Abstract

Objective

The combination of immune checkpoint inhibitors (ICIs) plus chemotherapy is currently being tested as the first-line treatment of advanced endometrial. We aimed to evaluate the efficacy and safety of this combination.

Design

We performed a meta-analysis of randomized clinical trials.

Population and setting

Patients with advanced endometrial carcinoma receiving ICIs plus chemotherapy in the experimental arm, compared with chemotherapy plus placebo in the control arm, were included.

Methods and Outcomes

We evaluated the progression-free survival (PFS) as an efficacy outcome and the number and grades of adverse events (AEs) for safety. Hazard ratios (HR) for PFS and risk ratios (RR) for AEs, with 95% confidence intervals (CI), were calculated.

Results

1303 patients were treated in the included studies. Adding ICIs to chemotherapy significantly improved PFS in mismatch repair deficient (dMMR—HR 0.29; 95% CI, 0.20–0.42; p < 0.00001) and in mismatch repair proficient (pMMR—HR 0.64; 95% CI, 0.46–0.90; p = 0.01) patients. No difference emerged for all-grades AEs (RR 1.00; p = 0.98), but the risk of ≥G3 AEs was increased in the ICIs + chemotherapy group (RR 1.22; 95% CI, 1.11–1.34; p < 0.0001).

Conclusions

Adding ICIs to chemotherapy significantly improves PFS in first-line endometrial cancer, regardless of MMR status.

Endometrial cancer represents the sixth most common female tumour. Platinum-based chemotherapy is the current standard of care in first-line treatment of advanced endometrial cancer. However, the prognosis is poor, with limited response rates and no standard of care after progression. Several immune checkpoint inhibitors have been approved for the treatment of advanced endometrial cancer, which was previously treated with platinum-based chemotherapy, i.e. pembrolizumab alone for mismatch repair deficient (dMMR)-microsatellite-instable (MSI) endometrial cancer or otherwise combined with the tyrosine-kinase inhibitor lenvatinib, and dostarlimab for dMMR/MSI disease.¹ Immune checkpoint inhibitors are currently being tested as first-line treatment for advanced endometrial cancer in addition to chemotherapy.

In this study we address the efficacy and safety of adding immune checkpoint inhibitors to standard chemotherapy as a first-line treatment of advanced endometrial cancer. We pooled data from two randomised phase III clinical trials, including patients receiving immune checkpoint inhibitors plus chemotherapy in the experimental arm, compared with chemotherapy plus placebo in the control arm.^{2, 3} We calculated hazard ratios for progression-free survival (PFS); and risk ratios for adverse events with 95% confidence intervals. A value of p < 0.05 was considered statistically significant, and all tests were two-sided. RevMan v.5.4 was used for the meta-analysis.

Overall, 1303 stage III/IV patients were treated in the included studies. Among them, 26.3% had MSI cancers and 73.7% had microsatellite stability (MSS) cancers. In the experimental arms, 407 patients received pembrolizumab + chemotherapy (followed by pembrolizumab maintenance) in the NRG-GY018 trial, and 241 received dostarlimab + chemotherapy (followed by dostarlimab maintenance) in the RUBY trial; in the control arms, 409 and 246 total patients were treated with chemotherapy and placebo in the two studies, respectively. Both studies had PFS as the primary end point. Adding immune checkpoint inhibitors to chemotherapy significantly improved PFS in dMMR/MSI and proficient MMR/MSS patients, compared with chemotherapy/placebo. No difference in all-grade adverse events emerged between the two arms; however, immune checkpoint inhibitors plus chemotherapy increased the risk of adverse events of Grade 3 or above (Figure 1). Overall survival data were not mature at the time of our analysis.

Adding immune checkpoint inhibitors to chemotherapy significantly improves PFS in first-line endometrial cancer, regardless of MMR status. Among the gynaecological tumours, endometrial cancer—especially the endometrial subtype—displays the highest rate of dMMR/MSI, found in 15–30% of cases. The presence of dMMR is often associated with poor prognostic factors, such as high grade or stage, and has an intermediate prognosis between ‘copy number low’ and p53-mutated tumours according to the ProMiSe classification.^{4, 5} In the metastatic setting, MMR is a useful biomarker for identifying patients with progressive disease despite platinum therapy, for which immune checkpoint inhibitors are effective alone or combined with other agents, such as tyrosine-kinase inhibitors.¹ However, first-line studies seem to topple this paradigm, and the reason for the different role of MMR status in this setting is not clear. Notwithstanding, MMR status is helpful for the individuation of Lynch syndrome and familiar prevention. Given a warning on adverse events of Grade 3 or above found in our analysis, OS data warrant a longer follow up to define the subset of patients who may achieve the utmost benefit from treatment intensification, sparing the other patients from unnecessary toxicities. Besides MMR, other biomarkers should be investigated for a possible prognostic role in using immune checkpoint inhibitors, such as programmed death-ligand 1, tumour mutational burden, or elements of the tumour microenvironment, building multi-marker classification.