Recurrent Endometrial Cancer Research Articles

P19 Incidence and implications of pseudoprogression in women with advanced or recurrent endometrial cancer on pembrolizumab/lenvatinib combination therapy

P19 Incidence and implications of pseudoprogression in women with advanced or recurrent endometrial cancer on pembrolizumab/lenvatinib combination therapy

Pembrolizumab Plus Chemotherapy in Advanced Endometrial Cancer

(Abstracted from N Engl J Med 2023;388(23):2159–2170) Endometrial cancer is one of the only cancer types for which both incidence and mortality are rising, and survival has not improved during the past 4 decades. First-line treatment for advanced or recurrent endometrial cancer typically involves paclitaxel plus carboplatin.

Considerations for pharmacologic thromboprophylaxis following inpatient brachytherapy for gynecologic malignancies

Brachytherapy irradiation carries risks of both bleeding and venous thromboembolism (VTE). No screening or management recommendations for VTE in this setting have been developed. Our study aims to understand the incidence of VTE, compile published anticoagulation guidelines, and call for future guidelines to address thromboprophylaxis in this population. A retrospective, single institution study of patients undergoing brachytherapy irradiation between 2012 and 2022 was undertaken. We analyzed 2 cohorts: 87 patients undergoing brachytherapy with an inpatient admission, and 66 patients assessed for risk of VTE or bleeding after discharge from an inpatient admission for brachytherapy. Caprini risk scores were calculated for each patient, and statistical analyses were performed. Eighty-seven patients were included, and 25% had a VTE diagnosis. Forty-seven (54%) of patients included underwent brachytherapy as definitive treatment of cervical cancer, and 16 (18%) received brachytherapy irradiation to treat recurrent endometrial cancer. In the cohort of 66 patients assessed for risk of VTE or bleeding after brachytherapy discharge, 23 (34.8%) were discharged with thromboprophylaxis, and 43 (65.2%) were discharged without thromboprophylaxis. None of the patients discharged on thromboprophylaxis were diagnosed with a VTE within 90 days of discharge after brachytherapy, whereas 3 of 43 (7%) discharged without thromboprophylaxis were diagnosed with a VTE, OR and 95% CI: 0.25 (0.01-5.29), p = 0.37. Of the 23 patients discharged on thromboprophylaxis, 1 was readmitted for bleeding OR and 95% CI: 5.8 (0.22-155.18), p = 0.29. The median Caprini score was 11. VTE is a common occurrence in patients undergoing brachytherapy. Patients undergoing brachytherapy irradiation who require inpatient admission represent a unique population, and specialty organizations should develop consensus recommendations to address these clinical challenges.

Safety, Efficacy, and Biomarker Analyses of Dostarlimab in Patients with Endometrial Cancer: Interim Results of the Phase I GARNET Study.

This interim report of the GARNET phase I trial presents efficacy and safety of dostarlimab in patients with advanced or recurrent endometrial cancer (EC), with an analysis of tumor biomarkers as prognostic indicators. A total of 153 patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) and 161 patients with mismatch repair proficient (MMRp)/microsatellite stable (MSS) EC were enrolled and dosed. Patients received 500 mg dostarlimab every 3 weeks for four cycles, then 1,000 mg every 6 weeks until progression. Primary endpoints were objective response rate (ORR) and duration of response (DOR). A total of 143 patients with dMMR/MSI-H EC and 156 patients with MMRp/MSS EC were evaluated for efficacy. ORR was 45.5% (n = 65) and 15.4% (n = 24) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. Median DOR for dMMR/MSI-H EC was not met (median follow-up, 27.6 months); median DOR for MMRp/MSS EC was 19.4 months. The ORRs by combined positive score (CPS) ≥1 status were 54.9% and 21.7% for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORRs by high tumor mutational burden (≥10 mutations/Mb) were 47.8% (43/90) and 45.5% (5/11) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORR in TP53mut or POLεmut molecular subgroups was 18.1% (17/94) and 40.0% (2/5), respectively. The safety profile of dostarlimab was consistent with previous reports. Dostarlimab demonstrated durable antitumor activity and safety in patients with dMMR/MSI-H EC. Biomarkers associated with EC may identify patients likely to respond to dostarlimab. See related commentary by Jangra and Dhani, p. 4521.

