scholarly journals Visualizing adverse events in clinical trials using correspondence analysis with R-package visae

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Márcio A. Diniz ◽  
Gillian Gresham ◽  
Sungjin Kim ◽  
Michael Luu ◽  
N. Lynn Henry ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Correspondence Analysis ◽  
Ductal Carcinoma ◽  
Single Agent ◽  
R Package ◽  
Two Dimensional ◽  
Loss Of Information ◽  
Essential Components ◽  
Shiny App

Abstract Background Graphical displays and data visualization are essential components of statistical analysis that can lead to improved understanding of clinical trial adverse event (AE) data. Correspondence analysis (CA) has been introduced decades ago as a multivariate technique that can communicate AE contingency tables using two-dimensional plots, while quantifying the loss of information as other dimension reduction techniques such as principal components and factor analysis. Methods We propose the application of stacked CA using contribution biplots as a tool to explore differences in AE data among treatments in clinical trials. We defined five levels of refinement for the analysis based on data derived from the Common Terminology Criteria for Adverse Events (CTCAE) grades, domains, terms and their combinations. In addition, we developed a Shiny app built in an R-package, visae, publicly available on Comprehensive R Archive Network (CRAN), to interactively investigate CA configurations based on the contribution to the explained variance and relative frequency of AEs. Data from two randomized controlled trials (RCT) were used to illustrate the proposed methods: NSABP R-04, a neoadjuvant rectal 2 × 2 factorial trial comparing radiation therapy with either capecitabine (Cape) or 5-fluorouracil (5-FU) alone with or without oxaliplatin (Oxa), and NSABP B-35, a double-blind RCT comparing tamoxifen to anastrozole in postmenopausal women with hormone-positive ductal carcinoma in situ. Results In the R04 trial (n = 1308), CA biplots displayed the discrepancies between single agent treatments and their combinations with Oxa at all levels of AE classes, such that these discrepancies were responsible for the largest portion of the explained variability among treatments. In addition, an interaction effect when adding Oxa to Cape/5-FU was identified when the distance between Cape+Oxa and 5-FU + Oxa was observed to be larger than the distance between 5-FU and Cape, with Cape+Oxa and 5-FU + Oxa in different quadrants of the CA biplots. In the B35 trial (n = 3009), CA biplots showed different patterns for non-adherent Anastrozole and Tamoxifen compared with their adherent counterparts. Conclusion CA with contribution biplot is an effective tool that can be used to summarize AE data in a two-dimensional display while minimizing the loss of information and interpretation.

scholarly journals Immune-related adverse events (irAEs) with single-agent PD-1 vs PD-L1 inhibitors: A meta-analysis of 8,730 patients from clinical trials

2019 ◽  
Vol 30 ◽  
pp. v527-v528
Author(s):  
G.P. Sonpavde ◽  
P. Grivas ◽  
Y. Lin ◽  
D. Hennessy ◽  
J.D. Hunt
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Meta Analysis ◽  
Single Agent

Efficacy and Safety of Single-Agent Ruxolitinib Therapy for Myelofibrosis and Polycythemia Vera: A Meta-Analysis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1622-1622
Author(s):  
Shijia Zhang ◽  
Yucai Wang ◽  
Larysa Sanchez ◽  
Narjust Duma ◽  
Victor Chang
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Polycythemia Vera ◽  
Standard Therapy ◽  
Meta Analysis ◽  
Single Agent ◽  
Efficacy And Safety ◽  
Spleen Volume ◽  
Peripheral Edema ◽  
Pooled Data

