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Clinical efficacy and safety of anti-PD-1/PD-L1 inhibitors for the treatment of advanced or metastatic cancer: a systematic review and meta-analysis.

ABSTRACT: Anti-PD-1/PD-L1 inhibitors provide a survival advantage over conventional therapies for treatment of advanced or metastatic cancer. However, the factors determining which patients benefit the most from anti-PD-1/PD-L1 inhibitors are unknown, making treatment-related decisions difficult. We performed a systematic review and meta-analysis of acquired data to assess the efficacy and toxicity of anti-PD-1/PD-L1 inhibitors in advanced and metastatic cancer. A thorough search strategy was applied to identify randomised controlled trials (RCTs) in Pubmed, Embase, Cochrane, and major conferences. Studies meeting predefined selection criteria were selected, and two independent investigators performed data extraction; overall survival (OS), progression-free survival (PFS), and overall response rate were compared between anti-PD-1/PD-L1 inhibitors and control therapies. We calculated the pooled response rate and 95% CIs of all-grade and high-grade (?3) adverse effects and evaluated the within-study heterogeneity using subgroup, sensitivity, and meta-regression analyses. In final, we included eligible 35 RCTs (21047 patients). The main estimated hazard ratios (HRs) for OS and PFS were 0.76 (0.71-0.82) and 0.81 (0.73-0.89) in a random-effects model. The anti-PD-1/PD-L1 inhibitor group had a significantly high risk for all-grade immune-related adverse events. Anti-PD-1/PD-L1 inhibitors were identified as a preferable treatment option for advanced or metastatic cancer patients who are male, aged?

SUBMITTER: Sun L

PROVIDER: S-EPMC7005709 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Clinical efficacy and safety of anti-PD-1/PD-L1 inhibitors for the treatment of advanced or metastatic cancer: a systematic review and meta-analysis.

Sun Leitao L Zhang Leyin L Yu Jieru J Zhang Yinan Y Pang Xi X Ma Chenghao C Shen Minhe M Ruan Shanming S Wasan Harpreet S HS Qiu Shengliang S

Scientific reports 20200207 1

Anti-PD-1/PD-L1 inhibitors provide a survival advantage over conventional therapies for treatment of advanced or metastatic cancer. However, the factors determining which patients benefit the most from anti-PD-1/PD-L1 inhibitors are unknown, making treatment-related decisions difficult. We performed a systematic review and meta-analysis of acquired data to assess the efficacy and toxicity of anti-PD-1/PD-L1 inhibitors in advanced and metastatic cancer. A thorough search strategy was applied to i ...[more]

PMID: 32034198

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Project description:Background: Success has been reported in PD-1/PD-L1 blockade via pembrolizumab, atezolizumab, or avelumab monotherapy in manifold malignancies including metastatic breast cancer. Due to lack of large-scale study, here we present interim analyses to evaluate the safety and efficacy of these promising strategies in patients with advanced breast cancer. Methods: Six studies including 586 advanced breast cancer patients treated with anti-PD-1/PD-L1 monotherapy agents before July 1, 2020, were included. The anti-PD-1/PD-L1 agents include pembrolizumab, atezolizumab, land avelumab. Statistics was analyzed by R software and IBM SPSS Statistics 22. Results: Global analysis showed that for this monotherapy, the complete response was 1.26%, partial response was 7.65%, objective response rate (ORR) was 9.85%, and disease control rate (DCR) was 18.33%. 1-year overall survival rate and 6-month progression-free survival rate were 43.34 and 17.24%. Overall incidence of adverse events (AEs) was 64.18% in any grade and 12.94% in severe grade, while the incidence of immune-related AEs (irAEs) was approximately 14.75%: the most common treatment-related AEs of any grade that occurred in at least 5% of patients were arthralgia and asthenia; the most common severe treatment-related AEs occurred in at least 1% of patients were anemia and autoimmune hepatitis; the most common irAEs were hypothyroidism. Besides, the incidence of discontinue and death due to treatment-related AEs was about 3.06 and 0.31%, respectively. Additionally, by comparing efficacy indicators between PD-L1-positive and PD-L1-negative groups, an implicated correspondence between efficacy and the expression of PD-L1 biomarker was found: the PR was 9.93 vs 2.69%; the ORR was 10.62 vs. 3.07%; the DCR was 17.95 vs. 4.71%. Conclusion: Anti-PD-1/PD-L1 monotherapy showed a manageable safety profile and had a promising and durable anti-tumor efficacy in metastatic breast cancer patients. Higher PD-L1 expression may be closely correlated to a better clinical efficacy.