Intra-operative tumor spillage in minimally invasive surgery for endometrial cancer and its impact on recurrence risk

ObjectiveThe prognostic impact of intra-operative tumor spillage (ITS) during minimally invasive surgery (MIS) for endometrial cancer (EC) is not well studied. The objective of this study was to determine if there is an association between ITS and EC recurrence. MethodsWe performed a case-control study of patients with a laparoscopic or robot-assisted hysterectomy with EC on final pathology between 2017 and 2022 and compared those with (case) and without (control) a subsequent EC recurrence. Electronic medical records were reviewed for demographic, intra-operative and pathologic details, and recurrence status. ITS was defined as uterine perforation with a manipulator, presence of extra-uterine tumor after colpotomy or specimen delivery, exposure of uncontained specimen into peritoneum, and/or pathology/operative reports noting specimen fragmentation. Conditional logistic regression was used to determine odds ratios for the association of cancer recurrence with ITS. We adjusted for >50% myoinvasion, tumor size, and adjuvant treatment. Results1057 patients underwent MIS for EC. Approximately 8% (n = 86) developed recurrent cancer and 172 patients were selected as controls. Twenty percent of recurrent cases (17/86) had ITS compared with 4% of nonrecurrent controls (7/172). When adjusted for tumor size, deep myoinvasion, and adjuvant treatment, patients with ITS had a 5.6 times increased odds (aOR 5.63, 95% CI 1.52–20.86) of recurrence compared to patients without ITS. ConclusionsIn patients with EC, we found an association between ITS and cancer recurrence. These findings warrant further investigation to determine if adjuvant therapy or surgical technique should be altered to improve outcomes.

Decision-making for Subsequent Therapy for Patients With Recurrent or Advanced Endometrial Cancer Based on the Platinum-free Interval.

The aim of this study was to evaluate the progression-free survival (PFS) and overall response rate (ORR) of patients with recurrent endometrial cancer (REC) or advanced endometrial cancer (AEC) retreated with platinum-containing chemotherapy (PCC) based on the platinum-free interval (PFI). We compared our results with those reported in the KEYNOTE-775 study (that used pembrolizumab plus lenvatinib). A retrospective analysis was conducted of 65 patients with REC or AEC retreated with PCC between 2005 and 2020 at our hospital. Various clinicopathologic variables were analyzed: (1) age, (2) performance status, (3) histology, (4) history of pelvic irradiation in the adjuvant setting, (5) PFI, (6) chemotherapy regimen, (7) PFS and overall survival after retreatment with PCC, and (8) best ORR. Survival analyses were performed using Kaplan-Meier curves and log-rank tests. The best ORR and PFS were 43.3% and 9.5 months, respectively, in patients with REC/AEC with a PFI ≥6 months. These results were comparable with those of patients treated with pembrolizumab and lenvatinib. The best ORR and PFS of patients with a PFI of <6 months appeared to be inferior to those of patients treated with pembrolizumab plus lenvatinib. Pembrolizumab plus lenvatinib seems to be a better treatment choice for patients with REC or AEC with a PFI of <6 months. For a PFI of ≥6 months, pembrolizumab plus lenvatinib or PCC can be used depending on the degree of residual side -effects associated with cytotoxic agents.

Treatment with lenvatinib plus pembrolizumab in recurrent or advanced endometrial cancer: A systematic review and meta-analysis.

e17630 Background: Endometrial cancer (EC) is the second most prevalent gynecological cancer. After failure to first-line platinum-based chemotherapy, treatment options are sparse, but recent studies have investigated new approaches with promising results. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of Lenvatinib plus Pembrolizumab in patients with advanced or recurrent EC. Methods: PubMed, Web of Science, Cochrane, Scopus, and LILACS databases, Central Register of Clinical Trials, and congresses publication websites were searched for studies using Lenvatinib plus Pembrolizumab in advanced or recurrent EC with progression after platinum-based chemotherapy. Outcomes of interest were best overall response rate (BORR) and disease control rate (DCR), on intention-to-treat (ITT) and per-protocol analyses, and according to mismatch repair status. Progression free-survival (PFS) and overall survival (OS) were also assessed. Heterogeneity was examined with the Cochran Q test and I2 statistics. We use a DerSimonian and Laird random-effects model. Results: Four studies, with 637 patients, were included: two clinical trials and two retrospective observational cohorts. Endometrioid EC was the predominant histology (53%), and most patients had mismatch repair-proficient tumors (pMMR, 86.5%). In a pooled analysis, with a medium follow-up of 12.2 months, BORR was 31% (95%CI 26, 37), and DCR was 74% (95%CI 65, 83) on ITT. CR, PR, and SD were documented in 37 (5.8%),168 (26.3%) and 284 (44.5%) patients, respectively. BORR was 48% in microsatellite unstable tumors compared to 31% in stable microsatellite disease (p = 0.07), while DCR was similar in both groups (p = 0.33). Median progression-free survival was 7.2 months (95%CI 3.2, 7.4), and median overall survival was 18.3 months (95%CI 8.6, 18.3) in patients receiving Lenvatinib and Pembrolizumab. The most common treatment-related adverse events (AE) included diarrhea 277/514 (53.8%), nausea 244/514 (47.4%), hypothyroidism 288/562 (39.1%), hypertension 338/632 (36.9%), fatigue 213/632 (31.0%), and vomiting 178/514 (34.6%). Grades 3 or 4 AE was reported in 436/514 (79.6%) patients. Overall, dose reductions, treatment interruptions, and discontinuation due to toxicities were required in 61%, 63%, and 27% of patients, respectively. Conclusions: This systematic review and meta-analysis reinforce the antitumor activity of the combination of Pembrolizumab and Lenvatinib in patients with advanced or recurrent EC, regardless of MMR status. Despite high rates of serious adverse events related to treatment, most were manageable.

