with consultation with a dietitian. While PERTs have been on the market for several decades, newer publications on their clinical efficacy and safety raised the need for a comprehensive review of the literature. We aimed to identify the available evidence on the clinical efficacy and safety of treatments for EPI to understand the current treatment landscape and unmet need in patients with EPI. Methods: A systematic literature review (SLR) was conducted in Embase, Medline, and Evidence-Based Medicine databases from 2010 to 2022; conference proceedings from 2020 to 2022 were also searched. Articles were screened independently by two reviewers at abstract and full-text stage against predefined eligibility criteria. Results: We identified 26 journal publications and two conference abstracts, reporting on 22 randomized control trials, four observational studies, and two single-arm interventional studies. The most reported treatment was pancrelipase, specifically Creon® (n = 12). Fourteen studies reported coefficient of fat absorption (CFA) results. Across studies, patients experienced a considerable increase in CFA post-initiation of treatment regardless of intervention or timepoint. Mean change in CFA ranged from 7.5% in patients with CP who received placebo to 36% in patients with CP treated with Creon®. Ten studies reported coefficient of nitrogen absorption (CNA). Where reported, pancrelipase (including Creon®) increased CNA levels in EPI patients compared to placebo. Only one study compared PERT brands head-to-head: no significant differences were reported in the CNA-72 h values (Creon® 82.0% [SE: 1.2] vs. Zenpep® 80.9% [SE: 1.2]). Loss of body weight and low body mass index (BMI) are important features of EPI. Overall, treatment with PERT increased BMI and body weight, or limited their decline, with increases ranging from 0.1 to 6.1 kg. Based on the 18 studies that reported safety outcomes, PERT was considered safe and well tolerated. Conclusions: This SLR confirmed that PERT is an effective and tolerable treatment option for patients with EPI. However, nutritional parameters and health-related quality of life data were sparsely reported, and future clinical trials should look to incorporate these data given their importance in clinical practice and patient outcomes. Introduction: Exocrine pancreatic insufficiency (EPI) is caused by multiple clinical conditions such as cystic fibrosis and chronic pancreatitis (CP). Standard management of EPI includes pancreatic enzyme replacement therapy (PERT) along with consultation with a dietitian. While PERTs have been on the market for several decades, newer publications on their clinical efficacy and safety raised the need for a comprehensive review of the literature. We aimed to identify the available evidence on the clinical efficacy and safety of treatments for EPI to understand the current treatment landscape and unmet need in patients with EPI. Methods: A systematic literature review (SLR) was conducted in Embase, Medline, and Evidence-Based Medicine databases from 2010 to 2022; conference proceedings from 2020 to 2022 were also searched. Articles were screened independently by two reviewers at abstract and full-text stage against predefined eligibility criteria. Results: We identified 26 journal publications and two conference abstracts, reporting on 22 randomized control trials, four observational studies, and two single-arm interventional studies. The most reported treatment was pancrelipase, specifically Creon® (n = 12). Fourteen studies reported coefficient of fat absorption (CFA) results. Across studies, patients experienced a considerable increase in CFA post-initiation of treatment regardless of intervention or timepoint. Mean change in CFA ranged from 7.5% in patients with CP who received placebo to 36% in patients with CP treated with Creon®. Ten studies reported coefficient of nitrogen absorption (CNA). Where reported, pancrelipase (including Creon®) increased CNA levels in EPI patients compared to placebo. Only one study compared PERT brands head-to-head: no significant differences were reported in the CNA-72 h values (Creon® 82.0% [SE: 1.2] vs. Zenpep® 80.9% [SE: 1.2]). Loss of body weight and low body mass index (BMI) are important features of EPI. Overall, treatment with PERT increased BMI and body weight, or limited their decline, with increases ranging from 0.1 to 6.1 kg. Based on the 18 studies that reported safety outcomes, PERT was considered safe and well tolerated. Conclusions: This SLR confirmed that PERT is an effective and tolerable treatment option for patients with EPI. However, nutritional parameters and health-related quality of life data were sparsely reported, and future clinical trials should look to incorporate these data given their importance in clinical practice and patient outcomes.