The incidence of endometrial cancer is increasing worldwide [1]. In Japan, approximately 10% of patients with endometrial cancer are diagnosed with distant metastatic disease, with a 5-year survival rate of 20.1% [2,3]. Systemic therapy is the treatment strategy of choice for unresectable advanced or recurrent endometrial cancers unsuitable for radiation therapy. Paclitaxel/carboplatin and doxorubicin/cisplatin are recommended first-line treatments for patients with advanced or recurrent endometrial cancer [4-6].

A recent KEYNOTE-775 trial demonstrated that treatment with lenvatinib and pembrolizumab (LEN/PEM) led to significantly longer median progression-free survival (PFS) and overall survival (OS) rates than those of chemotherapy in patients with advanced endometrial cancer who showed disease progression after receiving systemic platinum-based therapy [7]. The results of this study suggest LEN/PEM as secondline treatment for advanced endometrial cancer. However, it is important to note that the KEYNOTE-775 trial utilized a single-agent chemotherapy regimen. Therefore, it remains unclear that which treatment, LEN/PEM or platinum doublet chemotherapy, is better for advanced or recurrent endometrial cancer.

Prior to the publication of the KEYNOTE-775 trial reports, the standard treatment approach for patients with advanced or recurrent endometrial cancer employed platinum doublet chemotherapy as either the first- or second-line regimen at our institution. Subsequently, LEN/PEM was adopted as the second-line regimen at our institution after the KEY- NOTE-775 trial results. This provided us with the opportunity to compare outcomes and adverse events in patients with advanced or recurrent endometrial cancer treated with platinum doublet chemotherapy or LEN/PEM at our institution. Accordingly, this study aimed to determine the appropriate regimen for patients with advanced and recurrent endometrial cancer.

Patients diagnosed with early endometrial cancer or resectable advanced endometrial cancer underwent hysterectomy and bilateral salpingo-oophorectomy with or without lymph node dissection. Patients with intermediate and high recurrence risk after surgery, as well as those with metastatic and unresectable endometrial cancer, were treated with platinum doublet chemotherapy.

In December 2021, LEN/PEM was approved in Japan for the treatment of patients with recurrent or advanced endometrial cancer and disease progression after platinum-based chemotherapy. Previously, physicians had to choose either platinum doublet or single-agent chemotherapy as the second-line regimen. After the approval of LEN/PEM, physicians could select LEN/PEM for patients with disease progression after platinum-based chemotherapy. Tumor imaging was conducted once every three cycles when physicians deemed it necessary. Responses were assessed using RECIST version 1.1, and adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

We conducted a retrospective analysis to investigate whether platinum doublet chemotherapy or LEN/PEM was appropriate for advanced or recurrent endometrial cancer. The inclusion criteria were patients with endometrial cancer who received either platinum doublet chemotherapy or LEN/ PEM at our institution and had a history of platinum-based chemotherapy between January 2013 and August 2023. Patients who did not undergo imaging were excluded from the study. Patient prognoses, immune-related adverse events (irAEs), and clinicopathological data, including age, body mass index (BMI), International Federation of Gynecology and Obstetrics (FIGO) stage, histological type, and mismatch repair (MMR) protein status, were obtained from medical records. The platinum-free interval (PFI) was defined as the period from the date of the last platinum-based chemotherapy to the date of recurrence.

Categorical variables were compared using the Fisher’s ex-act test, and continuous variables were compared using the Mann-Whitney U-test. PFS was defined as the period from the date of prior treatment to the date of disease progression or death from any cause. Survival curves were constructed using the Kaplan-Meier method, and a univariate log-rank test was used to assess statistical significance. Multivariate analyses of PFS were performed using the Cox proportional hazard model. We used complete case analysis to address missing data. All statistical analyses were performed using JMP version 15 software (SAS Institute Inc., Cary, NC, USA). This study was approved by the Institutional Review Board of our institution (IRB Approval R2022-042).

During the study period, 11 regimens were identified in the platinum doublet chemotherapy group, and 11 regimens were found in the LEN/PEM group. The median follow-up period was 6 months (range, 1-16). Patient characteristics are summarized in Table 1. The median age, BMI, FIGO stage, status, proportion of histology, MMR status, and prior lines of chemotherapy were not significantly different between the two groups. A significant difference was observed in the PFI between the LEN/PEM and platinum doublet chemotherapy groups.

The best overall responses for the two groups are presented in Table 2. Notably, the objective response rate (ORR) was not significantly different between the two groups.

The Kaplan-Meier estimates of PFS in the platinum doublet and LEN/PEM groups are shown in Fig. 1. The 6-month PFS rates of the platinum doublet and LEN/PEM groups were 27.3% (95% confidence interval [CI], 13.8%-40.7%) and 70.0% (95% CI, 55.5%-84.5%) respectively, with significant differences noted between the two groups. Multivariate analyses of histology, prior lines of chemotherapy, PFI, and regimens revealed that the LEN/PEM group had significantly higher PFS rates than that of the platinum doublet chemotherapy group (Table 3).

