Fatal adverse events associated with pembrolizumab in cancer patients: A meta-analysis.

2561 Background: Pembrolizumab, an immune checkpoint inhibitor (ICI) against programmed cell death-1(PD-1) protein has emerged as an effective treatment for many cancers. Although better tolerated than chemotherapy, it has unique immune related adverse event and little is known about its risk of fatal adverse events (FAE). Therefore, we conducted a meta-analysis of clinical trials to determine the incidence and risk of fatal adverse events with pembrolizumab. Methods: A systematic search for phase I-III clinical trials of pembrolizumab was conducted using databases from PUBMED, and abstracts presented at the American Society of Clinical Oncology (ASCO) conferences until October 2018. Eligible studies included prospective clinical trials of pembrolizumab with available data on FAE. Data on FAE was extracted from each study and pooled for calculations. Incidence, relative risk (RR) and 95% confidence intervals (CI) were calculated by employing fixed or random-effects models. Results: A total of 11 clinical trials of pembrolizumab, with 3713 patients were included for analysis. The overall incidence of FAE with pembrolizumab was 1.2% (95% CI: 0.5-2.8%).The incidence of FAE significantly varied among different tumor types (P=0.02), ranging from 0.2% in melanoma to 3.1% in breast cancer.The incidence of FAE was significantly higher (P<0.001) with chemotherapy plus pembrolizumab (7.0%, 95%CI: 4.9-10%) as compared to pembrolizumab alone (0.7%, 95% CI: 0.4-1.2, p=<0.001). There was no significant difference in the risk of FAEs when pembrolizumab was compared with chemotherapy with RR=1.24 (95% CI: 0.8-1.89, P=0.31). Conclusions: Pembrolizumab is similar to chemotherapy in the risk of fatal adverse events in cancer patients. Combination of pembrolizumab with chemotherapy increased the risk of FAE in comparison with pembrolizumab alone. Further studies are needed to identify risk factors. [Table: see text]

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Improving tolerability of pembrolizumab with weight based dosing: A meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2639 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2639-2639

Author(s):

Nabeela Khan Patail ◽

Amna Falak Sher ◽

Shenhong Wu

Keyword(s):

Clinical Trials ◽

Adverse Events ◽

Cancer Patients ◽

Meta Analysis ◽

Placebo Control ◽

Clinical Activity ◽

Discontinuation Rate ◽

Random Effects Models ◽

American Society ◽

The Impact

2639 Background: Pembrolizumab, a PD-1 immune checkpoint inhibitor (ICI), has demonstrated significant clinical activity in various cancers. Despite a favorable toxicity profile, discontinuation due to adverse events including immune related adverse events (irAE) has been reported. We conducted a meta-analysis of published clinical trials to evaluate the tolerability of pembrolizumab in cancer patients. Methods: A systematic review was conducted of relevant studies from the databases of PubMed and abstracts presented at American Society of Clinical Oncology (ASCO) from June 2015 until September 2020. Eligible studies included prospective clinical trials that reported a discontinuation rate due to adverse effects. Incidence, relative risk and 95% confidence intervals (CI) were calculated by employing fixed or random effects models. Results: A total of 6,380 patients with a variety of hematologic and solid malignancies from 20 studies of pembrolizumab were included for analysis. The overall rate of pembrolizumab discontinuation due to adverse events was 8.2% (95% CI: 6.4-10.4%). The discontinuation rate of pembrolizumab was not significantly lower than the chemotherapy controls, with RR of 0.84 (95% CI: 0.58-1.12, p = 0.33). However, the discontinuation rate of pembrolizumab was significantly higher compared to placebo control with RR of 2.20 (95% CI: 1.36-3.54, p < 0.001), and significantly lower compared to ipilimumab with RR of 0.58 (95% CI: 0.34-0.99, p = 0.04) respectively. The discontinuation rate varied widely among different tumor types with the lowest rate of 0.8% (95% CI: 0.2-3%) in gastric cancer, and the highest of 13.5% (95% CI: 10.8-16.8%) in head and neck squamous cell carcinoma. Interestingly, the discontinuation rate varied with pembrolizumab dosing, with the fixed dosing of 200mg being 9.2% (95% CI: 6.9-12%) and the weight-based dosing being 6.5% (95% CI: 4.8-8.8%). The weight-based dosing was associated with a significantly lower discontinuation rate compared to controls with RR of 0.62 (95% CI: 0.47-0.81, p < 0.0001), while the fixed dosing had similar discontinuation rate with RR of 1.03 (95% CI: 0.89-1.20, p = 0.67). Conclusions: The tolerability of pembrolizumab may be comparable to chemotherapy in cancer patients and may vary with its dosing. Future studies are warranted to evaluate the impact of different dosing.

