Dataset Information

PD-1/PD-L1 Inhibitor Plus Chemotherapy Versus PD-1/PD-L1 Inhibitor in Microsatellite Instability Gastrointestinal Cancers: A Multicenter Retrospective Study.

ABSTRACT:

Purpose

To investigate the efficacy of PD-1/PD-L1 inhibitors plus chemotherapy versus anti-PD-1/PD-L1 monotherapy in advanced microsatellite instability (MSI)/mismatch repair-deficient (dMMR) gastrointestinal cancers.

Methods

We retrospectively recruited patients with MSI/dMMR gastrointestinal cancer who received anti-PD-1/PD-L1 with or without chemotherapy and compared objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) of PD-1/PD-L1 inhibitor plus chemotherapy (chemo-anti-PD-1/PD-L1 group) and PD-1/PD-L1 inhibitor alone (anti-PD-1/PD-L1 group). Propensity score-based overlap weighting analysis was conducted to adjust the baseline covariable imbalance. Sensitivity analysis was performed to confirm the stability of the results by propensity score matching and multivariable Cox and logistic regression models.

Results

A total of 256 patients were eligible, with 68 and 188 receiving chemo-anti-PD-1/PD-L1 and anti-PD-1/PD-L1, respectively. The chemo-anti-PD-1/PD-L1 group showed significant improvements versus the anti-PD-1/PD-L1 group in ORR (61.8% v 38.8%; P = .001), DCR (92.6% v 74.5%; P = .002), PFS (median PFS [mPFS], not reached [NR] v 27.9 months; P = .004), and OS (median OS [mOS], NR v NR; P = .014). After overlap weighting, the improvements tended to be more significant with chemo-anti-PD-1/PD-L1 versus anti-PD-1/PD-L1 in ORR (62.5% v. 38.3%; P < .001), DCR (93.8% v 74.2%; P < .001), PFS (mPFS, NR v 26.0 months; P = .004), and OS (mOS, NR v NR; P = .010). These results were solidified through sensitivity analysis.

Conclusion

Chemo-anti-PD-1/PD-L1 is superior to anti-PD-1/PD-L1 in MSI/dMMR gastrointestinal cancers with improved efficacy.

SUBMITTER: Chen M

PROVIDER: S-EPMC10309553 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

PD-1/PD-L1 Inhibitor Plus Chemotherapy Versus PD-1/PD-L1 Inhibitor in Microsatellite Instability Gastrointestinal Cancers: A Multicenter Retrospective Study.

Chen Mifen M Wang Zhenghang Z Liu Zimin Z Deng Ting T Wang Xiaodong X Chang Zhiwei Z Zhang Qi Q Yang Wenlei W Liu Ning N Ji Zhi Z Zhang Xiaotian X Wang Xicheng X Peng Zhi Z Li Yi Y Cao Yujuan Y Jin Xuan X Lu Hongxia H Qu Huajun H Tang Yong Y Xu Chunlei C Fang Weijia W Zhang Hangyu H Yan Dong D Wang Li L Li Jiayi J Zhang Jingdong J Wang Qiwei Q Xue Liying L Yin Fei F Han Guangjie G Cheng Zhiqiang Z Liu Qing Q Jin Yongdong Y Zhang Yinjie Y Li Lanxing L Cao Baoshan B Yao Yanhong Y Chen Zhiyu Z Zou Jianling J Ying Jieer J Wei Qing Q Tian Tiantian T Zhao Weifeng W Li Longmei L Zhang Tong T Song Fanghua F Ba Ya-Er YE Li Na N Gao Hui H Ji Yinghua Y Bao Liying L Zhao Xiaochen X Cai Jinping J Yuan Zheping Z Shen Lin L Li Jian J

JCO precision oncology 20230301

<h4>Purpose</h4>To investigate the efficacy of PD-1/PD-L1 inhibitors plus chemotherapy versus anti-PD-1/PD-L1 monotherapy in advanced microsatellite instability (MSI)/mismatch repair-deficient (dMMR) gastrointestinal cancers.<h4>Methods</h4>We retrospectively recruited patients with MSI/dMMR gastrointestinal cancer who received anti-PD-1/PD-L1 with or without chemotherapy and compared objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival ...[more]

PMID: 36996375

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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.

Project description:PD-L1 Inhibitor Regulates the miR-33a-5p/PTEN Signaling Pathway and Can Be Targeted to Sensitize Glioblastomas to Radiation. Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Ionizing radiation (IR) is a standard treatment for GBM patients and results in DNA damage. However, the clinical efficacy of IR is limited due to therapeutic resistance. The programmed death ligand 1 (PD-L1) blockade has a shown the potential to increase the efficacy of radiotherapy by inhibiting DNA damage and repair responses. The miR-33a-5p is an essential microRNA that promotes GBM growth and self-renewal. In this study, we investigated whether a PD-L1 inhibitor (a small molecule inhibitor) exerted radio-sensitive effects to impart an anti-tumor function in GBM cells by modulating miR-33a-5p. U87 MG cells and U251 cells were pretreated with PD-L1 inhibitor. The PD-L1 inhibitor-induced radio-sensitivity in these cells was assessed by assaying cellular apoptosis, clonogenic survival assays, and migration. TargetScan and luciferase assay showed that miR-33a-5p targeted the phosphatase and tensin homolog (PTEN) 3' untranslated region. The expression level of PTEN was measured by western blotting, and was also silenced using small interfering RNAs. The levels of DNA damage following radiation was measured by the presence of γ-H2AX foci, cell cycle, and the mRNA of the DNA damage-related genes, BRCA1, NBS1, RAD50, and MRE11. Our results demonstrated that the PD-L1 inhibitor significantly decreased the expression of the target gene, miR-33a-5p. In addition, pretreatment of U87 MG and U251 cells with the PD-L1 inhibitor increased radio-sensitivity, as indicated by increased apoptosis, while decreased survival and migration of GBM cells. Mir-33a-5p overexpression or silencing PTEN in U87 MG and U251 cells significantly attenuated PD-L1 radiosensitive effect. Additionally, PD-L1 inhibitor treatment suppressed the expression of the DNA damage response-related genes, BRCA1, NBS1, RAD50, and MRE11. Our results demonstrated a novel role for the PD-L1 inhibitor in inducing radio- sensitivity in GBM cells, where inhibiting miR-33a-5p, leading to PTEN activated, and inducing DNA damage was crucial for antitumor immunotherapies to treat GBM.

Dataset Information

PD-1/PD-L1 Inhibitor Plus Chemotherapy Versus PD-1/PD-L1 Inhibitor in Microsatellite Instability Gastrointestinal Cancers: A Multicenter Retrospective Study.

Purpose

Methods

Results

Conclusion

Publications

PD-1/PD-L1 Inhibitor Plus Chemotherapy Versus PD-1/PD-L1 Inhibitor in Microsatellite Instability Gastrointestinal Cancers: A Multicenter Retrospective Study.

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