Endometrial cancer is the most prevalent gynecological cancer in high-income countries, and its incidence is rising globally [9, 10]. In Japan, there were 17,880 new diagnoses in 2019, and 2,644 deaths in 2020, indicating an upward trend [11]. While aging and a reduction in benign hysterectomies contribute to this increase, obesity is the primary risk factor. Obesity complicates both diagnosis and treatment, highlighting the need for further research to establish primary prevention strategies for high-risk women and to enhance survivorship in endometrial cancer patients. Most endometrial cancers are treatable through hysterectomy if detected early, particularly when accompanied by postmenopausal bleeding, but advanced cases tend to have a poor prognosis [9].

Treatment decisions are influenced by the lesion’s location, the patient’s PS, comorbidities, and the presence of hormone receptors [12]. The preferred drug therapies include TC therapy or doxorubicin combined with cisplatin; however, options become limited once these treatments fail [12]. The incidence of MSI-high in endometrial cancer is approximately 17%, which is the highest among cancers [7]. Furthermore, it has been reported that endometrial cancer with MSI-high/dMMR constitutes about 25–31% of all cases [13].

Compared to microsatellite-stable endometrial cancers, MSI-high/dMMR endometrial cancers exhibit a higher neoantigen burden and contain greater numbers of CD3-positive, CD8-positive, PD-1-expressing tumor-infiltrating lymphocytes, and PD-L1-expressing immune cells within and around the tumor [14].

The anti-PD-1 antibody Pem demonstrates antitumor activity in patients with MSI-high/dMMR endometrial cancer [7]. In the KEYNOTE-158 study, Pem provided sustained antitumor effects and favorable survival outcomes, with manageable toxicity in patients with advanced MSI-high/dMMR endometrial cancer who had previously received treatment and had a PS of 0–1 [7]. Additionally, about 25–31% of endometrial cancers are reported to be MSI-high or dMMR [13]. However, the efficacy and safety of ICIs for advanced endometrial cancer with poor PS have not yet been fully validated.

With the same PS grade, patients may have varying conditions. In this case, pain from a large tumor reduced ADL, worsening PS.

Although the apparent PS was low, major organ function remained intact. PS assessment is subjective and may be affected by factors such as cancer pain and ADL impairment from bone metastases, which can lower the observed PS.

Lee et al.’s recent analysis identified a significant inverse relationship between low albumin levels and progression-free survival (PFS) following ICI therapy [15]. Alongside poor PS and hypoalbuminemia, liver metastases were also notably linked with lower survival rates in NSCLC patients treated with ICIs. Additionally, examining individual metastases in ICI responders indicated a generally uniform response across distant lesions, suggesting that systemic immune responses mediated by peripheral cloned T cells might exert a greater effect on antitumor responses than locally infiltrating lymphocytes [16].

Although molecular and genomic testing holds shows potential for predicting outcomes, it cannot fully replace the critical roles of nutritional status, functional reserve, and metastatic disease in decisions about treatment continuation. Current predictive tools for ICI efficacy are limited; thus, a more detailed combination of patient characteristics and molecular markers is needed to optimize future treatments [1].

While ICIs have proven effective and safe in NSCLC, the impact on patients with poor PS remains less defined. Real-world data in lung cancer showed that 101 (80.8%) out of 125 patients had an ECOG PS of ≥ 2. Within 12 months, 50 immune-related adverse events (irAEs) were observed, but patient factors did not significantly affect irAE occurrence or overall survival (OS), except for race (p = 0.045) [17].

Tomasik et al. conducted a systematic review and meta-analysis across 67 interventional and observational studies (26,442 patients) to evaluate the efficacy and safety of ICIs in NSCLC patients with PS ≤ 1 versus PS ≥ 2 [18]. Patients with a lower PS were approximately twice as likely to have reduced responsiveness to ICIs compared to those with PS ≤ 1, indicating that a lower PS is both prognostic and predictive of ICI response, though it did not affect the safety profile. The pooled hazard ratio for PFS was 2.17 (95%CI 1.96–2.39; I2, 65%), and for OS, it was 2.76 (95%CI, 2.43–3.14; I2, 76%). However, the odds ratio for adverse events (AEs) was 1.12 (95%CI 0.84–1.48), showing a consistent safety profile regardless of PS. Prospective randomized studies are still needed to establish the potential benefits of ICIs in patients with low PS.

In the KEYNOTE-158 study, Pem showed an objective response rate of 48% in patients with MSI-high/dMMR advanced endometrial cancer, with a median response duration of 48 months, median PFS of 13.1 months, and median OS of at least 48 months [7]. Pem’s toxicity was manageable, with most treatment-related AEs being mild to moderate in severity among the 90 patients evaluated for safety. Treatment discontinuations due to treatment-related or immune-mediated AEs were low, affecting six and two patients, respectively [7]. However, the study included only patients with PS 0–1, excluding those with advanced endometrial cancer and poor PS from the trial.

Multiple reports indicate that ICIs can be highly effective with manageable toxicity in advanced endometrial cancer patients with poor PS. Ducceschi et al. documented a multicenter case series of six patients with PS 3–4 treated with the anti-PD-1 antibody costalimai for advanced endometrial cancer, showing rapid responses and notable PS improvement [15]. The median time for clinical response (from PS 3–4 to PS 0–1) was 6 weeks. In these cases, PS 3 or higher was solely attributed to disease burden in 5 out of 6 cases. In these cases, cancer pain decreased PS. Pietrantonio et al. also demonsrtated anti-PD-1 antibody efficacy in 27 patients with MSI-high/dMMR malignancies and PS 2 (74%) or PS 3 (26%), including one endometrial cancer case. After a median of 6 weeks, 52% improved to PS 1, and of these, 30% further improved to PS 0 after 10 weeks. Grade 3 or higher AEs occurred in 11% (3/27) of cases, including colitis, hepatitis, and pancreatitis, with no treatment-related deaths reported. In the present case, disease control lasted over 48 months, with PS improving from 4 to 0. Grade 2 adrenal insufficiency and hypothyroidism were managed by temporarily suspending Pem and using appropriate hormone replacement. Watanabe et al. reported a case involving a young woman with a PS of 4, primarily due to cancer pain from tumor invasion into the pelvic wall, but with intact cardiac, hepatic, and renal function, no comorbidities, and no prior medical history. Treated with Pem alone, her PS improved to 0 within 10 weeks [19]. In this case, her poor PS was solely disease-related, without any organ dysfunction. Such occurrences are termed Lazarus-type responses, named after the biblical resurrection story [20]. These reactions are commonly observed in NSCLC and, to a lesser extent, in endometrial cancer. Although the precise mechanisms remain unclear, attention to this in phenomenon in MSI-high/dMMR endometrial cancer is advised. Furthermore, assessing whether poor PS in advanced endometrial cancer stems from the disease itself, other complications, or organ failure may be crucial when considering Pem therapy.