Project description:BackgroundInhibitors of programmed cell death 1 (PD-1)/programmed cell death ligand 1(PD-L1) checkpoint have been approved for metastatic triple negative breast cancer (mTNBC) in patients positive for PD-L1 expression. Negative results from the recent phase III trials (IMPassion131 and IMPassion132) have raises questions on the efficacy of PD-1/PD-L1 checkpoint inhibitors and the predictive value of PD-L1 expression. Here we attempt to systematically analyze the biomarker value of PD-L1 expression for predicting the response of PD-1/PD-L1 checkpoint inhibitors in mTNBC.Materials and methodsPubMed database was searched until Dec 2021 for studies evaluating PD-1/PD-L1 checkpoint inhibitors plus/minus chemotherapy in mTNBC. Outcome of interest included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Review Manager (RevMan) version 5.4. was used for data-analysis.ResultsIn total, 20 clinical trials comprising 3962 mTNBC patients (ICT: 2665 (67%); CT: 1297 (33%) were included in this study. Overall ORR was 22% (95%CI, 14-30%) and significant improvement was observed for PD-L1+ patients (ORR 1.78 [95%CI, 1.45-2.19], p<0.00001) as compared to PD-L1- cohort. Pooled outcome also indicated a significant 1-year PFS and 2-year OS advantage for patients with PD-L1 expression (1-year PFS: ORR 1.39 [95%CI, 1.04-1.85], p=0.02; I2 = 0%; 2-year OS: (ORR 2.47 [95%CI, 1.30-4.69], p=0.006; I2 = 63%). Subgroup analysis indicated that PD-L1 expression can successfully predict tumor response and 2-year OS benefit in mTNBC patients regardless of the type of investigating agent, line of treatment administration, and to some extent the type of treatment. Biomarker ability of PD-L1 expression to predict 1-year PFS was slightly better with pembrolizumab (p=0.09) than atezolizumab (p=0.18), and significantly better when treatment was administered in the first-line setting (OR 1.38 [95%CI, 1.02-1.87], p=0.04) and chemotherapy was added (OR 1.38 [95%CI, 1.02-1.86], p=0.03). Immune-related toxicity of any grade and grade≥3 was 39% (95%CI, 26%-52%) and 10% (95%CI, 8%-13%), respectively.ConclusionsPD-L1 expression can predict objective response rate and 2-year OS in mTNBC patients receiving PD-1/PD-L1 checkpoint inhibitors. One-year PFS is also predicted in selected patients. PD-L1 expression can be a useful biomarker of efficacy of PD-1/PD-L1 checkpoint inhibitors in mTNBC.

Project description:ObjectiveTo evaluate the efficacy and safety of PD-1/L1 inhibitors as first-line therapy in metastatic colorectal cancer(mCRC).MethodArticles evaluating first-line PD-1/L1 inhibitors for mCRC were sought in four databases (Pubmed, Embase, Web of Science, and the Cochrane Library) from the inception of the databases until 11 November 2023. Meta-analyses were conducted to assess the rates of progression-free survival (PFS), overall survival (OS), complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rate (ORR), disease control rate (DCR), and grade ≥ 3 treatment-related adverse events (trAEs).ResultsTotally nine studies were included for meta-analysis. A subgroup analysis was performed based on mismatch repair(MMR) status and regimens. In patients diagnosed with mismatch repair-deficient(dMMR) mCRC who received PD-1/L1 inhibitors as their first-line treatment, the ORR was 0.54 (95% CI, 0.39 to 0.68), the median PFS was 53.2 months, the Grade≥ 3 TRAEs rate was 0.33(95% CI, 0.12 to 0.60) and the median OS was not determined. For patients with proficient mismatch repair (pMMR) mCRC who underwent a combined treatment of PD-1/L1 inhibitors, anti-VEGF monoclonal antibody and chemotherapy as their first-line therapy, the ORR was 0.62 (95% CI, 0.56 to 0.68), the median PFS was 10.1 months, the median OS was 26.7 months, and the Grade≥ 3 TRAEs rate was 0.59(95% CI, 0.39 to 0.77).ConclusionOur results revealed that the utilization of PD-1/L1 inhibitors as first-line therapy for dMMR mCRC yielded highly favorable outcomes, while maintaining an acceptable level of safety. Administering a combination of PD-1/L1 inhibitors, anti-VEGF monoclonal antibody, and chemotherapy as first-line treatment in patients with pMMR mCRC led to an improved ORR. However, there was no significant improvement in the long-term prognosis of the tumor.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024506196, identifier CRD42024506196.