In the LEN/PEM group, irAEs occurred in five of the 11 patients. In particular, three patients in the LEN/PEM group (27.3%) discontinued treatment because of grade 2 interstitial pneumonia in two patients and grade 3 hypoadrenocorticism in one patient. Other irAEs that were controlled with medical treatment included grade 2 destructive thyroiditis (one patient), grade 2 hypoadrenocorticism (one patient), and grade 2 psoriasis (one patient) (Table 4).

This retrospective study compared the prognoses of patients with recurrent endometrial cancer treated with platinum doublet chemotherapy or LEN/PEM. Univariate and multivariate analyses revealed that treatment with LEN/PEM resulted in a significantly longer PFS than that with platinum doublet chemotherapy.

The KEYNOTE-775 trial compared the efficacy and safety of LEN/PEM with the physician’s preference for either doxorubicin or paclitaxel chemotherapy in patients with advanced endometrial cancer who showed disease progression after receiving at least one platinum-based chemotherapy [7]. A noteworthy aspect of the trial was that the control arm for LEN/PEM received single-agent chemotherapy. Despite this, data comparing the efficacy of platinum doublet chemotherapy and LEN/PEM as second-line treatments for advanced or recurrent endometrial cancer are lacking. Our investigation revealed that treatment with LEN/PEM resulted in a longer PFS than that of platinum doublet chemotherapy; interestingly, the ORR was similar between the two groups. The advantage of LEN/PEM is that patients can receive up to 35 concomitant cycles of pembrolizumab and lenvatinib. In contrast, platinum doublet chemotherapy cannot be administered for an extended period owing to its side effects.

Data regarding the efficacy of second-line chemotherapy are scarce [8]. Some retrospective studies have shown that the PFI or treatment-free interval is a predictor of the response to second-line platinum doublet chemotherapy. Patients with PFI >12 months had significantly longer PFS and OS rates after second-line platinum doublet chemotherapy [9-12]. Conversely, treatment with single-agent chemotherapy as second-line chemotherapy resulted in limited activity. The overall response rate to paclitaxel in patients with recurrent endometrial cancer for whom prior chemotherapy had failed was 27.3%, with a median response duration of 4.2 months [13]. In contrast, doxorubicin had a 0% response rate in the second-line treatment setting [14,15]. Considering these results, re-treatment with paclitaxel/carboplatin (TC) represents a reasonable choice over single-agent chemotherapy in patients with PFI >12 months. However, deciding between TC or LEN/PEM as the subsequent treatment for patients with PFI >12 months is challenging. Because the subgroup analysis of the KEYNOTE-775 trial showed that the treatment with LEN/PEM was not significantly effective after two prior regimens, we decided to use LEN/PEM for patients with disease progression after prior platinum-based chemotherapy, regardless of PFI. However, the clinical question of which is better, re-treatment with TC or LEN/PEM, could not be answered in our study, as only a single patient with PFI >12 months received LEN/PEM.

ENGOT-en9/LEAP-001 is a randomized, open-label phase 3 trial that evaluated LEN/PEM versus TC as the first-line treatment for advanced or recurrent endometrial carcinoma [16]. Unfortunately, the trial did not meet the dual primary endpoints of OS and PFS, and we await forthcoming publications for further insights. Our study that evaluated second-line regimens and ENGOT-en9/LEAP-001 that evaluated first-line regimens investigated the efficacy of TC and LEN/PEM but yielded different results. Based on the results of these two studies, it is currently considered desirable for patients with advanced or recurrent endometrial cancer to receive TC as the first-line regimen and LEN/PEM as the second-line regimen.

The KEYNOTE-775 trial showed that trial adverse events of any grade led to trial drug discontinuation in 33% of patients receiving LEN/PEM [7]. This rate is similar to that observed in our study. However, the rate of interstitial pneumonia, a clinically significant irAE, was higher in our study than in the KEYNOTE-775 trial (18.2% vs. 1.2%). In melanoma or non-small-cell lung cancer treatment, patients who develop irAEs have a better prognosis than those who do not receive nivolumab [17-19]. The ORR of LEN/PEM in our study was higher than that reported in the KEYNOTE-775 trial (54.5% vs. 31.9%, respectively). These differences in prognoses may be related to the incidence of interstitial pneumonia. All patients who developed irAEs in our study achieved complete or partial remission; therefore, patients who respond to LEN/ PEM should be monitored for irAEs.

One limitation of the present study is that it is a retrospective study with a small sample size. Moreover, patient backgrounds in the two groups differed, although historical control data were used. Subsequently, we performed multivariate analyses to reduce bias and found significant differences, although the sample size was small. To overcome these limitations and validate the findings of our study, further large-scale cohort studies including patients with PFI >12 months should be performed.

The present study revealed that the treatment with LEN/ PEM resulted in a significantly longer PFS than treatment with platinum doublet chemotherapy in patients with advanced and recurrent endometrial cancer. Further large-scale studies are required to validate these findings.