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Risk of pneumonitis with mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e13573 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e13573-e13573

Author(s):

Vishal Navnitray Ranpura ◽

Shenhong Wu

Keyword(s):

Clinical Trials ◽

Cancer Patients ◽

Meta Analysis ◽

Single Agent ◽

Mammalian Target Of Rapamycin ◽

Cancer Therapeutics ◽

Mtor Inhibitors ◽

High Grade ◽

Significant Difference ◽

American Society

e13573 Background: Pneumonitis is associated with the use of mTOR inhibitors, everolimus and temsirolimus, which have been used widely in cancer therapeutics and clinical trials. Currently, the overall risk of pneumonits in patients treated with mTOR inhibitors has not been defined. We performed a systematic review and meta-analysis of published clinical trials to assess the risk of pneumonitis in cancer patients treated with mTOR inhibitors. Methods: Databases from PUBMED, the Web of Science, and abstracts presented at the American Society of Clinical Oncology conferences until May 2012 were searched to identify relevant studies. Eligible studies included prospective clinical trials in which patients received treatment with everolimus or temsirolimus as a single agent or in combination with other agents. Summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated employing a fixed- or random-effects model based upon the heterogeneity of the included studies. Results: A total of 2,303 patients with a variety of tumors from 18 studies (everolimus: 12, temsirolimus: 6) were included for the analysis. The overall incidences of all-grade and high-grade pneumonitis with mTOR inhibitors were 6.5% (95% CI: 3.7-11.1%) and 2.5% (95% CI 1.2-5.4%) respectively. The risk of all-grade pneumonitis did not vary significantly with tumor types (P=0.079), but vary significantly with their combination with other agents (P<0.001). There was no significant difference between everolimus and temsirolimus in the incidence of all-grade (P=0.22) and high-grade (P=0.28) pneumonitis. In comparison with controls, mTOR inhibitors significantly increased the risk of all-grade (RR=5.2, 95% CI: 2.09-12.93, P<0.001) but not high-grade pneumonits (RR=2.63, 95% CI: 0.66-10.40, P=0.41). Conclusions: The risk of pneumonitis is increased in cancer patients receiving mTOR inhibitors without significant difference between everolimus and temsirolimus.

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Risk of proteinuria with the new angiogenesis inhibitor axitinib in patients with cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e20602 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e20602-e20602

Author(s):

Andrew Kuei ◽

Xiaolei Zhu ◽

Shenhong Wu

Keyword(s):

Clinical Trials ◽

Cancer Patients ◽

Meta Analysis ◽

Significant Risk ◽

Angiogenesis Inhibitor ◽

Growth Factor Receptor ◽

High Grade ◽

Random Effects Models ◽

Treatment Interruptions ◽

Significant Difference

e20602 Background: The use of axitinib, a potent inhibitor of vascular endothelial growth factor receptor (VEGFR), is associated with proteinuria, which may cause morbidity and treatment interruptions in cancer patients. We performed a systematic review and meta-analysis of published clinical trials to assess the overall risk of proteinuria with axitinib. Methods: Potentially relevant studies were identified by searching databases including Pubmed and abstracts presented at the American Society of Clinical Oncology annual meetings until June, 2012. Eligible studies included prospective clinical trials in cancer patients treated with axitinib containing data on proteinuria. Summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated using the fixed- or random-effects models. Results: A total of 1,671 patients with advanced renal cell carcinoma (RCC) and other solid tumors from 9 studies were included for analysis. The overall incidences of all-grade and high-grade (grade 3 or 4) proteinuria with axitinib were 22.7% (95% CI: 10.4-42.6%) and 3.8% (95% CI: 2.6-5.7%) respectively. The risk did not vary significantly with tumor types (P=0.13). There was no significant difference between RCC and non-RCC patients (P=0.45), although the incidence in RCC patients was higher (30.0%, 95% CI: 8.4-66.7 versus 17.5%, 95% CI: 7.4-36.3%). In comparison with a control (gemcitabine), axitinib significantly increased the incidence of high-grade proteinuria (3.3%, 95% CI: 1.6-6.5% versus 0.1%, 95% CI: 0-2.3%; P=0.031). When compared to another angiogenesis inhibitor sorafenib, axitinib did not have a significantly higher risk of all-grade (RR=1.48, 95% CI: 0.92-2.38, P=0.10) and high-grade proteinuria (RR=1.81, 95% CI: 0.68-4.85, P=0.24). Conclusions: There was a significant risk of proteinuria associated with the use of axitinib in cancer patients.

