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The Efficacy and Safety of Programmed Cell Death 1 and Programmed Cell Death 1 Ligand Inhibitors for Advanced Melanoma: A Meta-Analysis of Clinical Trials Following the PRISMA Guidelines.

ABSTRACT: The purpose of this study was to investigate the efficacy and safety of programmed cell death 1 (PD-1) and programmed cell death 1 ligand (PD-L1) inhibitors using a meta-analysis of present trials for advanced melanoma. A fully recursive literature search of the primary electronic databases for available trials was performed. The objective response rate (ORR) and the median progression-free survival (PFS) of clinical responses were considered the main endpoints to evaluate the efficacy, whereas Grade 3-4 adverse effects (AEs) were analyzed to evaluate safety. The ORR of PD-1 and PD-L1 inhibitors was 30% (95% CI: 25-35%). No significant difference in the ORR was observed after the comparisons of low-dose, median-dose, and high-dose cohorts. In addition, the rate of Grade 3-4 AEs was 9% (95% CI: 6-12%). According to the 3 randomized controlled trials that compared PD-1 inhibitors with chemotherapy, the difference between these 2 groups was found to be statistically significant with respect to the ORR, PFS and the incidence of Grade 3-4 AEs; that is, the relative risk (RR) of the ORR was 3.42 (95% CI: 2.49-4.69, P < 0.001), the hazard ratio (HR) of the PFS was 0.50 (95% CI: 0.44-0.58, P < 0.001), and the RR of Grade 3-4 AEs was 0.45 (95% CI: 0.31-0.65, P < 0.001). According to a meta-analysis of limited concurrent studies, PD-1 and PD-L1 inhibitors appear to be associated with improved response rates, superior response durability and tolerable toxicity in patients with advanced melanoma.

SUBMITTER: Guan X

PROVIDER: S-EPMC4839950 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Introduction:Programmed cell death-1/programmed cell death ligand-1 (PD-1/PDL-1) inhibitors are the newest class of approved drugs for advanced urothelial cancer (AdUC). This review aims to collate the evidence for their efficacy and safety in various treatment settings. Methods:Extensive search of databases was performed (updated May 2018) and the protocol was registered on PROSPERO (CRD42017081568). The review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis statement. STATA (v 12) and Revman 5.3.5 were used for data analysis. Results:Ten nonrandomized, open-label clinical trials were included in this review. PD-1/PD-L1 inhibitors were used as second-line, stand-alone in eight trials and as first-line in cisplatin-ineligible in two trials. Heterogeneity was observed for study design, PDL-1 testing methods, cutoff criterias used and translational markers evaluated. The pooled objective response rate (ORR) was 18.2% (95% confidence interval [CI] 15.1-21.2, n = 1785) with PD-1/PDL-1 inhibitors in second-line settings as compared to 12.6% (95% CI 10.3-14.9, n = 736) with second-line chemotherapy and 23.7% (95% CI 19.9-27.4, n = 489) with PD-1/PDL-1 inhibitors as first-line therapy in cisplatin-ineligible patients. The median progression-free survival and overall survival was similar with PD-1/PD-L1 inhibitors in both second- and first-line treatment settings (1.5-2.9 vs. 2.0-2.7 months and 7.9-18.2 vs. 15.9 months) and second-line chemotherapy (3.3-4.0 months and 7.4-8 months). Odds of achieving ORR was 0.10 (95% CI 0.03-0.31, n = 229) in the second-line, stand-alone setting with a combined positive score (CPS) cutoff of 25% and was 0.34 (95% CI 0.19-0.62, n = 265) with a CPS cut-off of 10% in first-line setting in the cisplatin-ineligible. Conclusions:PD-1/PDL-1 inhibitors appear to be promising in the treatment of AdUC and CPS may be a potentially reliable biomarker for predicting response but needs validation. Caution needs to be exercised until more data are available on imAEs and further studies are required to prove their worth as the standard of care.

Project description:BackgroundInhibitors of programmed cell death-1 (PD-1) and its ligand (PD-L1) have represented a novel approach for the management of advanced non-small cell lung cancer (NSCLC). In this study, we aimed to estimate five anti-PD-1/L1 agents (nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab) using network meta-analyses (NMAs) and the Bayesian method to provide suggestions for advanced NSCLC treatments.MethodsWe searched PubMed, Web of Science, Embase, and the Wiley Online Library for eligible studies published up to March 2020. Both pairwise analyses and NMAs were conducted with clinical outcomes, including overall survival (OS), progression-free survival (PFS), objective response rate, and the incidences of adverse events. Results were presented in several patient populations according to treatment lines and PD-L1 status.ResultsNineteen randomized clinical trials (RCTs) involving 11,456 patients were included in our study. PD-1/L1 inhibitors showed significant benefits over chemotherapies in OS regardless of tumor PD-L1 status [first-line settings: OS =0.85, 95% CI (0.77, 0.94), I2=37%; second- or further-line settings: OS =0.77, 95% CI (0.71, 0.84), I2=37%]. The combined regimen of pembrolizumab and chemotherapy stood out to be the most effective and safest for patients in the first-line settings. Pembrolizumab monotherapy was showed to be the best especially for patients with PD-L1 ≥50%. In the subsequent-line settings, nivolumab ranked the best in improving the survival of patients, and durvalumab had the greatest effect in tumor shrinkage. Atezolizumab, followed by nivolumab, ranked the safest in reducing adverse events, whereas durvalumab was showed with the largest side effects among the five inhibitors.ConclusionsThe combination of pembrolizumab with chemotherapy is suitable for advanced NSCLC patients who have not received any systematic treatments before, and pembrolizumab monotherapy should also be considered, especially for patients with highly-expressed PD-L1 (≥50%). Nivolumab is the best option for patients with advanced NSCLC whose tumors have progressed following chemotherapies or combined modalities of treatments including chemotherapy. However, our results need to be further validated in future head-to-head clinical trials.

