Pembrolizumab as a single agent for patients with MSI-H advanced endometrial carcinoma

Turinetto, Margherita; Lombardo, Valentina; Pisano, Carmela; Musacchio, Lucia; Pignata, Sandro

doi:10.1080/14737140.2022.2126356

Cited by 4 publications

(4 citation statements)

References 39 publications

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“…35 Therefore, LOH-high status might have more value as an indicator of HRD in primary EC as opposed to this recurrent pretreated patient population cohort deficient EC with response rates ranging between 27% and 48%. [36][37][38] The activity of single-agent olaparib in this study is consistent with the response rate of 4.4% and the median PFS of 2.5 months observed in a single-arm study (N = 25) of niraparib in a heavily pretreated EC population. A follow-on cohort in this trial investigated the combination of niraparib and the PDL1 inhibitor dostarlimab, demonstrating modest efficacy with a response rate of 14% and median PFS of 2.4 months.…”

Section: Discussionsupporting

confidence: 88%

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NRG‐GY012: Randomized phase 2 study comparing olaparib, cediranib, and the combination of cediranib/olaparib in women with recurrent, persistent, or metastatic endometrial cancer

Rimel,

Enserro,

Bender

et al. 2023

Cancer

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PurposeThis paper reports the efficacy of the poly (ADP‐ribose) polymerase inhibitor olaparib alone and in combination with the antiangiogenesis agent cediranib compared with cediranib alone in patients with advanced endometrial cancer.MethodsThis was open‐label, randomized, phase 2 trial (NCT03660826). Eligible patients had recurrent endometrial cancer, received at least one (<3) prior lines of chemotherapy, and were Eastern Cooperative Oncology Group performance status 0 to 2. Patients were randomly assigned (1:1:1), stratified by histology (serous vs. other) to receive cediranib alone (reference arm), olaparib, or olaparib and cediranib for 28‐day cycles until progression or unacceptable toxicity. The primary end point was progression‐free survival in the intention‐to‐treat population. Homologous repair deficiency was explored using the BROCA‐GO sequencing panel.ResultsA total of 120 patients were enrolled and all were included in the intention‐to‐treat analysis. Median age was 66 (range, 41–86) years and 47 (39.2%) had serous histology. Median progression‐free survival for cediranib was 3.8 months compared with 2.0 months for olaparib (hazard ratio, 1.45 [95% CI, 0.91‐2.3] p = .935) and 5.5 months for olaparib/cediranib (hazard ratio, 0.7 [95% CI, 0.43–1.14] p = .064). Four patients receiving the combination had a durable response lasting more than 20 months. The most common grade 3/4 toxicities were hypertension in the cediranib (36%) and olaparib/cediranib (33%) arms, fatigue (20.5% olaparib/cediranib), and diarrhea (17.9% cediranib). The BROCA‐GO panel results were not associated with response.ConclusionThe combination of cediranib and olaparib demonstrated modest clinical efficacy; however, the primary end point of the study was not met. The combination was safe without unexpected toxicity.

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Section: Discussionsupporting

confidence: 88%

“…Alternate trials focused on specific EC subgroups, depending on the agents under consideration, may be appropriate. For example, since this study was implemented, immune checkpoint inhibitors have demonstrated efficacy in patients with mismatch repair‐deficient EC with response rates ranging between 27% and 48% 36–38 …”

Section: Discussionmentioning

confidence: 99%

NRG‐GY012: Randomized phase 2 study comparing olaparib, cediranib, and the combination of cediranib/olaparib in women with recurrent, persistent, or metastatic endometrial cancer

Rimel,

Enserro,

Bender

et al. 2023

Cancer

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“…The results of this study showed that CXCL9 was associated with the expression of a variety of immune cells and that a higher proportion of anti-tumor immune cells were found in the high expression group. In recent years, with the widespread use of TCGA molecular typing in clinical practice, immunogenicity is good for POLE hypermutant and microsatellite mutant types, and patients can bene t more from immunotherapy [37] . European approval of the anti-programmed cell death protein-1 (PD-1) dostalizumab (TSR-042) as a monotherapy option for patients with advanced microsatellite instability in endometrial cancer [38] .…”

Section: Discussionmentioning

confidence: 99%

High expression of CXCL9 gene promotes immune invasion and improves the prognosis of patients with endometrial cancer