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Efficacy and safety of sprifermin injection for knee osteoarthritis treatment: a meta-analysis

Arthritis Research & Therapy ◽

10.1186/s13075-021-02488-w ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Ni Zeng ◽

Xin-Yuan Chen ◽

Zhi-Peng Yan ◽

Jie-Ting Li ◽

Tao Liao ◽

...

Keyword(s):

Adverse Events ◽

Knee Osteoarthritis ◽

Meta Analysis ◽

Placebo Treatment ◽

Cartilage Volume ◽

Cartilage Thickness ◽

Random Effects Models ◽

Structural Progression ◽

Significant Difference ◽

Mean Differences

Abstract Objective To perform a meta-analysis comparing the structural progression and clinical symptom outcomes as well as adverse events experienced from intra-articular injections of sprifermin compared to a placebo treatment for patients with knee osteoarthritis (KOA). Method We systematically searched the literature for studies that compared long-term outcomes between sprifermin and placebo injections for KOA treatment. Meta-analysis was performed with RevMan5.3 using an inverse variance approach with fixed or random effects models. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. Results Eight studies were included. Overall, there was significantly less improvement of WOMAC total scores in patients receiving sprifermin, compared with the placebo (mean difference (MD) = 3.23, 95% CI 0.76–5.69; I2 = 0%; P = 0.01). Further, sprifermin injection patients gained more, and lost less, cartilage thickness and volume in total femorotibial joint (cartilage thickness: standardized mean differences (SMD) = 0.55, 95% CI 0.26–0.84; I2 = 78%; P = 0.0002; cartilage volume: SMD = 0.39, 95% CI 0.20–0.58; I2 = 49%; P < 0.0001). Changes in the cartilage surface morphology of the medial tibio-femoral joint (MD = −0.30, 95% CI −0.44 to −0.16; I2 = 0%; P < 0.0001) and patello-femoral joint (MD = −0.22; 95% CI −0.37 to −0.07; I2 = 0%; P = 0.004) showed a significant difference between the sprifermin and placebo injections. Moreover, there were no significant differences between sprifermin and the placebo in the risk of treatment-emergent adverse events (OR = 1.05; 95% CI 0.52–2.14; I2 = 48%; P = 0.89). Conclusion The data from the included studies provide strong evidence to determine the effect of intra-articular sprifermin on joint structure in individuals with KOA and show no specific adverse effects. Nevertheless, intra-articular sprifermin did not likely have any positive effect on symptom alleviation.

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Efficacy and Safety of Capecitabine Alone or in Combination in Advanced Metastatic Breast Cancer Patients Previously Treated with Anthracycline and Taxane: A Systematic Review and Meta-Analysis

Oncology Research and Treatment ◽

10.1159/000510356 ◽

2020 ◽

Vol 43 (12) ◽

pp. 694-702

Author(s):

Louai Alsaloumi ◽

Shaima Shawagfeh ◽

Abdikarim Abdi ◽

Bilgen Basgut

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Adverse Events ◽

Cancer Patients ◽

Meta Analysis ◽

Metastatic Breast ◽

Efficacy And Safety ◽

Breast Cancer Patients ◽

Significant Difference ◽

Hand Foot Syndrome

Background: Capecitabine is frequently used alone or combined with other chemotherapy agents for the treatment of metastatic breast cancer in relapsed patients. Objective: The objective of this meta-analysis is to evaluate the effectiveness and safety of capecitabine monotherapy versus combination in the treatment of metastatic breast cancer patients pretreated with anthracycline and taxane. Methods: Eligible randomized controlled trials examining the efficacy and safety of capecitabine alone compared to capecitabine combination were systematically searched. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and grades 3–4 drug-related adverse events were the outcomes assessed. Results: A total of 6,714 patients of 9 trials were involved in the pooled analysis. Our findings demonstrated that capecitabine combination is significantly superior to capecitabine monotherapy in improving PFS (hazard ratio [HR] 1.32, 95% CI 1.13–1.54, p < 0.0001) and ORR (risk ratio [RR] 0.67, 95% CI 0.54–0.83, p < 0.001), but it was insignificant in OS (HR 1.09, 95% CI 0.98–1.22, p = 0.12). On the other hand, the incidence of non-hematological adverse events such as hand-foot syndrome and diarrhea was lower in capecitabine combination compared to capecitabine monotherapy. Conclusion: Capecitabine-based combination chemotherapy showed superiority over capecitabine monotherapy in terms of PFS and ORR, with no significant difference in OS. Non-hematological adverse effects such as hand-foot syndrome were fewer with a combination regimen. However, hematological adverse events were fewer with capecitabine monotherapy regimen.