Abstract Background: Ruxolitinib, a potent JAK1/JAK2 inhibitor, was approved by the FDA for the treatment of myelofibrosis (MF) and polycythemia vera (PV) in 2011 and 2014, respectively. The aim of this study was to evaluate the efficacy and safety data of single-agent ruxolitinib in patients with MF or PV through meta-analysis of reported clinical trials. Methods: PubMed and Web of Science databases were searched for clinical trials of ruxolitinib for the treatment of MF or PV through June 30th, 2015. Only clinical trials in which ruxolitinib was used as single-agent therapy for MF or PV were included in this meta-analysis. Pooled odds ratios (ORs) for proportion of patients with >= 35% reduction in spleen volume (primary outcome) and risk ratios (RRs) for dichotomous data with 95% confidence interval (CI) were analyzed using OpenMeta[Analyst] with a random effect model. Pooled ratios of adverse events of ruxolitinib therapy were also calculated. Results: Six clinical trials including 3 randomized controlled trials (RCTs) of 987 patients were identified and included in the analysis. Four studies were conducted in MF patients, and 2 studies in PV patients. Pooled data from the 3 RCTs (2 for MF and 1 for PV) showed that ruxolitinib, compared to placebo or standard therapy/best available therapy (BAT), significantly increased the proportion of patients with a reduction in spleen volume of 35% or more (OR = 79.55, 95% CI = 22.51-281.11, p < 0.001). Ruxolitinib improved the symptoms associated with MF or PV. Only the 2 RCTs for MF analyzed overall survival (OS), one of which showed OS benefit with ruxolitinib. Pooled data from all 6 trials showed that the most common hematologic adverse events were all grades anemia (71.8%) and thrombocytopenia (54.1%), regardless of whether or not they were deemed related to ruxolitinib therapy. Incidence of grades 3/4 anemia and thrombocytopenia was 30.2% and 15.3%, respectively, but rarely led to discontinuation of the drug. The most common non-hematologic adverse events were diarrhea (all grades = 18.1%, grades 3/4 = 1.1%), fatigue (all grades = 14.0%, grades 3/4 = 2.0%), peripheral edema (all grades = 12.0%, grades 3/4 = 0%), and dyspnea (all grades = 10.0%, grades 3/4 = 0.9%). Further analysis was conducted to evaluate the attributable risks of the adverse events using data from the 3 RCTs. Compared to placebo or standard therapy/BAT, ruxolitinib significantly increased the risk of developing all grades anemia (RR = 1.10, 95% CI = 1.03-1.17, p = 0.005), grades 3/4 anemia (RR = 1.87, 95% CI = 1.20-2.93, p = 0.006), all grades thrombocytopenia (RR = 2.04, 95% CI = 1.47-2.83, p < 0.001), but not grades 3/4 thrombocytopenia (RR = 2.04, 95% CI = 0.72-7.98, p = 0.153), all grades diarrhea (RR = 1.45, 95% CI = 0.96-2.20, p = 0.079), fatigue (RR = 0.865, 95% CI = 0.62-1.20, p = 0.382), peripheral edema (RR = 0.85, 95% CI = 0.61-1.18, p = 0.337), and dyspnea (RR = 1.25, 95% CI = 0.63-2.49, p = 0.520). Conclusions: Single-agent ruxolitinib therapy results in improvement of symptoms in MF or PV and significant reduction in spleen size compared to placebo or standard therapy/BAT. Anemia and thrombocytopenia were the most common hematologic adverse events, but rarely led to the discontinuation of therapy. Diarrhea, fatigue, peripheral edema and dyspnea were the most common non-hematologic adverse events, but not significant compared to placebo or standard therapy/BAT. Disclosures Chang: Johnson & Johnson: Other: Stock.

scholarly journals A Phase II Study of Brentuximab Vedotin (BV) in the Treatment of Elderly Hodgkin Lymphoma (HL) Patients at First Relapse or with Primary Refractory Disease — FIL_BVHD01

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2920-2920 ◽  
Author(s):  
Lorenzo Tonialini ◽  
Vittorio Stefoni ◽  
Alessandro Re ◽  
Arben Lleshi ◽  
Maurizio Bonfichi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Phase Ii Study ◽  
Single Agent ◽  
Brentuximab Vedotin ◽  
Advisory Committees ◽  
Younger Patients ◽  
First Relapse

