Recurrent Endometrial Cancer: Local and Systemic Treatment Options

The treatment of recurrent endometrial cancer is a challenge. Because of earlier treatments and the site of locoregional recurrence, in the vaginal vault or pelvis, morbidity can be high. A total of about 4 to 20% of the patients with endometrial cancer develop a locoregional recurrence, mostly among patients with locally advanced disease. The treatment options are dependent on previous treatments and the site of recurrence. Local and locoregional recurrences can be treated curatively with surgery or (chemo)radiotherapy with acceptable toxicity and control rates. Distant recurrences can be treated with palliative systemic therapy, i.e., first-line chemotherapy or hormonal therapy. Based on the tumor characteristics and molecular profile, there can be a role for immunotherapy. The evidence on targeted therapy is limited, with no approved treatment in the current guidelines. In selected cases, there might be an indication for local treatment in oligometastatic disease. Because of the novel techniques in radiotherapy, disease control can often be achieved at limited toxicity. Further studies are warranted to analyze the survival outcome and toxicity of newer treatment strategies. Patient selection is very important in deciding which treatment is of most benefit, and better prediction models based on the patient- and tumor characteristics are necessary.

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001

BackgroundPembrolizumab plus lenvatinib is a novel combination with promising efficacy in patients with advanced and recurrent endometrial cancer. This combination demonstrated high objective response rates in a single-arm phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with advanced endometrial cancer (KEYNOTE-146/Study 111) after ≤2 previous lines of therapy. In a randomized phase 3 trial of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer (KEYNOTE-775/Study 309), after 1‒2 previous lines of therapy (including neoadjuvant/adjuvant), this combination improved objective response rates, progression-free survival, and overall survival compared with chemotherapy.Primary ObjectiveTo compare the efficacy and safety of first-line pembrolizumab plus lenvatinib versus paclitaxel plus carboplatin in patients with newly diagnosed stage III/IV or recurrent endometrial cancer, with measurable or radiographically apparent disease.Study HypothesisPembrolizumab plus lenvatinib is superior to chemotherapy with respect to progression-free survival and overall survival in patients with mismatch repair-proficient tumors and all patients (all-comers).Trial DesignPhase 3, randomized (1:1), open-label, active-controlled trial. Patients will receive pembrolizumab intravenously every 3 weeks plus lenvatinib orally daily or paclitaxel plus carboplatin intravenously every 3 weeks, stratified by mismatch repair status (proficient vs deficient). Patients with mismatch repair-proficient tumors will be further stratified by Eastern Cooperative Oncology Group performance status (0/1), measurable disease (yes/no), and prior chemotherapy and/or chemoradiation (yes/no).Major Inclusion/Exclusion CriteriaAdults with stage III/IV/recurrent histologically confirmed endometrial cancer that is measurable or radiographically apparent per blinded independent central review. Patients may have received previous chemotherapy only as neoadjuvant/adjuvant therapy and/or concurrently with radiation. Patients with carcinosarcoma (malignant mixed Müllerian tumor), endometrial leiomyosarcoma, or other high grade sarcomas, or endometrial stromal sarcomas were excluded.Primary EndpointsProgression-free and overall survival (dual primary endpoints).Sample SizeAbout 875 patients.Estimated Dates for Completing Accrual and Presenting ResultsEnrollment is expected to take approximately 24 months, with presentation of results in 2022.Trial RegistrationClinicalTrials.gov, NCT03884101.

956 Retifanlimab (INCMGA00012) in patients with recurrent MSI-H or dMMR endometrial cancer: results from the POD1UM-101 study