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Treatment related severe and fatal adverse events with cetuximab in colorectal cancer patients: a meta-analysis

Journal of Chemotherapy ◽

10.1179/1973947813y.0000000070 ◽

2013 ◽

Vol 25 (3) ◽

pp. 170-175 ◽

Cited By ~ 9

Author(s):

Di Zhang ◽

Junjie Ye ◽

Tangpeng Xu ◽

Bin Xiong

Keyword(s):

Colorectal Cancer ◽

Adverse Events ◽

Cancer Patients ◽

Meta Analysis ◽

Fatal Adverse Events ◽

Colorectal Cancer Patients

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Safety and Efficacy of Thrombopoietin Receptor Agonists in Patients with Previously Treated Chronic Immune Thrombocytopenia: A Systematic Review and Meta-Analysis

Blood ◽

10.1182/blood.v128.22.4925.4925 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4925-4925

Author(s):

Yuji Yamada ◽

Takeo Fujii ◽

Caroline Cromwell ◽

Ilan Shapira

Keyword(s):

Adverse Events ◽

Immune Thrombocytopenia ◽

Meta Analysis ◽

Thrombopoietin Receptor Agonists ◽

Receptor Agonists ◽

Thrombopoietin Receptor ◽

Significant Difference ◽

Previously Treated ◽

Grade 3 ◽

American Society

Abstract Background: The current American Society of Hematology guideline recommends the use of thrombopoietin receptor agonists, eltrombopag or romiplostim as one of the second-line therapies for chronic immune thrombocytopenia (ITP). The efficacy and safety of those drugs have been tested in several clinical trials. However, the safety profile was not consistent throughout trials and is not yet well understood. We herein conducted a meta-analysis of randomized control trials to compare the safety and efficacy of thrombopoietin receptor agonists; eltrombopag and romiplostim versus placebo in patients with previously treated chronic ITP. Our primary outcome was drug-related adverse events greater than CTCAE grade 3. Methods: We performed a literature search in MEDLINE, EMBASE, Cochrane library, and the American Society of Hematology website up to September, 2015 by two independent authors according to PRISMA guideline. We included only randomized clinical trials comparing eltrombopag or romiplostim versus placebo. Random-effects model was used to estimate pooled odds ratio (OR) with 95% confidence interval (CI). Results: A total of eight trials involving 834 participants were included in the analysis. There was no significant difference of grade 3 or higher adverse events between placebo and treatment group (OR=1.01, 95% CI=0.57-1.78). Thromboembolism (OR=0.59, 95% CI=0.20-1.73), elevated ALT (OR=0.68, 95% CI=0.26-1.74), headache (OR=1.26, 95% CI=0.90-1.78), nausea (OR=0.82, 95% CI=0.43-1.55), or fatigue (OR=1.13, 95% CI=0.65-1.91) did not show a significant difference between groups, either. Clinical response, which is defined as platelets ≥50,000/μL at least once on treatment was significantly better in treatment group than in placebo group (OR=0.10, 95% CI=0.07-0.15). Bleeding symptoms (WHO Grades 1-4) were significantly more frequent in the placebo group (OR=1.60, 95% CI=1.14-2.24) during treatment. Conclusions: Although several studies have suggested clinically significant treatment-related adverse events, such as thromboembolism, this meta-analysis showed that thrombopoietin receptor agonists are safe, well-tolerated, and effective in patients with previously treated chronic ITP. Disclosures No relevant conflicts of interest to declare.

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A Systematic Review and Meta-Analysis of Therapeutic Efficacy and Safety of Alirocumab and Evolocumab on Familial Hypercholesterolemia

BioMed Research International ◽

10.1155/2021/8032978 ◽

2021 ◽

Vol 2021 ◽

pp. 1-16

Author(s):

Xiaoyue Ge ◽

Tiantian Zhu ◽

Hao Zeng ◽

Xin Yu ◽

Juan Li ◽

...