EE264 Immunotherapy for Advanced and Recurrent dMMR Endometrial Cancer: A Cost-Effectiveness Analysis

Few treatment options exist for patients with advanced or recurrent endometrial cancer (EC) that has progressed after treatment with platinum-based therapy. Dostarlimab and pembrolizumab are approved for patients with advanced cancers that have not responded to prior therapy and are mismatch repair deficient (dMMR). This analysis aimed to add to the evidence on the cost-effectiveness of immunotherapy for advanced or recurrent dMMR EC.

Overall survival and subsequent therapy from a phase II study of sintilimab and anlotinib in patients with advanced or recurrent endometrial cancer.

5598 Background: Although the combination of immunotherapy and antiangiogenic agents has been proved a promising strategy in endometrial cancer, studies in Chinese patients are limited. In the earlier phase II study (NCT04157491), Chinese patients with recurrent or advanced endometrial cancer treated with sintilimab + anlotinib had an objective response rate of 73.9% (95% confidence interval [CI]: 51.6% to 89.8%). Here we further updated overall survival (OS) and subsequent therapy for this study. Methods: Patients with endometrial carcinoma progressed after platinum-based chemotherapy were enrolled. Sintilimab 200 mg was supplied intravenously on day one, whereas anlotinib 12 mg was administered orally on day 1 - 14 every three weeks. Results: Twenty-three patients were enrolled in the study. 47.8% of patients received ≥ 2 lines of prior chemotherapy; microsatellite instability-high/mismatch repair deficiency (MSI-H/dMMR) and microsatellite instability stable/mismatch repair proficient (MSS/pMMR) accounted for 39.1% and 60.9% of patients, respectively. We observed a median OS of 17.8 months (95% CI, 9.4 to 26.3 months). Patients with microsatellite instability-high (MSI-H) had superior OS than their counterparts (not available vs. 13.3 months; HR 0.15, 95% CI, 0.33-0.70; P = 0.006). All patients had dropped out of the cohort [56.5% progression disease (PD), 13.0% adverse events (AE)]. Notably, five patients with partial responses (PRs) obtained pathological or radiography complete responses (CRs) in the follow-up. Pathological CRs were confirmed in three patients with long-lasting PRs who underwent surgery, consistent with PET/CT scans. Two patients with PR continued to have tumor shrinkage following treatment cessation due to AE and achieved CR during follow-up. Three out of four patients with CR experienced recurrences. There were no new grade 3-4 AEs associated with therapy. Conclusions: In terms of OS, combining sintilimab and anlotinib had promising therapeutic effects. Pathological CR was observed in patients with long-lasting PR, thus exploratory surgery may be required in selected patients. Clinical trial information: NCT04157491 . [Table: see text]

ENGOT-EN20/GOG-3083/xport-EC-042: A phase 3, randomized, placebo-controlled, double-blind, multicenter trial of selinexor in maintenance therapy after systemic therapy for patients with P53 wild-type, advanced or recurrent endometrial carcinoma.

TPS5627 Background: Patients (pts) with first-line metastatic or recurrent endometrial cancer (EC) have a poor prognosis. Selinexor is an oral XPO1 inhibitor, which leads to nuclear accumulation of tumor suppressor proteins, including p53. Selinexor is FDA-approved for use in multiple myeloma and diffuse large B-cell lymphoma, and has shown clinical activity in previously treated, advanced EC. Molecular characterization of EC is critical in directing treatment for advanced and recurrent disease. Of the EC molecular subtypes, TP53 wild type (wt) tumors represent 50% of advanced and recurrent tumors. A recent phase 3 study in maintenance after chemotherapy found that, despite the primary endpoint (PFS) not reaching statistical significance, prolonged PFS of oral once-weekly selinexor versus placebo (13.7 months and 3.7 months, respectively) was observed in a prespecified exploratory subgroup analysis of patients with advanced or recurrent TP53wt EC. Methods: XPORT-EC-042 (NCT05611931) is a Phase 3 randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of selinexor as maintenance therapy in pts with TP53wt advanced or recurrent EC, who have achieved a partial response or complete response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 after completing at least 12 weeks of platinum combination chemotherapy ±immunotherapy for primary stage IV or recurrent disease. Eligible pts must be ≥18 years of age, have histologically confirmed EC, and TP53 wt disease based on NGS sequencing assessed by Foundation Medicine. Pts will be randomized 1:1 with either selinexor 60 mg or placebo once weekly in 28-day cycles until progressive disease, toxicity, or 3 years if in complete response. A total of 220 pts will be enrolled at sites across the United States, Canada, Europe, and Israel. The primary objective is to compare PFS in pts treated with selinexor compared to placebo based on RECIST v1.1 criteria as assessed by the Investigator. Key secondary objective is overall survival. Other secondary objectives are safety, time to first subsequent therapy, time to second subsequent therapy, time from randomization until the second progression event (PFS2), and PFS by a blinded independent central review. Patient enrollment is ongoing. Clinical trial information: NCT05611931 .

