María Jesús Rubio

Background/Objectives: Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with increasing incidence and limited options in advanced disease. Molecular classification has redefined risk stratification and therapeutic decision-making, particularly with the incorporation of immunotherapy. This review provides a clinically oriented overview of immunotherapy in EC across molecular subgroups and treatment settings. Methods: A narrative review was conducted using PubMed/MEDLINE, Embase, and Web of Science, focusing on clinical trials and studies with direct clinical relevance. Results: Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have demonstrated significant benefit in EC, particularly in mismatch repair-deficient (dMMR)/microsatellite instability–high (MSI-H) tumors, where durable responses are observed. In contrast, mismatch repair-proficient (pMMR) tumors show limited sensitivity to monotherapy and require combination approaches. Recent phase III trials have established chemoimmunotherapy as a first-line standard, with greater benefit in dMMR tumors and clinically meaningful improvements in pMMR disease. In the second-line setting, PD-1 inhibitor monotherapy is standard for dMMR tumors, while lenvatinib plus pembrolizumab is a key option for pMMR disease. However, responses remain heterogeneous and are not fully explained by MMR status alone. Conclusions: Immunotherapy is a cornerstone in advanced EC management, guided by molecular classification. Key challenges include limited efficacy in pMMR tumors, lack of robust predictive biomarkers, and uncertainty in treatment sequencing. Future strategies should focus on biomarker-driven approaches and rational combinations.

The OVOC study was carried out to evaluate the management and clinical evolution of patients with advanced ovarian cancer (AOC) in routine clinical practice in Spain. A retrospective study was made in women diagnosed with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (FIGO IIIB-IV) who had received at least one line of treatment between 2013 and 2016, before the establishment of poly ADP ribose polymerase (PARP) inhibitors as first-line treatment. A total of 400 patients (median age: 61.7 years; FIGO IIIC: 60.0%; high-grade serous carcinoma: 75.0%) received a median of two therapy lines. Primary and interval debulking surgery was performed in 37.0% and 54.3% of the patients. Germline BRCA1 and BRCA2 mutations were found in 16.2% and 12.0% of the patients. The median progression-free survival (PFS) from the start of the first-/second-/third-line of treatment was 14.2/8.7/4.5 months. The median treatment-free interval (TFI) to the start of the second line was 9.9 months. The median overall survival (OS) was 42.6 months. At first relapse, 65.9% of the patients were platinum-sensitive and 34.1% platinum-resistant. Biologic therapies were administered in 25.2% of the platinum-sensitive and 16.2% of the platinum-resistant patients. Patients harboring BRCA mutations had a lower risk of progression/relapse after the first (BRCA1 and BRCA2 mutation versus native: p < 0.0001) and second line (BRCA1 and BRCA2 mutation versus native: p = 0.021 and p = 0.037, respectively). Patients with BRCA2 mutations had a lower mortality risk than those without (p = 0.015). The median PFS was significantly higher in patients receiving targeted therapy in the first (17.4 versus 11.6 months; p = 0.039) and second line (11.1 versus 7.8 months; p < 0.001). This study provides real-world data on therapeutic management and outcomes in AOC patients in Spain. A longer PFS was achieved in patients receiving targeted therapies. BRCA1/2 mutations were a favorable prognostic factor for PFS and BRCA2 mutation for OS.

PURPOSE: Lenvatinib plus pembrolizumab (len + pembro) significantly improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in previously treated advanced or recurrent endometrial cancer (aEC) in the phase III Study 309/KEYNOTE-775. We report results from the phase III, randomized, open-label European Network of Gynaecological Oncological Trial-en9/LEAP-001 study (ClinicalTrials.gov identifier: NCT03884101 ) that evaluated len + pembro versus chemotherapy in first-line aEC. METHODS: Patients with stage III to IV or recurrent, radiographically apparent EC and no previous chemotherapy or disease progression ≥6 months after neo/adjuvant platinum-based chemotherapy were randomly assigned 1:1 to lenvatinib 20 mg once daily plus pembrolizumab 200 mg once every 3 weeks or paclitaxel 175 mg/m ² plus carboplatin AUC 6 mg/mL/min once every 3 weeks. Primary end points were PFS and OS, evaluated in the mismatch repair-proficient (pMMR) and all-comers populations. Noninferiority was assessed for OS at final analysis (FA) for len + pembro versus chemotherapy (multiplicity-adjusted, one-sided nominal alpha, .0159; null hypothesis–tested hazard ratio [HR], 1.1). RESULTS: Eight hundred forty-two patients were randomly assigned (len + pembro, n = 420 [pMMR population, n = 320]; chemotherapy, n = 422 [pMMR population, n = 322]). At FA (data cutoff, October 2, 2023), median PFS (95% CI) in the pMMR population was 9.6 (8.2 to 11.9) versus 10.2 (8.4 to 10.5) months with len + pembro versus chemotherapy (hazard ratio [HR], 0.99 [95% CI, 0.82 to 1.21]) and among all-comers was 12.5 (10.3 to 15.1) versus 10.2 (8.4 to 10.4) months (HR, 0.91 [95% CI, 0.76 to 1.09]; descriptive analyses). Median OS (95% CI) in the pMMR population was 30.9 (25.4 to 37.7) versus 29.4 (26.2 to 35.4) months with len + pembro versus chemotherapy (HR, 1.02 [95% CI, 0.83 to 1.26]; noninferiority P = .246, not statistically significant per multiplicity control strategy) and among all-comers was 37.7 (32.2 to 43.6) versus 32.1 (27.2 to 35.7) months (HR, 0.93 [95% CI, 0.77 to 1.12]). Grade ≥3 treatment-related adverse events occurred in 331/420 (79%) versus 274/411 (67%) treated patients. CONCLUSION: First-line len + pembro did not meet prespecified statistical criteria for PFS or OS versus chemotherapy in pMMR aEC.