Zhang¹,

Zhang

et al. 2023

Preprint

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Objective: CXCL9 plays a key role in immune cell chemotaxis and inhibition of tumor angiogenesis. The aim of this study was to investigate the prognostic value of CXCL9 in endometrial cancer (EC) and the impact on the immune microenvironment. Methods：RNA sequencing data for EC patients were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, while clinicopathological information for EC patients was obtained from the TCGA database. Cox univariate and multivariate analyses were used, followed by the construction and validation of nomograms. CXCL9 expression and survival analysis, gene correlation and immune infiltration correlation analysis, and pathway enrichment analysis were performed using UALCAN, Kaplan-Meier, GeneMANIA, STRING, TIMER, cBioPortal, muTarget, CIBERSORT, TISIDB, GO, KEGG and GSEA tools. Results：CXCL9 was significantly upregulated in EC. Cox univariate and multivariate analysis showed that CXCL9 was an independent predictor of overall survival (OS), disease specific survival (DSS) and progression free interval (PFI) (P<0.05). However, increased CXCL9 expression predicted prolonged OS, DSS and PFI (P<0.05). In addition, CXCL9 was positively correlated with immune cell infiltration and correlated with marker genes of multiple immune pathways as well as marker genes of immune checkpoints. GSEA enrichment analysis suggests that high CXCL9 expression plays an important role in immune cell migration, activation and other functions. Conclusion: The results of this study suggest that high CXCL9 expression was a predictor of good prognosis in patients with EC and may be associated with the recruitment of immune cells to the tumor microenvironment in the tumor tissue to function as an anti-tumor immune response.

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“…Frontiers in Pharmacology frontiersin.org Dioun et al, 2023); three publications were excluded because they overlapped with the same cohort of patients, and the latest study data was more complete (Oaknin et al, 2020a;Oaknin et al, 2020b;Marabelle et al, 2020); and five publications were excluded because they were reviews (Sobecki-Rausch and Barroilhet, 2019;Kasherman et al, 2021;Costa and Vale, 2022;Turinetto et al, 2022;Walker et al, 2023). Finally, a total of 11 articles were included in the meta-analysis.…”

Section: Figurementioning

confidence: 99%

Effectiveness and safety of PD-1/PD-L1 inhibitors in advanced or recurrent endometrial cancer: a systematic review and meta-analysis

Han,

Guo,

Song

et al. 2023

Front. Pharmacol.

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Background: Studies in recent years have shown that PD-1/PD-L1 inhibitors may have better effectiveness in patients with advanced or recurrent endometrial cancer. The effectiveness of PD-1/PD-L1 inhibitors is thought to be related to mismatch repair-deficient (dMMR) and mismatch repair-proficient (pMMR) classification in advanced or recurrent endometrial cancer. This study aims to evaluate the effectiveness of PD-1/PD-L1 inhibitors in patients classified as dMMR and pMMR.Methods: Medical databases were searched to identify relevant publications up to 30 November 2022. The primary outcome was comparison of objective response rate (ORR) in patients with dMMR and pMMR following treatment with PD-1/PD-L1 inhibitors; secondary outcomes were single-group ORR in patients with dMMR and in patients with pMMR, respectively.Results: Eleven studies were eligible for analysis and patients with advanced or recurrent endometrial cancer with molecular classification of dMMR had a higher total ORR than those with pMMR [odds ratio (OR), 7.70; 95% confidence interval (CI), 3.22–18.38; p < 0.01], with low evidence of between-study heterogeneity (I2 = 0%). The total ORR of patients with advanced or recurrent endometrial cancer with molecular type dMMR was 51.9% (95% CI, 33.6%–69.9%). The overall ORR of patients with advanced or recurrent endometrial cancer with molecular type pMMR was 16.1% (95% CI, 5.5%–30.3%).Conclusion: In our including studies, the patients with advanced or recurrent endometrial cancer with molecular types of dMMR and pMMR, following treatment with PD-1/PD-L1 inhibitors, the total ORR of patients with dMMR was higher than that of patients with pMMR. Since the current number of studies is not very large, it is possible that more studies will be published in the future and more precise results will be discussed further.

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Pembrolizumab as a single agent for patients with MSI-H advanced endometrial carcinoma

Cited by 4 publications

References 39 publications

NRG‐GY012: Randomized phase 2 study comparing olaparib, cediranib, and the combination of cediranib/olaparib in women with recurrent, persistent, or metastatic endometrial cancer

NRG‐GY012: Randomized phase 2 study comparing olaparib, cediranib, and the combination of cediranib/olaparib in women with recurrent, persistent, or metastatic endometrial cancer

High expression of CXCL9 gene promotes immune invasion and improves the prognosis of patients with endometrial cancer

Effectiveness and safety of PD-1/PD-L1 inhibitors in advanced or recurrent endometrial cancer: a systematic review and meta-analysis

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