Response Efficacy of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-Analysis

BackgroundImmune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have demonstrated promise in treating a variety of advanced cancers; however, little is known regarding their efficacy under various clinical situations, including different cancer types, treatment lines, drug combinations, and therapeutic regimens.MethodsPublished articles and conference abstracts (in English) in PubMed, Embase, the Cochrane Central Register, and Web of Science were searched up to February 10, 2020. The data were analyzed by the meta-analysis program in Stata.ResultsA total of 16,400 patients from 91 clinical trials were included in this meta-analysis. PD-1/PD-L1 inhibitors had a mean ORR of 19.56% (95% CI: 15.09–24.03), a median TTR of 2.05 months (m) (95%CI: 1.85–2.26), and a median DOR of 10.65 m (95%CI: 7.78–13.52). First-line treatment had a higher ORR (36.57% vs. 13.18%) but a shorter DOR (9.00 m vs. 13.42 m) compared to the second-line or subsequent treatment. Immunotherapy combined with chemotherapy (I+C) (46.81% [95%CI: 36.02–57.60]) had a statistically significant higher ORR compared to immunotherapy (I) (17.75% [95%CI: 14.47–21.03]) or immunotherapy combined with immunotherapy (I+O) (12.25% [95%CI: 1.56–22.94]), while I+C (8.09 m [95%CI: 6.86–9.32]) appeared to reduce the DOR compared to I (12.39 m [95%CI: 7.60–17.18]). PD-1 inhibitors were associated with better ORR (21.65% vs. 17.60%) and DOR (11.26 m vs. 10.03 m) compared to PD-L1 inhibitors. There were no significant differences in TTR under different situations.ConclusionsPD-1/PD-L1 inhibitors were promising immunotherapeutic agents to achieve satisfactory response efficacies with different cancer types, treatment lines, drug combinations, and therapeutic regimens. This comprehensive summary of the response efficacy of PD-1/PD-L1 inhibitors serves as a reference for clinicians to make evidence-based decisions.

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Safety and Efficacy in Relapsed or Refractory Classic Hodgkin’s Lymphoma Treated with PD-1 Inhibitors: A Meta-Analysis of 9 Prospective Clinical Trials

BioMed Research International ◽

10.1155/2019/9283860 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 1

Author(s):

Xueyan Zhang ◽

Li Chen ◽

Yawei Zhao ◽

Huiru Yin ◽

He Ma ◽

...

Keyword(s):

Clinical Trials ◽

Immune Checkpoint ◽

Hodgkin’S Lymphoma ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Survival Rates ◽

Hodgkin's Lymphoma ◽

Controlled Trials ◽

Cochrane Central Register ◽

Safety And Efficacy

Background. Classic Hodgkin’s lymphoma (cHL) is characterized by the unique biology in which rare Hodgkin-Reed-Sternberg cells propagate an immunosuppressive microenvironment. Checkpoint inhibitors that target the interaction of PD-1 immune checkpoint receptors have demonstrated remarkable activities in various cancers, such as cHL. This study aims to evaluate the safety and efficacy of PD-1 inhibitors in treating relapsed or refractory cHL (rrHL). Methods. We searched PubMed, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Wanfang, Chinese Biological Medical Literature, and Abstracts of Conference proceedings of annual meetings without any language restrictions to limit language bias (up to January 2019) for prospective clinical trials that evaluate PD-1 inhibitors in treating relapsed or refractory cHL. Results. A total of 9 prospective clinical trials with 731 patients were included in the meta-analysis. The pooled risks of all-grade and grade ≥3 adverse events (AEs) were 0.86 (95% CI: 0.66–0.98) and 0.21 (95% CI: 0.17–0.24), respectively. The pooled response, complete response, partial response, and stable disease rates were 0.74 (95% CI: 0.70–0.79), 0.24 (95% CI: 0.18–0.34), 0.48 (95% CI: 0.41–0.55), and 0.15 (95% CI: 0.12–0.17), respectively. The pooled 6-month progression-free survival and 1-year overall survival rates were 0.76 (95% CI: 0.72–0.79) and 0.93 (95% CI: 0.90–0.96), correspondingly. Conclusions. Our meta-analysis suggested that anti-PD1 monoclonal antibodies improve the outcomes of response and survival rates with tolerable AEs in cHL. However, evidence of immune checkpoint inhibitors for patients with cHL remained insufficient. Well-designed randomized controlled trials or at least nonrandomized trials with a control group should be conducted to confirm the findings of this meta-analysis.