Background Granulosa cell ovarian tumors (GCTs) are a rare neoplasia characterized by a pathognomonic mutation in the FOXL2 gene. In vitro studies have demonstrated an overactivation of hormone activity due to this alteration. Thus, we aimed to determine the activity of orteronel, a CYP17 inhibitor, in advanced disease. Methods We designed a multicentric open-label phase II clinical trial. Eligible patients were adult woman with advanced or unresectable GCTs. Primary objective was clinical benefit rate, defined as the average of patients with radiological response plus stable disease longer than 6 months. Results From October 1, 2014 to May 20, 2016, ten patients were included in six participating institutions members of the GETTHI group. The study was terminated early due to a low recruitment rate. Up to 40% (CI 95% [9.6–70.4%]) cases presented a disease stabilization longer than 6 months and two of them, longer than 12 months. One patient continued on treatment at database closure 29 months after inclusion in the trial. No patient reached partial or complete response by RECIST criteria on the independent radiological review. The drug was well tolerated with nausea as the only grade 3 adverse event in one case. Conclusion Low accrual led to an early interruption of the study. However, orteronel achieved a promising clinical benefit rate that supports further development of new hormonotherapies in this tumor. ClinicalTrials.gov identifier NCT02101684.

PURPOSE: To evaluate atezolizumab combined with platinum-based chemotherapy (CT) followed by maintenance niraparib for late-relapsing recurrent ovarian cancer. METHODS: The multicenter placebo-controlled double-blind randomized phase III ENGOT-OV41/GEICO 69-O/ANITA trial (ClinicalTrials.gov identifier: NCT03598270 ) enrolled patients with measurable high-grade serous, endometrioid, or undifferentiated recurrent ovarian cancer who had received one or two previous CT lines (most recent including platinum) and had a treatment-free interval since last platinum (TFIp) of >6 months. Patients were stratified by investigator-selected carboplatin doublet, TFIp, BRCA status, and PD-L1 status in de novo biopsy and randomly assigned 1:1 to receive either atezolizumab or placebo throughout standard therapy comprising six cycles of a carboplatin doublet followed (in patients with response/stable disease) by maintenance niraparib until progression. The primary end point was investigator-assessed progression-free survival (PFS) per RECIST v1.1. RESULTS: Between November 2018 and January 2022, 417 patients were randomly assigned (15% BRCA- mutated, 36% PD-L1–positive, 66% TFIp >12 months, 11% previous poly [ADP-ribose] polymerase inhibitor after frontline CT, and 53% previous bevacizumab). Median follow-up was 28.6 months (95% CI, 26.6 to 30.5 months). Atezolizumab did not significantly improve PFS (hazard ratio, 0.89 [95% CI, 0.71 to 1.10]; P = .28). Median PFS was 11.2 months (95% CI, 10.1 to 12.1 months) with atezolizumab versus 10.1 months (95% CI, 9.2 to 11.2 months) with standard therapy. Subgroup analyses generally showed consistent results, including analyses by PD-L1 status. The objective response rate (ORR) was 45% (95% CI, 39 to 52) with atezolizumab and 43% (95% CI, 36 to 49) with standard therapy. The safety profile was as expected from previous experience of these drugs. CONCLUSION: Combining atezolizumab with CT and maintenance niraparib for late-relapsing recurrent ovarian cancer did not significantly improve PFS or the ORR.

Purpose: The aim of our study was to elucidate the impact of bevacizumab added to neoadjuvant chemotherapy (NACT) on the tumor immune microenvironment and correlate the changes with the clinical outcome of the patients. Experimental Design: Immunohistochemistry and multiplex immunofluorescence for lymphoid and myeloid lineage markers were performed in matched tumor samples from 23 ovarian cancer patients enrolled in GEICO 1205/NOVA clinical study before NACT and at the time of interval cytoreductive surgery. Results: Our results showed that the addition of bevacizumab to NACT plays a role mainly on lymphoid populations at the stromal compartment, detecting a significant decrease of CD4+ T cells, an increase of CD8+ T cells and an upregulation effector/regulatory cells ratio (CD8+/CD4+FOXP3+). None of the changes observed were detected in the intra-epithelial site in any arm (NACT or NACT-bevacizumab). No differences were found in myeloid lineage (macrophages-like). The percentage of Treg populations and effector/regulatory cell ratio in the stroma were the only two variables significative associated with PFS. Conclusions: The addition of bevacizumab to NACT did not have an impact on PFS in the GEICO 1205 study. However, at cellular level, changes in CD4+, CD8+lymphocyte populations, and CD8+/CD4+FOXP3 ratio have been detected only at the stromal site. Based on our results, we hypothesize about the existence of mechanisms of resistance that could prevent the trafficking of T effector cells into the epithelial component of the tumor as a potential explanation for the lack of efficacy of ICI in the first line of advanced EOC.

Supplementary Table 1. Clinical characteristics of the patients included in the study diagnosed with epithelial ovarian cancer.