Dostarlimab for primary advanced or recurrent (A/R) endometrial cancer (EC): Outcomes by blinded independent central review (BICR) of the RUBY trial (ENGOT-EN6-NSGO/GOG-3031/RUBY).

5503 Background: RUBY (NCT03981796) evaluated the efficacy and safety of the anti–programmed death 1 (PD-1) dostarlimab + standard of care (SOC) carboplatin paclitaxel (CP) versus CP alone in A/R EC. The primary endpoint of PFS by investigator assessment (INV) per RECIST v1.1 was significantly longer with dostarlimab+CP than placebo (PBO)+CP in the mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H; HR 0.28; 95% CI 0.162–0.495) and overall populations (HR 0.64, 95% CI 0.507–0.800). Here we present secondary efficacy endpoints by BICR. Methods: RUBY is a phase 3, global, randomized, double-blind, multicenter, PBO-controlled study. Patients (pts) with primary advanced stage III or IV or first recurrent EC were randomized 1:1 to receive dostarlimab 500 mg, or PBO, plus carboplatin AUC 5 and paclitaxel 175 mg/m2 Q3W (6 cycles), followed by dostarlimab 1000 mg, or PBO, monotherapy Q6W for up to 3 y. Secondary endpoints by BICR assessment per RECIST v1.1 were PFS, ORR, DOR, and DCR in the overall and dMMR/MSI-H populations. Results: 494 pts were randomized (245:dostarlimab+CP; 249:PBO+CP); 47.8% had recurrent disease, 18.6% and 33.6% had primary stage III and IV disease, respectively. PFS by BICR was longer with dostarlimab+CP than PBO+CP in the dMMR/MSI-H (HR 0.29; 95% CI 0.158–0.543) and overall populations (HR 0.66; 95% CI 0.517–0.853; Table). Consistent benefits were seen with dostarlimab+CP for ORR, DCR, and DOR by BICR in the dMMR/MSI-H and overall populations (Table). Safety was previously reported. Conclusions: Dostarlimab+CP showed clinically meaningful improvement in BICR-assessed PFS in the dMMR/MSI-H and overall populations compared with CP alone. The HRs for PFS per BICR and per INV were consistent, which supports the reliability of PFS by INV in EC trials. Benefits were seen in all BICR-assessed endpoints, which were consistent with INV. Dostarlimab+CP represents a new SOC for pts with primary A/R EC. Clinical trial information: NCT03981796 . [Table: see text]

A phase II, randomized, double-blind study of the use of rucaparib vs placebo maintenance therapy in metastatic and recurrent endometrial cancer.

TPS5626 Background: There are currently no approved maintenance therapies for metastatic and recurrent endometrial cancer, which carries a dismal long-term prognosis. The PARP inhibitor drug class has demonstrated significant clinical benefit as a maintenance therapy for patients with germline/somatic BRCA mutations or homologous recombination deficiency (HRD) in ovarian cancers. However, BRCA mutations are not common in endometrial cancer. Loss of function of the tumor suppressor gene PTEN has been demonstrated in greater than 80% of endometrioid endometrial cancers 1. PTEN loss of function is well known to lead to activation of the PI3K-AKT-mTOR pathway but has also been shown to lead to defects in homologous recombination (HR) DNA repair of double strand breaks 2. Specifically, PTEN silencing leads to decreased RAD51 foci formation. Based on this mechanism, in vitro data on endometrial cancer cell lines has demonstrated sensitivity to PARP inhibitors. Notably, sensitivity of PARP inhibition in PTEN loss of function is independent of microsatellite instability (MSI) 3. Methods: This is a multi-center phase II, placebo controlled, double-blinded study of the use of rucaparib as maintenance therapy in patients with metastatic or recurrent endometrial cancer. A maximum of 138 patients will be randomized 1:1 to receive rucaparib at starting dose of 600mg BID dosing vs. placebo. Standard dose reductions of known toxicities will be followed based on FDA approved indications of rucaparib. Patients will remain on therapy until progression of disease or toxicity induced discontinuation. Eligible patients will have Stage III/IV or recurrent endometrial cancer and must have received one or two prior lines of chemotherapy. All histologic subtypes, including carcinosarcoma will be included. Treatment arms will be stratified on histology, number of lines of prior therapy, and complete vs partial response to prior line of therapy. The primary endpoint is progression free survival (PFS). Secondary endpoints include overall survival (OS), overall response rate (ORR), and toxicity. To date, 79 patients have been enrolled. 1. Mutter GL, Lin MC, Fitzgerald JT, et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst. 2000;92(11):924-930. 2. Shen WH, Balajee AS, Wang J, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell. 2007;128(1):157-170. 3. Dedes KJ, Wetterskog D, Mendes-Pereira AM, et al. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Transl Med. 2010;2(53):53ra75. Clinical trial information: NCT03617679 .