Abstract Older age (≥60 years) has consistently been identified as an independent adverse prognostic factor for Hodgkin lymphoma (HL) survival in population-based studies and clinical trials in the last several decades. Elderly HL patients are significantly underrepresented in clinical trials and have a markedly inferior prognosis compared with younger patients. Brentuximab vedotin (BV) is an antibody-drug conjugate linking the microtubule-disrupting agent monomethylauristatin E to an anti-CD30 antibody. BV monotherapy yields an objective response rate (ORR) of 75% in relapsed HL, with a subset of patients having durable remissions at 5 years. In a retrospective analysis of BV activity in patients aged ≥60 years with relapsed HL, ORR was 56%. Although higher rates of adverse events (AEs) such as anemia, fatigue, and neuropathy were seen in older compared with younger patients, BV was tolerable overall, and a significant proportion of older patients had clinical benefit. Based upon this favorable experience, our phase II study evaluated the efficacy and safety of BV as a single agent in elderly patients at first relapse or with primary refractory HL. This was a single-arm, open-label, multicenter, clinical trial. The primary endpoint of this study was the ORR. Main secondary endpoints were: duration of response, complete remission rate, progression free and overall survival at 1 year and type, incidence, severity, seriousness, and relatedness of any adverse events occurring during the study period. ClinicalTrials.gov identifier NCT02227433. Twenty patients were enrolled, 2 results in screening failure and 1 patient was treated in protocol violation (more of 1 previous therapy). Eighteen patients were considered for safety analysis, whereas 17 subjects were included in the efficacy analysis. BV (1.8 mg/kg) was administered as a single IV infusion on Day 1 of each 21-day cycle for a maximum of 16 cycles. Three patients interrupted BV treatment before the first scheduled restaging (right after the IV cycle): 2 due to toxicity and 1 due to clinical progression of disease (PD). At first restaging, ORR was 52.9% (4 complete response [CR] and 5 partial response [PR]). Eight patients proceeded till the second restaging (VIII cycle) with and ORR of 17.7% (1 CR and 2 PR). Only 2 patients completed all the 16 scheduled cycles: they achieved finally a CR and a PR, respectively. These two patients are still in response at the latest available follow up. Seven patients had early treatment discontinuation due to toxicity, mainly due to neuropathy grade II-III (3 out of 7). The objective of the study, i.e. at least 13 responses, was not reached and BV doesn't seem to be an effective single agent for elderly HL patients at first relapse. Nevertheless, prolonged disease control (more than 12 months) was registered in two patients, suggesting that some subjects can benefit from this salvage treatment. Disclosures Zinzani: Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau; Astra Zeneca: Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Efficacy and Toxicity Profile of Elotuzumab for Multiple Myeloma: A Systematic Review and Meta-Analysis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5640-5640
Author(s):  
Faiza Jamil ◽  
Madeeha Shafqat ◽  
Sharoon Samuel ◽  
Zunairah Shah ◽  
Ceren Durer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Adverse Events ◽  
Meta Analysis ◽  
Single Agent ◽  
Random Effect Model ◽  
Drug Regimen ◽  
Pooled Analysis ◽  
Cochrane Library ◽  
Control Group

