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Risk of immune-related colitis with PD-1/PD-L1 inhibitors vs chemotherapy in solid tumors: systems assessment.

ABSTRACT: Background: We performed a meta-analysis to evaluate the risk of immune-related colitis associated with PD1/PD-L1 inhibitors as compared to chemotherapy in solid tumor patients. Methods: Eligible studies were identified through a comprehensive search of multiple databases and included solid tumor patients in randomized controlled trials (RCTs) with PD-1/PD-L1 inhibitors. The data was analyzed by Stata version 12.0 software. Results: After exclusion of ineligible studies, 11 clinical trials were considered eligible for the meta-analysis, including 5751 patients. Compared with chemotherapy, the risk ratios (RRs) of all-grade colitis were significant for the PD-1 inhibitor subgroup (RR 2.69, 95% confidence interval (CI): 1.15-6.29, p=0.023), and for pembrolizumab subgroup (RR 3.17, 95% CI: 1.08-9.37, p=0.037), but not for nivolumab treatment and PD-L1 inhibitor (atezolizumab) treatment (RR 2.05, 95% CI: 0.52-8.13, p=0.305; RR 4.75,95% CI: 0.56-40.50, p=0.154, respectively). The RR of all-grade colitis was significant for PD-1/PD-L1 inhibitor in NSCLC (RR 4.34, 95% CI: 1.37-13.82, p=0.013), and not significant in melanoma (RR 2.11, 95% CI: 0.54-8.34, p=0.285). Moreover, the RRs of all-grade diarrhea were significant for the PD-1 inhibitor subgroup (RR 0.61, 95% CI: 0.44-0.83, p=0.002), for the nivolumab subgroup (RR 0.54, 95% CI: 0.34-0.87, p=0.012), and for atezolizumab subgroup (RR 0.48, 95% CI: 0.25-0.89, p=0.021). The RR of high-grade diarrhea was significant for atezolizumab subgroup (RR 0.34, 95% CI: 0.12-0.94, p=0.037). Conclusions: Our meta-analysis demonstrates that compared with chemotherapy, pembrolizumab may result in a higher risk of all-grade immune-mediated colitis. PD-1/PD-L1 inhibitor treatment in NSCLC patients, but not in melanoma patients, increases the risk of all-grade colitis incidence.

SUBMITTER: Su Q

PROVIDER: S-EPMC5950591 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Risk of immune-related colitis with PD-1/PD-L1 inhibitors vs chemotherapy in solid tumors: systems assessment.

Su Qiang Q Zhang Xiaochen X Shen Xinhua X Hou Yanli Y Sun Zhigang Z Gao Zu Hua ZH

Journal of Cancer 20180412 9

Background: We performed a meta-analysis to evaluate the risk of immune-related colitis associated with PD1/PD-L1 inhibitors as compared to chemotherapy in solid tumor patients. Methods: Eligible studies were identified through a comprehensive search of multiple databases and included solid tumor patients in randomized controlled trials (RCTs) with PD-1/PD-L1 inhibitors. The data was analyzed by Stata version 12.0 software. Results: After exclusion of ineligible studies, 11 ...[more]

PMID: 29760800

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Project description:Purpose: The clinical use of immunotherapies targeting programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) is rapid expanding, but the equivalency of these inhibitors remains unclear. We aimed to comprehensively compare the efficacy and safety of PD-1/PD-L1 inhibitors with a systematic review and Bayesian network meta-analysis Methods: We searched PubMed, Web of Knowledge, related reviews and abstracts for randomized controlled trials of five PD-1/PD-L1 inhibitors for patients with solid tumors before November 30th, 2018. We estimated summary hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and odds ratios (ORs) for grade 3-5 treatment-related adverse events (TrAEs) using pairwise and network meta-analysis with random-effects. This study was registered with PROSPERO (#CRD42018116624). Results: Totally, 43 reports of 35 trials comprising 21261 patients were eligible for the analysis. Nivolumab, pembrolizumab, atezolizumab and durvalumab were more effective than control treatment, and no significant differences were identified in OS and PFS between any two inhibitors. Avelumab was associated with significantly inferior OS to nivolumab (HR 1.37, 95%CrI 1.05-1.78) and pembrolizumab (HR 1.33, 95%CrI 1.02-1.73), and with inferior PFS to nivolumab (HR 1.60, 95%CrI 1.03-2.51). Compared with placebo, nivolumab had increased risk of grade 3-5 TrAEs (OR 2.35, 95%CrI 1.35-4.17). Compared with standard-of-care, nivolumab (OR 0.39, 95%CrI 0.28-0.54), pembrolizumab (OR 0.43, 95%CrI 0.30-0.60), atezolizumab (OR 0.37, 95%CrI 0.21-0.64) and avelumab (OR 0.24, 95%CrI 0.12-0.48) significantly reduced grade 3-5 TrAEs. There were not significant differences in grade 3-5 TrAEs between any two inhibitors. Conclusion: This Bayesian network meta-analysis revealed that nivolumab, pembrolizumab, atezolizumab and durvalumab yielded equivalent survival, while avelumab was associated with unfavorable survival. PD-1/PD-L1 inhibitors were comparable in the risk of TrAEs, and safer than conventional therapies.

Project description:Preliminary clinical studies of anti-programmed cell death-1 (anti-PD-1) therapy in gastro-esophageal cancers have suggested promising single-agent activity. In patients who received prior treatment for advanced disease, pembrolizumab has been associated with a response rate of 20% in programmed cell death-1 ligand 1 (PD-L1)-positive tumors, and nivolumab with a response rate of 12% in unselected tumors. Both agents yielded a median duration of response lasting ~6-7 months. PD-L1 expression and microsatellite instability (MSI) have emerged as potential predictive markers for PD-1/PD-L1 blockade. PD-L1 expression in tumor cells and in immune cells within the tumor microenvironment has been detected in 14-24% and ~35% of patients with gastro-esophageal cancer, respectively. PD-L1 tumor cell expression appears to be more common in Epstein-Barr virus (EBV)-positive gastric cancers (GCs) and has been associated with an increased density of tumor-infiltrating lymphocytes (TIL). To date, data are too sparse to determine whether PD-L1 expression predicts efficacy of anti-PD-1 therapy in gastro-esophageal cancer, but data from other tumor types have not been consistent regarding its predictive value. MSI occurs in 10-20% of gastro-esophageal cancers and arises from deficient mismatch repair (MMR). MSI is highly correlated with non-synonymous mutation burden, as well as a dense accumulation of TILs. MSI has been associated with improved response to anti-PD-1 therapy in gastrointestinal cancers. Multiple studies are ongoing which examine therapeutic blockade of the PD-1/PD-L1 axis in unselected patients with gastro-esophageal cancer, as well as patients whose tumors express PD-L1 or exhibit MSI. These studies will clarify their activity in this disease and potentially can determine whether identify a strong predictive biomarker can be identified. Checkpoint inhibition is also being studied in combination with curative-intent chemo (radio) therapy and surgery.

Dataset Information

Risk of immune-related colitis with PD-1/PD-L1 inhibitors vs chemotherapy in solid tumors: systems assessment.

Publications

Risk of immune-related colitis with PD-1/PD-L1 inhibitors vs chemotherapy in solid tumors: systems assessment.

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