Camrelizumab plus apatinib in patients with advanced or recurrent endometrial cancer after failure of at least one prior systemic therapy: A single-arm phase II trial.

5516 Background: The first stage results of a Simon’s two-stage single-arm phase II trial showed promising antitumor activity and manageable safety of camrelizumab (a humanized anti-PD-1 monoclonal antibody) plus apatinib (a highly selective VEGFR2 inhibitor) in patients with advanced or recurrent endometrial cancer after failure of prior systemic therapy. Here, we report the primary results of this trial. Methods: This open-label, single-arm, phase II trial used a minimax Simon’s two-stage design. Patients with advanced or recurrent endometrial cancer that had progressed after at least one prior systemic therapy were treated with camrelizumab (200 mg, intravenously, every two weeks) and apatinib (250 mg, orally, daily) on a four-week cycle until disease progression or intolerable toxicity. The primary endpoint was the objective response rate per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Other assessed endpoints were disease control rate, time to response, duration of response, time to treatment failure, progression-free survival, overall survival, and treatment-related adverse events. Results: Between January 20, 2020 and October 14, 2022, 36 patients (median age: 60 [range: 29, 76] years; 17 [47.2%] had Eastern Cooperative Oncology Group [ECOG] performance status 1; 15 [41.7%] had received at least two prior systemic therapies) were enrolled. At the date of data cutoff (December 31, 2022), the median follow-up time was 13.9 (interquartile range: 5.8-23.2) months. All 36 patients were evaluable for efficacy, the confirmed objective response rate was 44.4% (95% CI: 27.9%, 61.9%) and the conformed disease control rate was 88.9% (95% CI: 73.9%, 96.9%), with two complete response, 14 partial response, and 16 stable disease. The median progression-free survival was 6.4 (95% CI: 5.2, 13.0) months. The treatment-related adverse events of grade 3 or greater occurred in 19 (52.8%) patients, with increased gamma-glutamyltransferase (8 [22.2%]), hyperglycemia (4 [11.1%]), hypertension (4 [11.1%]) and increased direct bilirubin (4 [11.1%]) being most common. Reactive cutaneous capillary endothelial proliferation occurred in 6 (16.7%) patients and all were grade 1 or 2. No treatment-related death occurred. Conclusions: Camrelizumab plus apatinib show promising antitumor activity and manageable toxicity in patients with advanced or recurrent endometrial cancer after failure of prior systemic therapy and warrant further investigation. Clinical trial information: ChiCTR2000031932 .

A phase 2, two-stage study of avelumab and axitinib in patients with mismatch repair–proficient (MMR-P) recurrent or persistent endometrial cancer (EC).

