Dataset Information

Immune Checkpoint Inhibitors Targeting the PD-1/PD-L1 Pathway in Advanced, Recurrent Endometrial Cancer: A Scoping Review with SWOT Analysis.

ABSTRACT: Results of recent clinical trials using the immune check point inhibitors (ICI) pembrolizumab or dostarlimab with/without lenvatinib has led to their approval for specific molecular subgroups of advanced recurrent endometrial cancer (EC). Herein, we summarise the clinical data leading to this first tissue-agnostic approval. As this novel therapy is not yet available in the United Kingdom standard care setting, we explore the strengths, weaknesses, opportunities, and threats (SWOT) of ICI treatment in EC. Major databases were searched focusing on clinical trials using programmed cell death protein 1 (PD-1) and its ligand (PD-L1) ICI which ultimately contributed to anti-PD-1 approval in EC. We performed a data quality assessment, reviewing survival and safety analysis. We included 15 studies involving 1609 EC patients: 458 with mismatch repair deficiency (MMRd)/microsatellite instability-high (MSI-H) status and 1084 with mismatch repair proficiency/microsatellite stable (MMRp/MSS) status. Pembrolizumab/dostarlimab have been approved for MMRd ECs, with the addition of lenvatinib for MMRp cases in the recurrent setting. Future efforts will focus on the pathological assessment of biomarkers to determine molecular phenotypes that correlate with response or resistance to ICI in order to identify patients most likely to benefit from this treatment.

SUBMITTER: Johnson RL

PROVIDER: S-EPMC10527181 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Immune Checkpoint Inhibitors Targeting the PD-1/PD-L1 Pathway in Advanced, Recurrent Endometrial Cancer: A Scoping Review with SWOT Analysis.

Johnson Racheal Louise RL Ganesan Subhasheenee S Thangavelu Amudha A Theophilou Georgios G de Jong Diederick D Hutson Richard R Nugent David D Broadhead Timothy T Laios Alexandros A Cummings Michele M Orsi Nicolas Michel NM

Cancers 20230919 18

Results of recent clinical trials using the immune check point inhibitors (ICI) pembrolizumab or dostarlimab with/without lenvatinib has led to their approval for specific molecular subgroups of advanced recurrent endometrial cancer (EC). Herein, we summarise the clinical data leading to this first tissue-agnostic approval. As this novel therapy is not yet available in the United Kingdom standard care setting, we explore the strengths, weaknesses, opportunities, and threats (SWOT) of ICI treatme ...[more]

PMID: 37760602

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Project description:BackgroundThe combination of programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors with chemotherapy (CT) is currently under evaluation as a first-line treatment for advanced or recurrent endometrial cancer (EC). This study sought to assess the efficacy and safety of this therapeutic combination in patients with advanced or recurrent EC.MethodsWe performed an exhaustive review of randomized controlled trials (RCTs) up to September 25, 2024, examining the efficacy and safety of combining PD-1/PD-L1 inhibitors with CT versus CT alone (or plus placebo) in advanced or recurrent EC. Efficacy was measured by progression-free survival (PFS) and overall survival (OS), while safety was assessed by the incidence of any grade or grade ≥ 3 adverse events (AEs). We calculated hazard ratios (HRs) for PFS and OS, as well as risk ratios (RRs) for AEs, each accompanied by 95% confidence intervals (CIs). To evaluate heterogeneity, we employed Cochran's Q test, I2 statistics, and 95% prediction intervals (PIs). Trial sequential analysis (TSA) was conducted using R Version 4.3.1, STATA Version 12.0, and TSA Version 0.9.5.10 Beta software.ResultsOur analysis incorporated 6 studies, encompassing a total of 2,954 patients. The combination of PD-1/PD-L1 inhibitors with CT significantly improved PFS (HR = 0.617, 95% CI: 0.506-0.752; 95% PI: 0.334-1.140) and OS (HR = 0.774, 95% CI: 0.664-0.902; 95% PI: 0.553-1.083) compared to CT alone (or plus placebo) in the overall population. Subgroup analysis based on mismatch repair (MMR) status revealed pronounced benefits in PFS and OS for patients with deficient MMR (dMMR) (PFS: HR = 0.344, 95% CI: 0.269-0.438; 95% PI: 0.231-0.510; OS: HR = 0.371, 95% CI: 0.245-0.562; 95% PI: 0.025-5.461) compared to those with proficient MMR (pMMR) (PFS: HR = 0.772, 95% CI: 0.627-0.950; 95% PI: 0.394-1.512; OS: HR = 0.996, 95% CI: 0.692-1.435; 95% PI: 0.021-47.662). Although there was no observed difference in the incidence of any grades AEs (RR = 0.994, 95% CI: 0.982-1.006; 95% PI: 0.978-1.009), the risk of grade ≥ 3 AEs was elevated in the group receiving PD-1/PD-L1 inhibitors in combination with CT (RR = 1.132, 95% CI: 1.023-1.252; 95% PI: 0.836-1.532).ConclusionThe combination of PD-1/PD-L1 inhibitors with CT significantly improved PFS and OS in advanced or recurrent EC patients, with particularly pronounced benefits observed in those with dMMR. Clinicians can tailor treatment strategies according to individual patient characteristics to optimize therapeutic outcomes, while remaining alert to the possibility of AEs in clinical practice.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024595455.