Project description:IntroductionThe clinical successes seen with anti-programmed cell death protein 1/programmed death-ligand 1 (anti-PD-[L]1) agents have galvanized the field of immuno-oncology. We evaluated the landscape and trends in immunotherapy trials involving the PD-(L)1 axis in intrathoracic tumors.MethodsWe identified clinical trials involving anti-PD-(L)1 agents on the ClinicalTrials.gov registry through November 13, 2020 for NSCLC, SCLC, mesothelioma, and thymic epithelial tumor. Clinical trials were indexed according to monotherapy versus combination approaches, PD-(L)1 agents under investigation, clinical settings, trial start date, and partner drug(s). We assessed redundancy among the clinical trials.ResultsWe found 686 clinical trials investigating anti-PD-(L)1 agents for intrathoracic tumors (540 trials in NSCLC, 96 in SCLC, 38 in mesothelioma, and 12 in thymic epithelial tumor). A total of 23 PD-(L)1 inhibitors are undergoing clinical development. A total of 81% of trials assess combination treatment. The number of clinical trials has been growing exponentially in the past decade. PD-(L)1 blockade was frequently combined with chemotherapy or immunomodulatory therapy. Various strategies are in development to overcome resistance to PD-(L)1 blockade in metastatic NSCLC. PD-(L)1 blockade is also increasingly evaluated in neoadjuvant and adjuvant settings. After the U.S. Food and Drug Administration's approval of an anti-PD-(L)1 agent for a specific indication, 14 trials were launched thereafter, which continued to randomize patients to treatments that were inferior to the best available therapy.ConclusionsThe number of clinical trials investigating anti-PD-(L)1 agents in intrathoracic tumors has experienced a steep increase over the past decade with a notable upward trend for combination trials. To reduce duplicative research efforts and accelerate the development of effective immunotherapeutics, improved coordination among key stakeholders and the adoption of innovative trial designs will be vital.

Project description:BackgroundProgrammed cell death protein-1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have remarkable clinical efficacy in the treatment of non-small cell lung cancer (NSCLC); however, the breakdown of immune escape causes a variety of immune-related adverse events (irAEs). With the increasing use of PD-1/PD-L1 inhibitors alone or in combination with other therapies, awareness and management of irAEs have become more important. We aimed to assess the incidence and nature of irAEs associated with PD-1 and PD-L1 inhibitors for NSCLC.MethodsArticles from the MEDLINE, EMBASE, and Cochrane databases were searched through December 2017. The incidence of overall and organ-specific irAEs was investigated in all clinical trials with nivolumab, pembrolizumab, atezolimumab, durvalumab, and avelumab as single agents for treatment of NSCLC. We calculated the pooled incidence using R software with package Meta.ResultsSixteen trials were included in the meta-analysis: 10 trials with PD-1 inhibitors (3734 patients) and 6 trials with PD-L1 inhibitors (2474 patients). The overall incidence of irAEs was 22% (95% confidence interval [CI], 17-28) for all grades and 4% (95% CI, 2-6) for high-grade irAEs. The frequency of irAEs varied based on drug type and organ, and patients treated with PD-1 inhibitors had an increased rate of any grade and high-grade irAEs compared with patients who received PD-L1 inhibitors. Organ-specific irAEs were most frequently observed in, in decreasing order, the endocrine system, skin, pulmonary tract, and gastrointestinal tract. The total number of patients whose death was attributed to irAEs was 14 (0.34%), and most (79%) of these patients died because of pneumonitis. The median time to the onset of irAEs after the initiation of treatment was 10 weeks (interquartile range, 6-19.5 weeks) and varied depending on the organ system involved.ConclusionsThe specificity of irAEs was closely associated with the mechanism of PD-1/PD-L1 antibodies involved in restarting anticancer immune attacks. Comprehensive understanding, timely detection, and effective management could improve the compliance of patients and guide the interruption of treatment.

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The Efficacy and Safety of Programmed Cell Death 1 and Programmed Cell Death 1 Ligand Inhibitors for Advanced Melanoma: A Meta-Analysis of Clinical Trials Following the PRISMA Guidelines.

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