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Efficacy and safety of approved first-line tyrosine kinase inhibitor (TKI) treatment in patients with metastatic renal cell carcinoma (mRCC): A network meta-analysis based on phase II/III randomised clinical trials (RCTs).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e16074 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e16074-e16074

Author(s):

Kirsi Manz ◽

Klaus Fenchel ◽

Andreas Eilers ◽

Jon Morgan ◽

Kirsten Wittling ◽

...

Keyword(s):

Phase Ii ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Cochrane Central Register ◽

Line Treatment ◽

Efficacy And Safety ◽

First Line ◽

Manual Search ◽

Grade 3 ◽

First Line Treatment

e16074 Background: During the last decade several novel treatment options including TKIs and immune checkpoint inhibitors have been developed for the treatment of mRCC patients. However, results from direct comparisons (head-to-head RCTs) to determine the optimal treatment are lacking for most of these agents. In this network meta-analysis we attempted to indirectly compare efficacy and safety of first-line TKIs in patients with mRCC. Methods: PubMed, Embase, Medline, the Cochrane Central Register of Controlled Trials were searched (English language only). Abstracts of conferences of relevant medical societies were also included from database inception (January 1, 2007) to January 15, 2019. A systematic manual search (including data requests from the publication authors) was also performed. For the purpose of this network meta-analysis only phase II/III RCTs assessing approved first-line TKI therapy for mRCC were analysed. The analysis was done using the software R with the netmeta package. Progression-free survival (PFS) was the primary endpoint; grade 3 and 4 adverse events (AEs) were secondary endpoints. Results: A database search identified 12 studies meeting the eligibility criteria reporting on 4,460 patients. For PFS cabozantinib and sunitinib were found to be superior to sorafenib, however, when compared to tivozanib, PFS did not significantly differ between the TKIs. Furthermore, tivozanib was found to have the highest probability of being the safest drug as first-line treatment in terms of grade 3 and 4 AEs (ranking safety, p score 0.9344). Conclusions: No significant PFS differences for all TKIs currently used for first-line treatment of mRCC have been found when compared with tivozanib. Compared with all approved TKIs tivozanib appears to be the best choice for first-line treatment of these patients because it has demonstrated the most favourable safety profile. These results may provide guidance to oncologists when making treatment decisions for mRCC patients.

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Acupuncture in oncological pain relief: A systematic review of randomized clinical trials

Fisioterapia em Movimento ◽

10.1590/fm.2021.34203 ◽

2021 ◽

Vol 34 ◽

Author(s):

Michel Marcos Dalmedico ◽

Caroline Machado de Toledo ◽

Paula Karina Hembecker ◽

Juliana Londero Silva Ávila ◽

Chayane Karla Lucena de Carvalho ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Cancer Pain ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Cochrane Central Register ◽

Opioid Use ◽

Central Register ◽

Considerable Impact ◽

Analgesic Use

Abstract Introduction: Cancer pain has a considerable impact on patients’ health and quality of life, and its treatment is essentially based on opioid use. Objective: To report the effectiveness of acupuncture in relieving cancer pain (secondary to the disease or to the corresponding therapy) or in decreasing opioid use compared to other interventions. Methods: A systematic review of randomized clinical trials was conducted following the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. The trials were selected from the PubMed, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) databases. Results: The search strategy resulted in the inclusion of eight trials, of which five compared acupuncture and drug therapy and three compared acupuncture and placebo. Seven trials reported decreased pain and analgesic use. The trials showed clinical heterogeneity, making a meta-analysis unfeasible. Conclusion: The findings herein provided no robust evidence to support the routine use of acupuncture as an adjuvant therapy in the treatment of cancer pain. However, its use is promising since the results showed a trend toward decreased pain and analgesic use, thus justifying further studies in the future.

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Anti–PD-1 and Anti–PD-L1 in Head and Neck Cancer: A Network Meta-Analysis

Frontiers in Immunology ◽

10.3389/fimmu.2021.705096 ◽

2021 ◽

Vol 12 ◽

Author(s):

Andrea Botticelli ◽

Alessio Cirillo ◽

Lidia Strigari ◽

Filippo Valentini ◽

Bruna Cerbelli ◽

...