Keyword(s):

Clinical Trials ◽

Adverse Events ◽

Familial Hypercholesterolemia ◽

Meta Analysis ◽

Density Lipoprotein ◽

Apolipoprotein A1 ◽

Cochrane Library ◽

Efficacy And Safety ◽

Apo B ◽

Significant Difference

Objectives. The aim of this study was to provide the first study to systematically analyze the efficacy and safety of PCSK9-mAbs in the treatment of familial hypercholesterolemia (FH). Methods. A computer was used to search the electronic Cochrane Library, PubMed/MEDLINE, and Embase databases for clinical trials using the following search terms: “AMG 145”, “evolocumab”, “SAR236553/REGN727”, “alirocumab”, “RG7652”, “LY3015014”, “RN316/bococizumab”, “PCSK9”, and “familial hypercholesterolemia” up to November 2020. Study quality was assessed with the Cochrane Collaboration’s tool, and publication bias was evaluated by a contour-enhanced funnel plot and the Harbord modification of the Egger test. After obtaining the data, a meta-analysis was performed using R software, version 4.0.3. Results. A meta-analysis was performed on 7 clinical trials (926 total patients). The results showed that PCSK9-mAbs reduced the LDL-C level by the greatest margin, WMD −49.14%, 95% CI: −55.81 to −42.47%, on FH versus control groups. PCSK9-mAbs also significantly reduced lipoprotein (a) (Lp (a)), total cholesterol (TC), triglycerides (TG), apolipoprotein-B (Apo-B), and non-high-density lipoprotein cholesterol (non-HDL-C) levels and increased HDL-C and apolipoprotein-A1 (Apo-A1) levels of beneficial lipoproteins. Moreover, no significant difference was found between PCSK9-mAbs treatment and placebo in common adverse events, serious events, and laboratory adverse events. Conclusion. PCSK9-mAbs significantly decreased LDL-C and other lipid levels with satisfactory safety and tolerability in FH treatment.

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Repurposing of drugs for Covid-19: a systematic review and meta-analysis

10.1101/2020.06.07.20124677 ◽

2020 ◽

Cited By ~ 1

Author(s):

Pinky Kotecha ◽

Alexander Light ◽

Enrico Checcucci ◽

Daniele Amparore ◽

Cristian Fiori ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Adverse Events ◽

Clinical Improvement ◽

Case Reports ◽

Meta Analysis ◽

Case Series ◽

Cochrane Library ◽

Control Group ◽

Significant Difference

AbstractObjectiveThe aim of this systematic review is to evaluate the data currently available regarding the repurposing of different drugs for Covid-19 treatment. Participants with suspected or diagnosed Covid-19 will be included. The interventions being considered are drugs being repurposed, and comparators will include standard of care treatment or placebo.MethodsWe searched Ovid-MEDLINE, EMBASE, Cochrane library, clinical trial registration site in the UK(NIHR), Europe (clinicaltrialsregister.eu), US (ClinicalTrials.gov) and internationally (isrctn.com), and reviewed the reference lists of articles for eligible articles published up to April 22, 2020. All studies in English that evaluated the efficacy of the listed drugs were included. Cochrane RoB 2.0 and ROBINS-I tool were used to assess study quality. This systematic review adheres to the PRISMA guidelines. The protocol is available at PROSPERO (CRD42020180915).ResultsFrom 708 identified studies or clinical trials, 16 studies and 16 case reports met our eligibility criteria. Of these, 6 were randomized controlled trials (763 patients), 7 cohort studies (321 patients) and 3 case series (191 patients). Chloroquine (CQ) had a 100% discharge rate compared to 50% with lopinavir-ritonavir at day 14, however a trial has recommended against a high dosage due to cardiotoxic events. Hydroxychloroquine (HCQ) has shown no significant improvement in negative seroconversion rate which is also seen in our meta-analysis (p=0.68). Adverse events with HCQ have a significant difference compared to the control group (p=0.001). Lopinavir-ritonavir has shown no improvement in time to clinical improvement which is seen in our meta-analyses (p=0.1). Remdesivir has shown no significant improvement in time to clinical improvement but this trial had insufficient power.DiscussionDue to the paucity in evidence, it is difficult to establish the efficacy of these drugs in the treatment of Covid-19 as currently there is no significant clinical effectiveness of the repurposed drugs. Further large clinical trials are required to achieve more reliable findings. A risk-benefit analysis is required on an individual basis to weigh out the potential improvement in clinical outcome and viral load reduction compared to the risks of the adverse events. (1-16)

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