Abstract Background: Elotuzumab (elo) is a humanized monoclonal antibody, which has been approved by the FDA for use in combination with lenalidomide (lena) and dexamethasone (dexa) in patients (pts) with relapsed and refractory multiple myeloma (RRMM). Elotuzumab is effective as a single agent, as well as in combination for multiple myeloma treatments, supporting the use of elo in pts with RRMM and newly diagnosed multiple myeloma (NDMM) pts. Method: After review of literature using database searches was done on 6/27/18 (Pubmed, Embase, Cochrane Library, Web of Science and Clinical Trials.gov), 9 prospective and 1 retrospective study with 1128 enrolled pts met the inclusion criteria to date in RRMM and 2 clinical trials including 123 pts in NDMM (Table 1). CMA software v.3 was used for meta-analysis. A random-effect model was applied. Result: Regimens used in RRMM: Based on pooled analysis (95% CI), an overall response rate (ORR) of 66% (54-76.2) was calculated in 685 evaluable pts treated with elo based regimens in RRMM (Figure 1). Most common grade (G) ≥ 3 hematological adverse events (HAE) and non-hematological adverse events (NHAE) based on regimen were calculated using pooled analysis in RRMM pts (Table 2). Anemia was noted in 12.1% ( 7.7-18.6) in 559 pts, while neutropenia in 14.5% (7.5-26.4) out of 591 pts and thrombocytopenia (tcp) in 11.9% (7.9-17.4) in 198 evaluable pts. Diarrhea 5.5% (3.6-8.3), pyrexia 2.4% (1.5-4), peripheral neuropathy (PN) 8.4% (3.8-17.8) were measured in 626, 668 and 143 pts respectively. Elotuzumab as monotherapy: 1 study (n=34) evaluated the efficacy of elo as single agent in RRMM. The median age, time from diagnosis and number of prior therapies were 64.5 years (y) (46-87), 4.4 y (0.9-12.8) and 4.5 y (2-10) respectively. It produced an ORR of 1.4% (0.1-19.1 95% CI) in 34 evaluable pts. Adverse events recorded were pyrexia and fatigue in 17.6% and 8.8% pts respectively. Elotuzumab in two drug regimen: In RRMM, 2 clinical trials (n=49) evaluated the efficacy (95% CI) of elo, ORR of 25% (4.1-72.3) was calculated. The best PFS (progression free survival) produced was in combination of elo 20 mg with bortezumib (bort) 1.3mg/m2 of 9.46 months as compared to 1.8 months when elo10mg/kg + dexamethasone (dexa) 28mg was used. In our analysis for safety, common G≥ 3 HAE calculated were, thrombocytopenia 8.7% (3.3-21.1) n=49, neutropenia 10.7 % (3.5-28.4) n=28 pts and anemia 7.1% (1.8-24.5) n=28 pts. NHAE included diarrhea 1.7% (0.1-22.3), PN 10.7% (3.5-28.4), pyrexia 1.7% (0.1-22.3) in 28 evaluable pts each. Elotuzumab in three drug regimen: In RRMM, 10 clinical trials including 602 pts evaluated the efficacy of elo as a part of triple drug regimen, producing an ORR of 72.2% (54-76.2). The best results were produced with the combination of elo 10-20mg/kg + lenalidomide (lena) 25mg + dexa 40mg producing a PFS of 32.2 mo and 28.62 mo in its phase I and II cohorts respectively. Based on pooled analysis (95% CI) common HAE calculated were neutropenia 17.5% (7.6-35.4) in n=563, thrombocytopenia 12.7% (8.2-19.4) in n=149 and anemia 13% (8-20.5) in n=531 pts. Common G ≥ 3 NHAE estimated were diarrhea 5.7% (3.7-8.6), PN 6.6% (2-19.2), pyrexia 2.5% (1.5-4.1) in 598, 115 and 640 pts respectively. Elotuzumab based regimen in NDMM: A currently ongoing clinical trial NCT02272803 has produced promising results in NDMM pts. As a part of three drug regimen with dose of elo 10mg/kg-20mg/kg, lena 25mg, dexa 20mg in 40 pts produced an ORR of 87.5% (73.2-95.8) versus control group of lena 25mg plus dexa 40mg in 42 pts with an ORR of 73.8% (58-86.1). The PFS rate recorded at 1 year was 93% (79-98%) and 91% (73-97%) respectively. The HAE G ≥ 3 included, neutropenia 18% and leukopenia 15%. In another study with 41 pts, elo was used in combination with lena, bort and dexa producing an ORR of 100% and greater than grade 3 adverse events including Tcp 15%, PN 2%. Conclusion: Results produced in our study suggest that elotuzumab is highly effective when used in pts with RRMM and NDMM. Combination regimens for elo produces an ORR ranging from 79-83% with elo + lena+ dexa, proving that the best results were produced by three drug regimens. Large prospective studies are required to evaluate efficacy and safety of elotuzumab in combination therapies. Disclosures No relevant conflicts of interest to declare.

Tolerability of axitinib in advanced renal cell carcinoma: A meta-analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16536-e16536
Author(s):  
Bareia Chaudhry ◽  
Shenhong Wu
Keyword(s):  
Renal Cell Carcinoma ◽  
Clinical Trials ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Fixed Effects ◽  
Meta Analysis ◽  
Single Agent ◽  
Advanced Renal Cell Carcinoma ◽  
Discontinuation Rate

e16536 Background: Axitinib has been used extensively as a single agent or in combination with immunotherapy in the treatment of advanced renal cell carcinoma. It can be often discontinued due to adverse events. A meta-analysis of clinical trials was performed to evaluate the overall tolerability of axitinib in this setting. Methods: PubMed (Up to November 2020) was searched to identify clinical trials of axitinib in advanced or metastatic renal cell carcinoma. Reported data was collected to include axitinib and control discontinuation due to adverse events. A random or fixed effects model was used to determine summary incidences, relative risks, and 95% confidence intervals depending on the heterogeneity of included studies. Results: A total of 11 studies including 4,056 patients (axitinib alone n = 1384, axitinib combination n = 987, control n = 1685) were included for analysis. The summary discontinuation rate for axitinib due to adverse events was 13.4% (95% CI; 11.7-15.2%) with 8.9% (95% CI: 5.3-14.6%) as a single agent and 26.6% (95% CI:17.8 –37.8%) in combination with other agents. In comparison with controls based on randomized controlled studies, axitinib overall has similar discontinuation rate due to adverse events (RR: 1.18, 95% CI: 0.77-1.80). However, there was a significantly higher discontinuation rate with axitinib in combination with other agents including immunotherapeutic agents PD-L1 inhibitors than control treatment (RR: 1.52, 95% CI: 1.24-1.86). Conclusions: The tolerability of axitinib may vary significantly with its use as a single agent or in combination in the treatment of advanced renal cell carcinoma. Further studies are needed to improve its tolerability as a part of combination therapy.