TPS5628 Background: Despite significant strides in understanding the molecular pathogenesis of EC, there remain few effective therapies for recurrent disease. Deeper insight into the roles of disordered tumor vasculature and HIF1α- and VEGF-mediated immunosuppressive effects on myeloid-derived suppressor cells, T-cells, and PD-L1 expression contributed to the development of new targeted regimens. By inhibiting VEGF receptor (VEGFR) and PD-L1 signaling, immunologically “cold” tumors may become inflamed. The combination of the anti-PD-L1 antibody avelumab with axitinib, an inhibitor of VEGFR 1-3 and PDGFR with more potent IC50 inhibitory activity than lenvatinib, has also shown synergistic activity and is FDA approved as first line treatment for patients with renal cell cancer. We therefore hypothesized that this combination would be well tolerated and efficacious in recurrent MMR-P EC. Objectives:This is a non-randomized two-stage phase 2 study in patients with MMR-P EC evaluating the activity of combined avelumab and axitinib, as assessed by the co-primary endpoints of (1) frequency of patients surviving progression-free for at least 6 months (PFS6), and (2) the objective response rate (ORR) as measured by RECIST 1.1. Methods: Patients must have MMR-P EC and have received at least one chemotherapeutic regimen, with no upper limit on the number of prior lines received. Prior use of immune checkpoint inhibitors (ICI) is excluded. Eligible patients received avelumab 800 mg IV every 2 weeks and axitinib 5 mg orally twice daily until disease progression or unacceptable toxicity. In the first stage of the study, 16 patients were enrolled; if there were ≥2 objective responses or ≥2 PFS6 responses, accrual continued to the second stage with enrollment of an additional 19 patients. The combination of avelumab/axitinib would be considered worthy of further study if overall there were ≥4 objective responses or ≥8 PFS6 responses. Results: As of the data-cutoff in September 2022, a total of 28 patients had received study treatment; one patient withdrew from the study due to toxicity, prior to her first radiographic assessment. The median number of prior lines was 1 (range 1-4). Median follow-up was 12.7 months. Of the 28 patients receiving study treatment, eleven patients (39.3%, 95% CI 21.5%-59.4%) achieved a PR [11/28; 8 confirmed PR (28.6%) and 3 unconfirmed PR (10.7%)]. An additional 39.3% (11/28) had stable disease as best response. Median PFS was 7.3 months (95% CI 3.9-9.0). PFS6 was 59.3% (95% CI 35.7%-76.7%) and at 6 months, 10 patients were still alive and progression-free. Updated efficacy data and safety data will be reported at the time of the meeting. Conclusions: With 8 confirmed PRs and 10 PFS6 responses, the co-primary endpoints were met and the combination of avelumab/axitinib is considered worthy of further study in this population of MMR-P EC. Clinical trial information: NCT02912572 .

The utilization of lenvatinib with pembrolizumab for the treatment of recurrent endometrial cancer.

e17627 Background: The landscape for the treatment of microsatellite-stable-recurrent endometrial cancer has changed with the published results of the KEYNOTE-775, demonstrating an overall response rate of 37.2% with Pembrolizumab and Lenvatinib 20 mg. However, recent retrospective studies have suggested that a lower dose of Lenvatinib may be safer and equally efficacious. We aimed to retrospectively review our institutional data to compare the efficacy and toxicity of Lenvatinib at a low (≤10 mg) vs. high (&gt;10 mg) dose. Methods: Retrospective review of patients with recurrent endometrial cancer who received ≥ 3 cycles of Pembrolizumab with Lenvatinib. A Univariate analysis was used to estimate the 1-year progression-free survival (PFS) and overall survival (OS), and a Multivariate Cox PH regression model was used to estimate the hazard ratio (HR) with a 95% confidence interval (CI) and p&lt;0.05. Results: 77 patients were included in this analysis, the median age and BMI were 70 years and 28.5 kg/m2, respectively (Table 1). Most tumors were PDL-1&lt;1% (67.2%) and were microsatellite stable (95%). 4 patients had MSI-H. Most patients started at a lower dose (66%, median of 10 mg), and 34% of patients started at a higher dose (n=26, median of 14 mg). The most common dose was 10 mg (41%, n=32) and 13% of patients received 20 mg (n=10). In the lower dose group, 71% had ECOG 0-1 vs. 77% in the higher dose, and were more likely to have &gt; 2 lines of treatment (45% vs. 22%). The median time to interruption was 41 vs. 51 days respectively. The PFS and OS were not statically different (Table 1). Multivariate analysis showed a significantly higher HR in the lower dose group (2.5 [CI 1.12-5.56], p=0.025). Conclusions: TheFDA-recommended dose of Lenvatinib of 20 mg is perceived to be difficult to tolerate and patients are often started on a lower dose. In this study, we observed that the time to interruption was longer in the higher dose than in the lower dose group. Though we failed to detect a significant differences in PFS/OS, when adjusted for age, we observed a significantly higher HR of progression or death in the lower dose group. Possible explanations for our observations are that patients who received a lower dose were older and frailer. Our findings call to question the common practice of starting Lenvatinib at a low dose. Further analysis is warranted to delineate the required dose that is both efficacious and safe. [Table: see text]

Patient-reported outcomes (PROs) in primary advanced or recurrent endometrial cancer (pA/rEC) for patients (pts) treated with dostarlimab plus carboplatin/paclitaxel (CP) as compared to CP in the ENGOT-EN6/GOG3031/RUBY trial.