Project description:PurposeBlocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. Therapeutics targeting this pathway are currently in clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory melanoma. Nivolumab has been associated with improved overall survival compared with dacarbazine in patients with previously untreated wild-type serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma. Although the most mature data are in the treatment of melanoma, the FDA has granted approval of nivolumab for squamous cell lung cancer and the breakthrough therapy designation to immune- checkpoint inhibitors for use in other cancers: nivolumab, an anti-PD-1 monoclonal antibody, for Hodgkin lymphoma, and MPDL-3280A, an anti-PD-L1 monoclonal antibody, for bladder cancer and non-small cell lung cancer. Here we review the literature on PD-1 and PD-L1 blockade and focus on the reported clinical studies that have included patients with melanoma.MethodsPubMed was searched to identify relevant clinical studies of PD-1/PD-L1-targeted therapies in melanoma. A review of data from the current trials on clinicaltrial.gov was incorporated, as well as data presented in abstracts at the 2014 annual meeting of the American Society of Clinical Oncology, given the limited number of published clinical trials on this topic.FindingsThe anti-PD-1 and anti-PD-L1 agents have been reported to have impressive antitumor effects in several malignancies, including melanoma. The greatest clinical activity in unselected patients has been seen in melanoma. Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive of response to immune-checkpoint blockade. However, tumors expressing little or no PD-L1 are less likely to respond to PD-1 pathway blockade. Combination checkpoint blockade with PD-1 plus cytotoxic T-lymphocyte antigen (CTLA)-4 blockade appears to improve response rates in patients who are less likely to respond to single-checkpoint blockade. Toxicity with PD-1 blocking agents is less than the toxicity with previous immunotherapies (eg, interleukin 2, CTLA-4 blockade). Certain adverse events can be severe and potentially life threatening, but most can be prevented or reversed with close monitoring and appropriate management.ImplicationsThis family of immune-checkpoint inhibitors benefits not only patients with metastatic melanoma but also those with historically less responsive tumor types. Although a subset of patients responds to single-agent blockade, the initial trial of checkpoint-inhibitor combinations has reported a potential to improve response rates. Combination therapies appear to be a means of increasing response rates, albeit with increased immune-related adverse events. As these treatments become available to patients, education regarding the recognition and management of immune-related effects of immune-checkpoint blockade will be essential for maximizing clinical benefit.

Dataset Information

Immune Checkpoint Inhibitors Targeting the PD-1/PD-L1 Pathway in Advanced, Recurrent Endometrial Cancer: A Scoping Review with SWOT Analysis.

Publications

Immune Checkpoint Inhibitors Targeting the PD-1/PD-L1 Pathway in Advanced, Recurrent Endometrial Cancer: A Scoping Review with SWOT Analysis.

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