PD-1 or PD-L1 inhibitors in addition to first-line chemotherapy for endometrial cancer: an extracted individual patient data meta-analysis

Abstract

Objective: To assess the impact of PD-1/PD-L1 inhibitors in first-line treatment of advanced or recurrent endometrial cancer (EC) through individual patient data (IPD) Meta-analysis, providing insights by integrated survival curves.

Methods: We searched PubMed, Embase, Cochrane and meetings up to April 2024 for randomised phase II or III trials (randomised controlled trials) investigating immunotherapy plus chemotherapy for EC. IPD was reconstructed from Kaplan-Meier plots using WebPlotDigitizer and the R package IPDfromKM, and then combined.

Results: NRG-GY018, RUBY, MITO END-3, AtTEnd/ENGOT-en7 and DUO-E were included. 2,436 patients were analysed for progression-free survival (PFS) and 2,317 for overall survival (OS). Among these, 621 patients had deficient DNA mismatch repair (dMMR) and 1,815 had the proficient disease (pMMR).The IPD analysis highlighted the significant benefit of adding immunotherapy to chemotherapy in dMMR patients, with 3-year absolute gains of 36% in PFS (HR 0.36, 95% CI 0.28-0.45) and 28% in OS (HR 0.41, 95% CI 0.30-0.48).For pMMR, a smaller benefit was observed in PFS, with a 3-year absolute gain of 6% (HR 0.78, 95% CI 0.69-0.88). Notably, a significant benefit occurred only with PD-1 inhibitors (PFS HR 0.66, 95% CI 0.55-0.79; OS: HR 0.78, 95% CI 0.62-0.96). No significant benefit was seen with PD-L1 inhibitors (PFS: 0.87, 95% CI 0.75-1.03; OS: HR: 0.93, 95% CI 0.75-1.16).

Conclusion: This meta-analysis validated the benefit of adding immunotherapy to platinum-based chemotherapy with respect to PFS. dMMR patients gain advantages from the inclusion of either anti-PD-1 or anti-PD-L1 agents, whereas pMMR patients only experience this benefit when treated with anti-PD-1 agents.

Keywords: advanced or recurrent endometrial cancer; extracted individual patient data; immunotherapy; meta-analysis.

Supplementary Table 2.. OS rates estimated for each group as time goes by.

Supplementary Table 3.. Median survivals.

Supplementary Figure 1.. Graphical representation of the trial-level meta-analysis random effect models (a): PFS in the dMMR population, (b): OS in the dMMR population, (c): PFS in the pMMR population and (d): OS in the pMMR population with the respective forest plots and heterogeneity analysis results in the bottom-left.

Supplementary Figure 2.. Trial level meta-analyses of first-line immune checkpoint inhibitor plus chemotherapy [Immunotherapy] versus chemotherapy [Control] for EC: (a): PFS with PD-1 inhibitors; (b): OS with PD-1 inhibitors; (c): Progression-free with PD-L1 inhibitors and (d): OS with PD-L1 inhibitors.

Figure 1.. Flowchart of the systematic review and included publications.

Figure 2.. Kaplan-Meier plots of extracted IPD. Placebo arms are plotted in blue, while immunotherapy arms are plotted in red. (a): PFS for dMMR patients and (b): OS for dMMR patients.

Figure 3.. Kaplan-Meier plots of extracted IPD. Placebo arms are plotted in blue, while immunotherapy arms are plotted in red. (a): PFS for pMMR patients and (b): OS for pMMR patients.

Figure 4.. Kaplan-Meier plots of extracted IPD according to PD-1 and PD-L1 therapy and MMR subgroup. (a): PFS with anti-PD1 for dMMR and pMMR; (b): PFS for anti PD-L1 for dMMR and pMMR; (c) OS with anti PD-1 for dMMR and pMMR; (d) OS with anti PD-L1 for dMMR and pMMR.