Landscape review of the patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) in oncology: Adoption and recent learnings.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18587-e18587
Author(s):  
Antoine Regnault ◽  
Stephane Quéré ◽  
Boris Gorsh ◽  
Sandhya Sapra ◽  
Angély Loubert ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Analytical Methods ◽  
Linear Models ◽  
Single Agent ◽  
Patient Reported Outcome ◽  
Item Selection ◽  
Antibody Drug Conjugate ◽  
Patient Reported ◽  
Over Time

e18587 Background: The PRO-CTCAE is a patient-reported outcome measure of symptomatic toxicity in oncology trials designed to complement CTCAE criteria (clinician’s measure of adverse events [AEs]). Items for evaluation are selected from 78 symptomatic toxicities in the CTCAE. PRO-CTCAE uptake and use has not been uniformly assessed; understanding how to best analyze and present PRO-CTCAE data is important. We reviewed literature on clinical trials reporting the PRO-CTCAE to ascertain its use and current analytical methods to inform future analyses. Methods: A review of the literature and ongoing oncology trials using PubMed, oncology and outcomes research conferences (ASCO, ASH, ISOQOL, ISPOR), and ClinicalTrials.gov was completed August 2019; updated November 2020. Selected literature included guidance on: item selection; analytical methods; PRO-CTCAE data/endpoint use in clinical trials. Analytical and visualization methods from the literature were used to inform the specification of PRO-CTCAE analyses conducted on data from the DREAMM-2 (NCT03525678) trial of single-agent belantamab mafodotin (belamaf; BLENREP), a B-cell maturation antigen–binding antibody–drug conjugate, in relapsed/refractory multiple myeloma. Results: After screening (n = 197), 45 articles were reviewed: 13 related to recommendations for use/analysis, 7 to item selection, and 25 to examples of PRO-CTCAE use. 118 completed/ongoing trials reported PRO-CTCAE use (17 [14%] Phase I or I/II; 73 [62%] Phase II, II/III, or III; 3 [3%] Phase IV; 25 had no phase reported). Most (92/118, 78%) trials included the PRO-CTCAE as a secondary endpoint. The number of trials using the PRO-CTCAE increased from 3 in 2015 to 30 in 2020. PRO-CTCAE data in the literature were reported descriptively using tables (maximum post-baseline ratings; mean change over time; ratings higher than a predefined cutoff) and graphs (line graphs; stacked bar charts; heatmaps). These and more sophisticated analyses were applied to DREAMM-2 data to best capture the dynamics of patient-reported AEs over time, or control for baseline PRO-CTCAE ratings (eg, Toxicity over Time approach; ordinal log-linear models). Conclusions: The importance of tolerability and symptomatic AEs for patients is increasingly recognized, particularly for new therapies. This landscape review demonstrates recent growth in interest and adoption of PRO-CTCAE. There are few existing standards for analysis; this research increases understanding of existing methods and further evaluates ways of analyzing and presenting PRO-CTCAE data over time. Additional research exploring innovative methods to analyze PRO-CTCAE data and address its challenges is needed. Funding Source: GlaxoSmithKline (212225). Drug linker technology licensed from Seagen Inc.; mAb produced using POTELLIGENT Technology licensed from BioWa.

scholarly journals Real-World Outcomes of Patients Treated with Single-Agent Ibrutinib for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): A Systematic Review and Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-14
Author(s):  
Matthew C. Cheung ◽  
Irina Amitai
Keyword(s):  
Atrial Fibrillation ◽  
Clinical Trials ◽  
Adverse Events ◽  
Real World ◽  
Meta Analysis ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Drug Discontinuation ◽  
Small Lymphocytic Lymphoma ◽  
Dose Reductions