BackgroundManagement of patients with recurrent endometrial cancer after failure on platinum-based therapy remains a clinical challenge. Retifanlimab (INCMGA00012) is an investigational humanized immunoglobulin G4 monoclonal antibody against programmed cell death 1 (PD-1). We previously reported encouraging results from a preplanned interim analysis in patients with microsatellite instability-high (MSI-H) recurrent endometrial cancer treated with retifanlimab in POD1UM-101 [1]. Here, we provide top-line results from the full cohort of patients in the POD1UM-101 study.MethodsEligible patients have histologically proven, unresectable recurrent MSI-H or deficient mismatch repair (dMMR) endometrial cancer (per local testing), ECOG PS ≤1, disease progression during or following 1 to ≤5 prior systemic treatments, measurable disease (per RECIST v1.1), and are naïve to prior immune checkpoint inhibitors. MSI-H and dMMR status were centrally confirmed using PCR and IHC, respectively. Patients receive retifanlimab 500 mg every 4 weeks for up to 2 years. The primary study endpoint is safety. Confirmed best overall response and duration of response (DOR) were evaluated by independent central review (ICR) using RECIST v1.1.ResultsAs of July 6, 2021, 76 patients with centrally confirmed MSI-H (65 [85.5%]) or dMMR (11 [14.5%]) endometrial cancer had received ≥1 dose of retifanlimab; median age was 67.0 (49–88) years, 70 (92.1%) had endometrioid histology, 67 (88.2%) had metastatic disease, and 61 (80.3%) had visceral metastases. Sixty-eight (89.5%) patients had prior surgery or procedure, 54 (71.1%) patients were treated with radiotherapy, and 75 (98.7%) patients had received prior systemic therapy for advanced disease (33 [43.4%] received ≥2 prior systemic therapies for advanced disease). Median retifanlimab exposure was 7.4 (0.03–23.0) months. At data cutoff, 2 (2.6%) patients completed treatment and 30 (39.5%) were on treatment. Grade ≥3 treatment emergent AEs (TEAEs) occurred in 33 (43.4%) patients, including 10 (13.2%) with anemia and 7 (9.2%) with an immune-related AE (nephritis, n=2; autoimmune hepatitis, hepatitis, myositis, rash, and pneumonitis, n=1 each). There were no treatment-related AEs with fatal outcome. Centrally confirmed objective responses were observed in 33 (43.4%) patients (95% CI, 32.1–55.3), with 11 (14.5%) complete and 22 (28.9%) partial responses. Of the 33 patients with objective response, 25 (75.8%) had DOR for ≥6 months; median DOR was not reached. Median follow-up time for response was 8.4 (range, 1.9–28.3) months.ConclusionsRetifanlimab was well tolerated and demonstrated encouraging antitumor activity in patients with pretreated recurrent MSI-H or dMMR endometrial cancer, consistent with that achieved with other PD-1 therapies.AcknowledgementsThis study is sponsored by Incyte Corporation (Wilmington, DE).Trial RegistrationClinicaltrialsgov NCT03059823, EudraCT 2017-000865-63ReferenceBerton-Rigaud D, et al. J ImmunoTher Cancer 2020;8(Suppl 3):A164–A165 [Abstract 268].Ethics ApprovalThis study was approved by institutional review boards or independent ethics committees in Belgium (Aan de Commissie Medische Ethiek University Hospitals Leuven [CEC: S62335]; Ethics Committee of Hospital-Faculty University of Liège [LEC: 2019/48]); Bulgaria (Ethics Committee for Clinical Trials, Sofia [RA: IAL-24443/08.06.2017; CEC: КИ-80/08.06.2017]); Finland (HUS Tutkimuseettiset toimikunnat Biomedicum Helsinki [RA: KLnro 124/2019]); France (CPP Île-de-France X Hôpital, Aulnay-sous-Bois cedex [RA: MED MSA NAT-2019-08-00080; CEC: CN-RIPH 19.02.17.56415/CPP 27-2019]); Germany (Ethik-Kommission der Albert-Ludwigs-Universität Freiburg, Freiburg [RA: 3102/012; EC: 506/18]; Ethics Committee at the Technical University of Dresden, Dresden [RA: 3102/012; EC: EK 4854 AB]; Ethics Committee of the State of Berlin, Berlin [RA: 3102/012; EC: 17/0411 EK 12/15]); Italy (Comitato Etico del Policlinico Gemelli Fondazione Policlinico Universitario ”Agostino Gemelli”, Roma (RM) [no approval number issued by RA or EC]; Comitato Etico IRCCS di Candiolo, Candiolo-TO [no approval number issued by RA or EC]); Latvia (Ethics Committee for Clinical Research at Development Society of Pauls Stradins Clinical University Hospital, Riga [no approval number issued by RA or EC]); Lithuania (Lithuanian Bioethics Committee, Vilnius [no approval number issued by RA or EC]); Poland (Komisja Bioetyczna przy Uniwersytecie Medycznym, Poznań [RA: UR.DBL.474.0350.2017; CEC: 622/17]); Spain (Comité de Ética de Investigación con Medicamentos, Madrid Centro Actividades Ambulatoria [RA: 17-073 (Locator: 2VK42NE57D); CEC: 17/211]); Ukraine (Ethical Committee at Prykarpatsky Regional Clinical Oncology Center of Ivano-Frankivsk Regional Rada, Ivano-Frankivsk [no approval number issued by RA or EC]); United States (IntegReview IRB, Austin, TX [no approval number issued by IRB]; The University of Texas MD Anderson Cancer Center Institutional Review Board, Houston, TX [no approval number issued by IRB]).

Treatment patterns among patients with advanced/recurrent endometrial cancer in the United States.