5504 Background: In RUBY, a phase 3, global, randomized, double-blind, placebo (PBO)-controlled trial, dostarlimab+carboplatin/paclitaxel demonstrated significant and clinically meaningful improvement in PFS compared with PBO+CP in pts with pA/rEC. PROs are reported here. Methods: 494 pts with pA/rEC were randomized 1:1 to dostarlimab (D)+CP or PBO+CP Q3W for 6 cycles followed by D or PBO monotherapy Q6W ≤3 yrs or to disease progression. EORTC QLQ-C30 and EN24 were prespecified secondary endpoints. PROs were administered on Day 1 of each treatment (tx) cycle (C), end of tx (EOT), and at safety and survival follow-ups and reported here for C7, the end of chemotherapy (chemo) and C13, and the end of 1 yr of study. Change (chg) from baseline (BL) to C7/C13 was calculated for all scales assessed. Mixed model for repeated measures analysis was conducted to generate least-squares means (LSM), adjusting for correlations across multiple time point assessments within a pt and controlling for the BL value for the global, pain, fatigue, and physical function (PF) scores. Results: PRO outcomes were similar for D+CP and PBO+CP through the chemo period (C7). The table shows selected scores at C7 and C13 for mean (SD) and chg from BL. Further, no differences across the 3 yr period between the 2 arms were reported; LSM (standard error) for global QoL was 0.5 (1.42; P=0.72), PF was −0.7 (1.39; P=0.63), fatigue was 0.2 (1.75; P=0.91) and pain was −1.0 (1.99; P=0.62). Mean chg from BL to EOT showed improvement in back/pelvic pain for D+CP and deterioration in global QoL/GHS, social functioning, body image, and chg in taste for pts on PBO+CP. Conclusions: Dostarlimab + CP significantly improved PFS while maintaining HRQoL, further supporting its use as a standard of care in pA/rEC. Clinical trial information: NCT03981796 . [Table: see text]

AFT-50 EndoMAP: A phase IB/II multi-cohort study of targeted agents for patients with recurrent or persistent endometrial cancer.

TPS5634 Background: The prognosis for women with recurrent or persistent EC after progressing on first-line chemotherapy is poor, with a median overall survival (OS) of 12 months, highlighting the need for more efficacious therapies for this population. Immune checkpoint inhibitors either as monotherapy or when combined with kinase inhibitors have recently demonstrated encouraging response rates in pts with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and MS-stable (MSS)/MMR-proficient (MMRp) EC, respectively. Atezo is a humanized monoclonal anti-programmed cell death ligand 1 (PD-L1) inhibitor that has demonstrated monotherapy antitumor activity with an acceptable safety profile in relapsed recurrent EC. Atezo has shown compelling clinical efficacy for pts with certain solid tumors (e.g., urothelial, NSCLC, triple negative breast cancer) as monotherapy and as part of combinatorial therapy. The AFT-50 EndoMAP trial is a platform trial designed to evaluate the efficacy and safety of Atezo in combination with biomarker-defined targeted agents in pts with recurrent or persistent EC. Recognizing pts may have either progressed through or received a checkpoint inhibitor in a prior line of therapy, a non atezo cohort will also be open to enrollment. Methods: This is a phase IB/II non-randomized, multicenter, multicohort, biomarker-driven platform study consisting of two cohorts: A (atezo containing) and B (non atezo). Eligible pts have recurrent or persistent EC and have received no more than 2 prior lines of therapy. FoundationOne CDx (F1CDx) NGS assay will be used for genomic tumor profiling. In cohort A, pts may be eligible for one of the following doublets: Atezo+ipatasertib (PIK3CA/PTEN/AKT1-altered cancers), Atezo+talazoparib (tumors with genomic loss of heterozygosity (LOH) ≥16%), Atezo+Trastuzumab emtansine (ERBB2/HER2 mutated and/or amplified tumors), Atezo+Tiragolumab (MSI-H and/or TMB&gt;10 mut/MB), and Atezo+bevacizumab (biomarker unmatched). Pts will receive Atezo in addition to the targeted agent (at the study approved dosing schedule) until progression, unacceptable toxicity, pt or physician decision to withdraw from the study, death, or study termination. Pts in cohort B, will be eligible for inavolisib (PIK3CA/PTEN/AKT1-altered cancers) + letrozole. Each cohort will enroll ~20 pts; however, the exact size of the cohort may be adjusted. The primary endpoint for Cohort A is confirmed overall response rate (ORR) for each cohort, and for Cohort B is progression free survival at 6 months. Secondary endpoints include disease control rate, duration of response, OS, safety and tolerability, 6-month PFS (cohort A). As a platform study, additional arms may be added, as supported by evolving understanding of EC and molecular targets. EndoMAP is actively enrolling at 17 sites in the US with a target of 25 sites nationwide. Clinical trial information: NCT04486352 .

A randomized phase II study comparing single-agent olaparib, single-agent cediranib, and the combinations of cediranib/olaparib, olaparib/durvalumab (MEDI4736), cediranib/durvalumab (MEDI4736), and olaparib/AZD5363 (capivasertib) in women with recurrent, persistent, or metastatic endometrial cancer.