Keyword(s):

Randomized Controlled Trials ◽

Head And Neck ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Head And Neck Carcinoma ◽

Controlled Trials ◽

Cochrane Central Register ◽

Risk Of Death ◽

Randomized Controlled ◽

Central Register

ObjectiveThe monoclonal antibodies anti-programmed death protein-1 (anti–PD-1) nivolumab and pembrolizumab are the first immune checkpoint inhibitors (ICIs) approved for treatment of recurrent/metastatic head and neck carcinoma R/M HNSCC in first line and in platinum refractory disease. This network meta-analysis aims to investigate the efficacy of anti–PD-1- vs anti–PD-L1-based therapy in R/M HNSCC cancer patients through a systematic review of the literature to provide support for evidence-based treatment decisions. In particular, the effectiveness of ICIs for R/M HNSCC is analyzed according to the different mechanisms of action of the check-points inhibitory drugs in different subgroups of patients.MethodsWe did a systematic literature review and network meta-analysis (NMA) of randomized controlled trials (RCTs) in PubMed, ClinicalTrials.gov, Embase, Medline, the Cochrane Central Register of Controlled Trials, Web of Science. Our search identified a total of five randomized controlled trials: Keynote 040, Keynote 048, Eagle, Condor, Checkmate 141. These trials included 3001 patients. Treatment was sub-categorized into PD-L1–based, PD-1–based, and standard chemotherapy. Treatments were indirectly compared with anti–PD-L1-based therapy.ResultsThe network meta-analysis demonstrated no significant differences in OS between different subgroups except for the metastatic patients in which anti–PD-1-based therapy was associated with significantly less risk of death. Furthermore, anti–PD-1-based therapy appeared to be effective in smoker patients and in human papilloma–negative (HPV) patients. Conversely, anti–PD-L1-based therapy seems to be better efficient in female patients, in locally recurrent setting and in HPV positive patients.ConclusionThis is the first NMA study that aimed to indirectly compare anti–PD-1- and anti–PD-L1-based therapy in HNSCC patients. The results of our NMA could help define a profile of patient responder or resistant to specific classes of immune drugs and can be used to guide/design future studies in the novel scenario of precision immune-oncology.

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Meta-analysis of drug efficacy in adult vs pediatric trials of patients with PGTC seizures

Neurology ◽

10.1212/wnl.0000000000009325 ◽

2020 ◽

Vol 94 (17) ◽

pp. e1845-e1852

Author(s):

Douglas R. Nordli ◽

Emilia Bagiella ◽

Alexis Arzimanoglou ◽

Jinping Wang ◽

Dinesh Kumar ◽

...

Keyword(s):

Clinical Trials ◽

Seizure Frequency ◽

Pediatric Population ◽

Meta Analysis ◽

Evaluation Criteria ◽

Drug Efficacy ◽

Cochrane Central Register ◽

Central Register ◽

Adults And Children ◽

Clonic Seizures

ObjectiveA meta-analysis of published studies was performed to determine whether the efficacy of antiseizure drugs in adults with primary generalized tonic-clonic seizures (PGTCS) is comparable with that in the pediatric population (2–12 years of age).MethodsElectronic searches were conducted in EMBASE, Medline, and the Cochrane Central Register of Controlled Trials for clinical trials of PGTCS in adults and children 2–12 years of age. Neurologists used standardized search and study evaluations to select eligible trials. Median percent reduction in seizure frequency from baseline and ≥50% responder rates were used to compare drug efficacy in adults and children.ResultsAmong 7 adjunctive-therapy PGTCS trials in adults and children (2–12 years of age) that met evaluation criteria, effect sizes were consistent between adults and children for lamotrigine and topiramate. The baseline-subtracted median percent seizure reduction in seizure frequency ranged from 50.0% to 79.7% in children and 57.0% to 64.0% in adults. The ≥50% responder rate was similar between children and adults in a topiramate study (50% in children compared with 58% in adults).ConclusionsThis meta-analysis supports the use of drug response from antiseizure drug clinical trials for PGTCS in adults to predict comparable treatment response in children 2–12 years of age with PGTCS.

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Effect of Gender on the Outcome of Patients Receiving Immune Checkpoint Inhibitors for Advanced Cancer: A Systematic Review and Meta-Analysis of Phase III Randomized Clinical Trials

10.20944/preprints201808.0307.v3 ◽

2018 ◽

Author(s):

Antonino Grassadonia ◽

Isabella Sperduti ◽

Patrizia Vici ◽

Laura Iezzi ◽

Davide Brocco ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Advanced Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Randomized Clinical Trials ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Phase Iii ◽

Cochrane Central Register

Evidence has recently emerged on the influence of gender on the immune system. In this systematic review and meta-analysis of phase III randomized clinical trials (RCTs), we explored the impact of gender on survival in patients with advanced cancer treated with immune checkpoint inhibitors (ICIs). We performed a comprehensive search of the literature updated to April 2018, including the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE. We extracted data on study characteristics and risk of bias in duplicate. Of 423 unique citations, 21 RCTs were included, inherently to 12,635 patients. Both males and females showed reduced risk of death associated with ICIs use (HR 0.73, p<0.001 and HR 0.77, p<0.001, respectively). Subgroup analyses by specific ICI showed similar OS in both genders for anti-PD-1/PDL-1. Anti-CTLA-4 use was associated with longer OS in men only (HR 0.77, p<0.012), with the exception of melanoma (in women, HR 0.80, p=0.006). PFS was longer in men than in women (HR 0.67, p<0.001 and HR 0.77, p=0.100, respectively). Conclusively, ICIs use was associated with more favorable outcomes in men, particularly for anti-CTLA-4 agents. In melanoma, not gender-related factors may influence the anti-tumor immune response evoked by ICIs.