291 Background: Among patients (pts) with endometrial cancer (EC), response rates for platinum-based regimens in the first-line (1L) setting range from 40% to 62% in clinical trials. This study describes patient characteristics, treatment patterns, time to next treatment (TTNT), and overall survival (OS) among pts with advanced/recurrent EC treated with a platinum-based regimen in a real-world setting in the US. Methods: This retrospective study used Optum Clinformatics Extended Data Mart de-identified databases from January 1, 2007, to December 31, 2019. Adult pts with advanced/recurrent EC who initiated a 1L platinum-based regimen and subsequently initiated second-line (2L) antineoplastic therapy were identified. Prior to initiation of 1L, a 12-month washout period of continuous enrollment without use of antineoplastic agents (except hormonal agents) was imposed. Kaplan-Meier (KM) rates were used to report TTNT and OS from 2L, third line (3L), and fourth line (4L), separately. Results: A total of 1878 pts with advanced/recurrent EC initiated 2L therapy following a platinum-based regimen in 1L. Among them, 739 (39.4%) pts initiated 3L and 330 (17.6%) initiated 4L or later (4L+) therapy. Median pt age was 68.0 years. More pts received platinum-based regimens (56.4%) in 2L than other options (Table). Few pts (3.3%) received immunotherapy. Among pts receiving 3L, a similar percentage of pts were treated with platinum-based (33.2%) and other chemotherapy regimens (33.8%); few pts received immunotherapy (3.0%). Among pts receiving 4L+, the most frequent treatment option was other chemotherapy (46.1%). Median TTNT was 17.7, 10.6, and 8.4 months for 2L, 3L, and 4L pts, respectively. KM rates of OS following initiation of 2L therapy at 1, 2, 3, and 4 years were 68.4%, 49.6%, 41.3%, and 33.6%, respectively, with a median OS of 23.5 months. Conclusions: Among pts with advanced/recurrent EC treated with platinum-based therapy in 1L, platinum-based regimens remain prevalent treatment choices in later lines of therapy. In this study, immunotherapy was used infrequently in 2L, 3L, and 4L+. The median TTNT decreased in later lines of therapy. This study highlights a critical need for novel, more effective treatment options in later lines of therapy to optimize outcomes among pts with advanced/recurrent EC.[Table: see text]

Oncobox molecular profiling for a patient with recurrent endometrial cancer

Relevance. Endometrial cancer (EC) is the most common gynecological tumor. As a rule, it has a good prognosis, but in case of relapse, it worsens significantly. The effectiveness of cytotoxic chemotherapy for the treatment of such patients remains low.Purpose. To present a clinical case demonstrating the possibilities of therapy performed according to the results of molecular profiling of the tumor by RNA sequencing methods.Methods. Analysis of the anamnesis data, the results of histological and immunohistochemical studies, PET-CT, ultrasound images, and RNA sequencing data was carried out. The results of therapy prescribed in accordance with the rating of targeted drugs obtained after processing the transcriptomic profile by the Oncobox diagnostic platform were evaluated.Results. After experimental second-line therapy, a partial response was recorded.Conclusion. Early molecular profiling and therapy assignment in accordance with its results can change the course of the disease and improve the quality of life of patients.

Management of Recurrent Endometrial Cancer or Atypical Endometrial Hyperplasia Patients After Primary Fertility-Sparing Therapy

ObjectiveTo evaluate the efficacy and prognosis of fertility-sparing re-treatment on patients with recurrent endometrial cancer (EC) and atypical endometrial hyperplasia (AEH) who wish to preserve their uterus after complete remission (CR) for primary conservative therapy.MethodsWe performed a retrospective study on recurrent EC or AEH patients who received fertility-sparing re-treatment after achieving CR. Data regarding clinicopathological factors, adverse events, treatment efficacy, tumor prognosis, and reproductive outcome were analyzed.ResultsOf the 98 recurrent patients with a median disease-free interval period of 19 (3–96) months, 18 patients decided to receive hysterectomy directly, and 80 patients received fertility-preserving re-treatment. Seventy-one (88.6%) cases achieved CR, 96.0% in AEH and 75.8% in EC patients, with the 6 (3–16) months’ median CR time. Seven (8.8%) patients failed to achieve CR and then underwent the hysterectomy: one partial response (PR), four stable disease (SD), and two progressive disease (PD). Forty-nine women attempted to get pregnant after CR, 13 (26.5%) became pregnant, seven (14.3%) successfully delivered, and six (12.2%) miscarried. During the follow-up period, 22 (31.0%) women had developed a second relapse with the median recurrence time of 12 (4–90) months, and 10 patients decided to receive the third round of fertility-sparing treatment. Seven (70.0%) patients, 33.3% in EC and 85.7% in AEH, achieved CR again. Hysterectomy was performed in two (20.0%) patients due to SD. After the third-round treatment, six women had the desire to conceive but no one became pregnant successfully.ConclusionFor patients with recurrent EC and AEH after primary conservative treatment, fertility-preserving re-treatment can still achieve a promising response, and patients have possibilities of completing childbirth.