BACKGROUND: Ibrutinib improves progression-free survival (PFS) compared to chemo-immunotherapy in both previously untreated and relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; hereafter, CLL) patients. Adverse events, such as atrial fibrillation, bleeding and fungal infections, are the leading cause of drug discontinuation. Observational studies of real-world patients suggest that the rate of ibrutinib-related adverse events is higher in practice than in clinical trials. Dose reductions and drug discontinuations are more common, which may affect outcomes, although evidence has been conflicting. OBJECTIVES: The objective of this study is to systematically review and synthesize real-world toxicity and tolerability of CLL patients on ibrutinib. METHODS: Prospective and retrospective cohort studies and case series of patients with CLL treated with single agent ibrutinib as first or subsequent line treatment outside of clinical trials were retrieved from the Pubmed, Embase, and CENTRAL databases. Studies were critically appraised using Joanna-Briggs Institute checklists. Meta-analyses of studies deemed of moderate to high quality were done if the risk of heterogeneity was low. RESULTS: We screened 4458 titles and abstracts and moved 251 records to full-text review. 25 full-text studies were included in the qualitative analysis. Most studies were of low to moderate quality. Rates of any bleeding ranged from 5.4 to 54.1 events/100 persons-year. Rates of severe bleeding ranged from 0 to 6.4 events/100 persons-year. Rate of infection was 9.2 to 49.8 infections/100 persons-year. Rate of atrial fibrillation varied from 2.5 to 26.0 events/100 persons-year. Pooled estimate of risk of atrial fibrillation per 100 person-years was 7.0 (95% CI 5.8, 8.2) by meta-analysis of moderate quality studies. Rate of dose reductions varied from 15.1 to 26.8 events/100 person-years, and dose reductions did not affect outcomes. The rate of drug discontinuation varied from 6.4 to 55.2 events/100 person-years. The most common cause for drug discontinuation was adverse events. CONCLUSION: The risk of atrial fibrillation is higher in the real-world than reported from clinical trials. There was a large range of prevalence of other bleeding and infection. These adverse events were the leading cause of dose reduction and drug discontinuation. This study has many limitations arising from heterogeneity of patient characteristics and outcomes ascertainment. This highlights the need for standardized post-marketing studies of new drugs and for inclusive criteria for inclusion into randomized controlled trials. Disclosures No relevant conflicts of interest to declare.

Crizotinib Versus Chemotherapy on ALK-positive NSCLC: A Systematic Review of Efficacy and Safety

2018 ◽  
Vol 19 (1) ◽  
pp. 41-49 ◽  
Author(s):  
Mingxia Wang ◽  
Guanqi Wang ◽  
Haiyan Ma ◽  
Baoen Shan
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Adverse Events ◽  
Objective Response Rate ◽  
Retrospective Studies ◽  
Response Rate ◽  
Objective Response ◽  
Treated Group ◽  
Efficacy And Safety ◽  
Alk Positive

Introduction: Crizotinib was approved to treat anaplastic lymphoma kinase (ALK)- positive non-small cell lung cancer (NSCLC) by the Food and Drug Administration in 2011.We conducted a systematic review of clinical trials and retrospective studies to compare the efficacy and safety of crizotinib with chemotherapy. </P><P> Methods: We searched electronic databases from inception to Dec. 2016. Clinical trials and retrospective studies regarding crizotinib and crizotinib versus chemotherapy in treatment of NSCLC were eligible. The primary outcomes were the objective response rate (ORR) and disease control rate (DCR). Results: Nine studies (five clinical trials and four retrospective studies) including 729 patients met the inclusion criteria. Crizotinib treatment revealed 1-year OS of 77.1% and PFS of 9.17 months. And crizotinib had a better performance than chemotherapy in ORR (OR: 4.97, 95%CI: 3.16 to 7.83, P<0.00001, I2=35%). DCR revealed superiority with crizotinib than chemotherapy (OR: 3.42, 95% CI: 2.33 to 5.01, P<0.00001, I2=0%). PR (partial response) were significant superior to that of chemotherapy through direct systematic review. No statistically significant difference in CR (complete response) was found between crizotinib-treated group and chemotherapy-treated group. Regarding SD (stable disease), chemotherapy-treated group had a better performance than crizotinib-treated group. Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, nausea, and hematologic toxicity. This systematic review revealed improved objective response rate and increased disease control rate in crizotinib group comparing with chemotherapy group. Crizotinib treatment would be a favorable treatment option for patients with ALK-positive NSCLC. ALK inhibitors may have future potential applications in other cancers driven by ALK or c-MET gene mutations.

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