Project description:IntroductionThis meta-analysis aims to evaluate the efficacy and safety of neoadjuvant PD-1 inhibitors or PD-L1 inhibitors [PD-(L)1 inhibitors] for muscle-invasive bladder carcinoma (MIBC).Materials and methodsFour databases (Medline, Embase, Web of Science, and 21 CENTRAL) were searched for articles studying neoadjuvant PD-(L)1 inhibitors for MIBC. The search time period was from the establishment of each database to 21 July 2023. Meta-analyses of pCR, pPR, Grade≥ 3 irAEs rate, RFS, and OS were performed.ResultsIn total, 22 studies were included for meta-analysis. The overall pooled pCR of neoadjuvant PD-(L)1 inhibitors was 0.36 (95%CI=0.30-0.42, p=0.00). In subgroup meta-analysis, the pooled PCR of PD-(L)1 inhibitors alone, PD-(L)1 inhibitors plus other ICI, and PD-(L)1 inhibitors plus chemotherapy was 0.27 (95%CI=0.19-0.35, p=0.1), 0.41 (95%CI=0.21-0.62, p=0.01), 0.43 (95%CI=0.35-0.50, p=0.06), respectively. The overall pooled pPR of neoadjuvant PD-(L)1 inhibitors was 0.53 (95%CI=0.46-0.60, p=0.00). In subgroup meta-analysis, the pooled pPR of PD-(L)1 inhibitors alone, PD-(L)1 inhibitors plus other ICI, and PD-(L)1 inhibitors plus chemotherapy was 0.36 (95%CI=0.22-0.51, p=0.01), 0.51 (95%CI=0.39-0.62, p=0.43), and 0.61 (95%CI=0.53-0.69, p=0.01), respectively. Kaplan-Meier curves for OS and RFS were reconstructed, but there was no significant difference among three groups in terms of OS or RFS. The pooled result of Grade≥ 3 irAEs rate for neoadjuvant PD-(L)1 inhibitors was 0.15 (95%CI=0.09-0.22, p=0.00%). In subgroup analysis, the pooled result of Grade≥ 3 irAEs rate for PD-(L)1 inhibitors alone, PD-(L)1 inhibitors plus other ICI, and PD-(L)1 inhibitors plus chemotherapy was 0.07 (95%CI=0.04-0.11, p=0.84), 0.31 (95%CI=0.16-0.47, p=0.06), and 0.17 (95%CI=0.06-0.31, I2 = 71.27%, p=0.01), respectively.ConclusionNeoadjuvant PD-(L)1 inhibitors were feasible and safe for muscle invasive bladder cancer. Compared with PD-(L)1 inhibitors alone, PD-(L)1 inhibitors plus other ICI and PD-(L)1 inhibitors plus chemotherapy were associated with higher pCR and pPR, but higher Grade≥3 irAEs. Kaplan-Meier curves for OS and RFS indicated that neoadjuvant PD-(L)1 inhibitors had an acceptable long-term prognostic, but it was not possible to discern statistical differences between the three neoadjuvant subgroups.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023452437, identifier PROSPERO (CRD42023452437).

Dataset Information

Clinical efficacy and safety of anti-PD-1/PD-L1 inhibitors for the treatment of advanced or metastatic cancer: a systematic review and meta-analysis.

Publications

Clinical efficacy and safety of anti-PD-1/PD-L1 inhibitors for the treatment of advanced or metastatic cancer: a systematic review and meta-analysis.

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