TPS5629 Background: Identifying new approaches for the treatment of advanced endometrial cancer (EC) is a priority. A platform study design allows for a faster investigation of novel drug combinations. NRG-GY012 is an ongoing platform study investigating drug combinations with the PARP inhibitor olaparib (O) and the anti-angiogenic agent cediranib (C). Results from the first set of arms established improved PFS for combination cediranib/olaparib over C alone, but did not meet its prespecified statistical significance. In this second set of arms, based on preclinical data, we are investigating the combination of O with an AKT inhibitor (capivasertib), O with durvalumab and C with durvalumab compared to the reference arm of C alone. Methods: This is a multicenter randomized four arm study for patients with recurrent, metastatic or persistent EC. Patients are randomized 1:1:1:1 to cediranib PO 30 mg Daily; olaparib 300 mg PO BID and capivasertib 400mg 4 day on/3 off schedule; olaparib 300 mg PO BID and durvalumab 1500mg q28 days; or the combination of cediranib 20 mg PO Daily 5 days on/2 days and durvalumab 1500mg q28. All treatment cycles are 28 days. Primary endpoint is progression free survival (PFS). The study is powered to detect a doubling in median PFS from 3.6 (based on cediranib alone) to 7.2 months with 90% power, using a one-sided test with α = 0.05 per comparison. Forty patients will be enrolled per arm, with an interim futility analysis planned at 50% information time. Eligibility includes endometroid, serous, and mixed histology EC; at least 1 prior line of chemotherapy (no more than 2 lines for metastatic disease), prior endocrine or immunotherapy alone is allowed; prior treatment with lenvatinib and pembrolizumab is excluded. Archival tumor tissue and blood samples are being collected for translational studies. The study is open across the NRG network; 76 of a planned 168 patients are enrolled to date. Safety analysis at the time of 36 patients enrolled did not demonstrate any new safety signals and the study was approved to continue enrollment. Clinical trial information: NCT03660826 .

Targeted Treatment of Advanced Endometrial Cancer: Focus on Pembrolizumab.

Endometrial cancer (EC) accounts for 2% of all new cancers. Advanced forms have a poor prognosis with barely 17% 5-year survival. The last few years improved our knowledge of EC with a new molecular classification derived from The Cancer Genome Atlas (TCGA). They are now divided between POLE mutant, Microsatellite Instability High (MSI-H) or deficient in Mismatch Repair System (dMMR), TP53 mutant and no specific molecular profile. Until now, treatments for advanced EC have included conventional platinum-based chemotherapy or hormonotherapy. The revolution in oncology represented by the advent of immune checkpoints inhibitors (ICI) has also led to a major advance in the management of recurrent and metastatic EC. Pembrolizumab, a well-known anti PD-1, has firstly been approved as monotherapy in the second-line setting for dMMR/MSI-H advanced EC. More recently, a combination of lenvatinib with pembrolizumab offered a new effective option in the second line setting irrespectively of the MMR status, giving a new opportunity for these patients who had no actual standard of care before. This combination is currently being evaluated as frontline therapy. Despite exciting results, the main problem in identifying solid biomarkers remains unresolved and further investigations are required. New original combinations of pembrolizumab with other drugs including chemotherapy, poly ADPribose polymerase inhibitors (PARP-i) or tyrosine kinase inhibitors are being tested and promise exciting new therapeutic evolutions in a close future.

Radiotherapy and Chemotherapy Features in the Treatment for Locoregional Recurrence of Endometrial Cancer: A Systematic Review.

Radiation therapy (RT) is the standard of care in patients with locoregional or isolated vaginal recurrence who never underwent irradiation. It is often associated with brachytherapy (BT), whereas chemotherapy (CT) is a rare treatment option. We systematically searched the PubMed and Scopus databases in February 2023. We included patients with relapsed endometrial cancer, describing the treatment of locoregional recurrence, and reporting at least one outcome of interest-disease-free survival (DFS), overall survival (OS), recurrence rate (RR), site of recurrence, and major complications. A total of 15 studies fulfilled the inclusion criteria. Overall, 11 evaluated RT only, 3 evaluated CT, and 1 analyzed oncological outcomes after administration with a combination of CT and RT. In total, 4.5-year OS ranged from 16% to 96%, and DFS ranged from 36.3% to 100% at 4.5 years. RR ranged from 3.7% to 98.2% during a median follow-up of 51.5 months. Overall, RT showed a 4.5-year DFS from 40% to 100%. CT revealed 36.3% DFS at 4.5 years. RT showed a 4.5-year OS ranging from 16% to 96%, whereas CT revealed a 27.7% OS rate. It would be appropriate to test multi-modality regimens to evaluate outcomes and toxicity. EBRT and BT are the most employed options to treat vaginal recurrences.