Anti–Programmed Cell Death (PD)-1 Immunotherapy for Malignant Tumor: A Systematic Review and Meta-Analysis

Abstract

This systematic review and meta-analysis evaluated anti–programmed cell death (PD)-1 immunotherapy (nivolumab or pembrolizumab) for overall efficacy, safety, and effective dose relative to standard chemotherapy or other conventional drugs in the treatment of malignant tumors. We searched the following databases, PubMed, Medline, Embase, Cochrane, Wangfang Data, Weipu, and China National Knowledge Infrastructure, and the reference lists of the selected articles for randomized controlled trials (RCTs) of anti–PD-1 therapies in humans. The outcome measures were overall survival, treatment response, and adverse events. Only four randomized controlled trials met our inclusion criteria. Three of these evaluated responses to nivolumab, whereas one tested pembrolizumab. The result of our analysis suggested that nivolumab may improve the overall response rate in treating melanoma relative to chemotherapy and has few associated adverse events. Similarly, in metastatic melanoma patients, nivolumab had a significant advantage over dacarbazine in terms of 1-year survival, progression-free survival, and objective response rate. Regarding dose levels of nivolumab for patients with metastatic renal cell carcinoma, the outcomes in response to 2 and 10 mg/kg were similar, but both had significant advantages over 0.3 mg/kg. In addition, pembrolizumab showed similar outcomes in response to 2- and 10-mg/kg treatment. Anti–PD-1 immunotherapy appears to be safe and effective for patients with melanoma or metastatic renal cell carcinoma. Our meta-analysis is limited, but additional clinical trials are warranted to verify this preliminary evidence of positive outcomes and before anti–PD-1 therapy can be recommended for routine clinical use.

Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials

“…Meta-analyses of the safety and tolerability of anti-PD-L1/PD-1 agents corroborate findings of improved safety profiles of ICIs compared with chemotherapy regimens used to treat patients with advanced cancers. [28][29][30][31] In a meta-analysis of 3450 patients from 7 randomized controlled trials, treatment with ICIs was associated with a lower incidence of any-grade AEs compared with chemotherapy (67.6% vs 82.9%) and grade 3 to 4 AEs (11.4% vs 35.7%), and treatment discontinuation occurred less frequently with anti-PD-L1/PD-1 agents compared with chemotherapy (4.5% vs 11.1%). 28 The incidence of TRAEs associated with ICIs ranged from 9% to 31%, with a pooled rate of 16% (95% confidence interval, 12%-21%).…”

A single-cell reference map for human blood and tissue T cell activation reveals functional states in health and disease

“…Interestingly, the tumor-associated CD8 + T cells exhibited transcriptional features similar to healthy activated CD8 + T cells including expression of multiple effector molecules such as perforin, IFN-γ and chemokines. We also examined the expression of multiple markers associated with exhaustion, a functionally hyporesponsive state found in tumorinfiltrating T cells targeted by checkpoint blockade immunotherapies 53,55,61 . Interestingly, exhaustion markers were upregulated in activated T cells in both healthy and tumor tissues 1 7 expressing CD8-associated cytokines.…”

“…A hallmark of tumor-associated T cells is a state of hyporesponsiveness or functional exhaustion, marked by persistent expression of surface inhibitory markers including PD-1, CTLA4, LAG3, TIM3 and others, many of which are expressed following T cell activation 17,50,51 . Some of these molecules (PD-1, CTLA4) are important targets for immunotherapy to promote anti-tumor immunity [52][53][54][55][56] . We compared expression of exhaustion and functional markers across healthy and tumor-associated T cells (Extended Data Fig.…”

The clinical value of combination of immune checkpoint inhibitors in cancer patients: A meta‐analysis of efficacy and safety

“…Previous meta-analyses have evaluated the efficacy of ICIs. [30][31][32][33][34][35][36][37][38] Some concluded that combination immunotherapy could result in better antitumor efficacy, but were based on only one or two studies. 31,38 One network meta-analysis compared ICIs with targeted therapies for metastatic melanoma, suggesting that a combination of BRAF and MEK inhibitors was superior to anti-CTLA-4 agents and anti-PD-1 agents.…”