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First Line Treatments for Newly Diagnosed Primary Immune Thrombocytopenia in Children: A Systematic Review and Network Meta-analysis

Current Pediatric Reviews ◽

10.2174/1573396315666191023122542 ◽

2020 ◽

Vol 16 (1) ◽

pp. 61-70

Author(s):

David O. Acero-Garcés ◽

Herney A. García-Perdomo

Keyword(s):

Platelet Count ◽

Adverse Effects ◽

Immune Thrombocytopenia ◽

Meta Analysis ◽

Response Rates ◽

Cochrane Central Register ◽

First Line ◽

Central Register ◽

Primary Immune Thrombocytopenia

Background: The first-line interventions in immune thrombocytopenia (ITP) include intravenous polyclonal immunoglobulins (IVIg), corticosteroids and anti-D immunoglobulin (anti-D). Objective: We aimed to compare the effectiveness and safety of first line treatments for newlydiagnosed primary ITP in children to increase the platelet count. Methods: We searched MEDLINE, EMBASE, LILACS and the Cochrane Central register of Controlled Trials (CENTRAL); and included the clinical trials. We performed the statistical analysis in R. Results: We included 12 studies for meta-analysis. Compared with IVIG 2g/kg, response rates were lower for prednisone 2mg/kg at 72 hours [RR 0.04 (95% CI 0.0 to 0.68)] and at 7 days [RR 0.23 (95% CI 0.08 to 0.67)]; at 48 hours, methylprednisolone 30mg/kg also showed lower response rates [RR 0.72 (95% CI 0.52 to 0.99)]. IVIG 2g/kg and 2.5g/kg had less adverse effects than Anti- D, methylprednisolone and IVIG 0.8g/kg. For rising platelet count, no statistical differences were found at 24 hours or in 7 days; at 48 hours, IVIG 2g/kg showed better results than Anti-D 75μg/kg [MD -58.84 (95% CI -87.02 to -25.66)]. After a month, platelet count with IVIG 2g/kg was higher than Anti-D 50 and 75μg/kg [-82.03 (95% CI -102.60 to -61.46) and -78.77 (95% CI -97.80 to - 59.74), respectively], but lower than methylprednisolone 50mg/kg [MD 118 (95% CI 3.88 to 232.12)]. Conclusion: The total platelet count rises higher in early and late phases with IVIG than Anti-D, but in long term it is higher with methylprednisolone. Additionally, IVIG causes less adverse effects than Anti-D and corticosteroids.

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Effect of Gender on the Outcome of Patients Receiving Immune Checkpoint Inhibitors for Advanced Cancer: A Systematic Review and Meta-Analysis of Phase III Randomized Clinical Trials

Journal of Clinical Medicine ◽

10.3390/jcm7120542 ◽

2018 ◽

Vol 7 (12) ◽

pp. 542 ◽

Cited By ~ 23

Author(s):

Antonino Grassadonia ◽

Isabella Sperduti ◽

Patrizia Vici ◽

Laura Iezzi ◽

Davide Brocco ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Advanced Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Randomized Clinical Trials ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Phase Iii ◽

Cochrane Central Register

Evidence has recently emerged on the influence of gender on the immune system. In this systematic review and meta-analysis of phase III randomized clinical trials (RCTs), we explored the impact of gender on survival in patients with advanced cancer treated with immune checkpoint inhibitors (ICIs). We performed a comprehensive search of the literature updated to April 2018, including the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE. We extracted data on study characteristics and risk of bias in duplicate. Of 423 unique citations, 21 RCTs were included, inherently to 12,635 patients. Both males and females showed reduced risk of death associated with ICIs use (HR 0.73, p < 0.001 and HR 0.77, p < 0.001, respectively). Subgroup analyses by specific ICI showed similar OS in both genders for anti-PD-1/PDL-1. Anti-CTLA-4 use was associated with longer OS in men only (HR 0.77, p < 0.012), with the exception of melanoma (in women, HR 0.80, p = 0.006). PFS was longer in men than in women (HR 0.67, p < 0.001 and HR 0.77, p = 0.100, respectively). Conclusively, ICIs use was associated with more favorable outcomes in men, particularly for anti-CTLA-4 agents. In melanoma, not gender-related factors may influence the anti-tumor immune response evoked by ICIs.

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