Persistent Endometrial Cancer Research Articles

AFT-50 EndoMAP: A phase IB/II multicohort study of targeted agents and/or immunotherapy for patients with recurrent or persistent endometrial cancer (EC).

TPS5642 Background: The landscape in the management of recurrent or persistent endometrial cancer (EC) continues to evolve. Anti-PD-1/PD-L1 immune checkpoint inhibitors (ICI) as monotherapy or when combined with the VEGF-targeted tyrosine kinase inhibitor, lenvatinib, have demonstrated promising response rates in patients (pts) with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and MS-stable (MSS)/MMR-proficient (MMRp) EC, respectively. Recent studies have also shown a benefit with adding ICI to standard of care chemotherapy in the frontline setting. Pts with MSI-H/dMMR tumors seem to derive the greatest benefit. Approximately, 30% of recurrent EC pts fall into this category. Pairing ICI with targeted therapies carries the potential to elicit prolonged anti-tumor effects. Atezolizumab (Atezo) is a humanized monoclonal PD-L1 inhibitor that has demonstrated monotherapy antitumor activity in relapsed recurrent EC, and other solid tumors (e.g. NSCLC, HCC) as monotherapy and as part of combinatorial therapy. The AFT-50/EndoMAP study is a phase IB/II non-randomized, multicenter, 2-arm, multi-cohort platform trial designed to evaluate the efficacy and safety of biomarker-driven combination regimens, both with Atezo (AFT-50A) and without Atezo (AFT-50B) with biomarker-defined targeted agents in pts with recurrent or persistent EC. Methods: Eligible pts have recurrent or persistent EC with no more than 2 prior lines of therapy. FoundationOne CDx (F1CDx) NGS assay will be used for genomic tumor profiling. In AFT-50A, pts may be eligible for one of the following doublets: Atezo+talazoparib (tumors with genomic loss of heterozygosity (gLOH ≥16%), Atezo+Trastuzumab emtansine (ERBB2/HER2 mutated or amplified tumors), and Atezo+Tiragolumab (MSI-H and/or TMB-H). The Atezo+bevacizumab (biomarker unmatched) and Atezo+ipatasertib (PIK3CA/PTEN/AKT1-altered tumors) cohorts have completed accrual. Each cohort will enroll ~20 pts with potential adjustment to account for statistical and clinical considerations. AFT-50A pts will receive Atezo in addition to a targeted agent (per study-approved dosing schedule) until progression, unacceptable toxicity, pt withdrawal, death, or study termination. AFT-50B pts will be eligible for inavolisib (PIK3CAm/PTEN and AKT1wt-altered tumors) + letrozole or giredestrant + abemaciclib (RB1wt, estrogen receptor positive tumors). The primary endpoint for AFT-50A is confirmed overall response rate (ORR) for each arm, and for AFT-50B is 6-month progression free survival. Secondary endpoints include disease control rate, duration of response, OS, safety and tolerability. As a platform study, additional arms may be added, as supported by evolving understanding of EC and molecular targets. EndoMAP is actively enrolling at 20 sites in the US with a target of 25 sites nationwide. Clinical trial information: NCT04486352 .

Abstract CT008: A phase 2, two-stage study of mirvetuximab soravtansine (IMGN853) in combination with pembrolizumab in patients with microsatellite stable (MSS) recurrent or persistent endometrial cancer

Abstract Background & Objectives: Folate receptor-alpha (FRα) expression is associated with poor prognosis in endometrial cancer (EC). Mirvetuximab soravtansine (MIRV), an antibody drug conjugate (ADC) comprising a FRα-binding antibody, cleavable linker, and the tubulin-disrupting maytansinoid DM4, showed tolerability and single agent activity in a Phase 1 dose expansion study in FRα-positive advanced/recurrent EC (NCT01609556). In addition to target-mediated cytotoxicity, MIRV activates monocytes and promotes phagocytosis of tumor cells through Fc-FcγR interactions. We therefore hypothesized that MIRV would improve the low response to immune checkpoint inhibitors (ICI) in MSS/pMMR EC and conducted this two-stage, phase 2, single cohort study evaluating the activity of MIRV in combination with pembrolizumab in patients with recurrent/persistent EC (NCT03835819). Methods: Patients with advanced or recurrent MSS/pMMR, FRα positive (defined as ≥50% of tumor cells with ≥2+ staining on IHC by Ventana, Inc.) serous EC received MIRV 6 mg/kg AIBW and pembrolizumab 200 mg every 21 days until disease progression or unacceptable toxicity. Patients could have received 1-3 prior lines of therapy; prior ICI therapy was allowed. The co-primary endpoints were objective response rate (ORR) as measured by RECIST 1.1 and frequency of patients surviving progression-free for 6 months (PFS6). In the first stage of the study, 16 patients were enrolled; if there were ≥2 objective responses or ≥2 PFS6 responses, an additional 19 patients would be enrolled in Stage 2. If a total of 4 objective responses or 8 PFS6 events were achieved, the combination would be considered worthy of further study. Data: Among 130 patient tumors prescreened for FRα expression, the median FRα (% of tumor cells with ≥2+ staining) was 30% (IQR: 5-55) and 43 (33.1%) were FRα positive (PS 2+ ≥50%). As of data-cutoff in November 2023, a total of 16 patients had received study treatment with median follow-up of 4.7 months (IQR 2.9, 17.3). Of 16 treated patients, 6 patients (37.5%, 95% CI: 15.2-64.6%) achieved an objective response, including 1 patient achieving a confirmed CR and 5 patients achieving a PR [3 confirmed PR (18.8%) and 2 unconfirmed PR (12.5%)] (Fig. 1). An additional 31.3% (5/16) had stable disease and two patients were alive and progression free at 6 months. The most common TRAEs included AST elevation (50%), blurred vision (44%), fatigue (44%) and diarrhea (43%); grade 3 TRAEs occurred in 2 patients (12.5%). Ocular toxicities of any grade were reported in 56.3% of patients. Updated efficacy and safety data as well as ongoing correlative studies will be reported at the time of the meeting. Conclusions: In this investigator-initiated study, the combination of MIRV and pembrolizumab met the co-primary endpoint to be considered worthy of further study in FRα-positive recurrent MSS/pMMR serous EC. Investigations into subpopulations most likely to derive clinical benefit from this combination are ongoing. Citation Format: Rebecca L. Porter, Niya Xiong, Nabihah Tayob, Madeline Polak, Hannah Sawyer, Martin Hayes, Jeanette Gardner, Susana Campos, Neil Horowitz, Carolyn Krasner, Elizabeth K. Lee, Joyce F. Liu, Elizabeth H. Stover, Jennifer Veneris, Alexi A. Wright, Ursula A. Matulonis, Panagiotis Konstantinopoulos. A phase 2, two-stage study of mirvetuximab soravtansine (IMGN853) in combination with pembrolizumab in patients with microsatellite stable (MSS) recurrent or persistent endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT008.

A randomized phase 2 study of sapanisertib in combination with paclitaxel versus paclitaxel alone in women with advanced, recurrent, or persistent endometrial cancer

ObjectiveThis phase 2 study investigated sapanisertib (selective dual inhibitor of mTORC1/2) alone, or in combination with paclitaxel or TAK-117 (a selective small molecule inhibitor of PI3K), versus paclitaxel alone in advanced, recurrent, or persistent endometrial cancer. MethodsPatients with histologic diagnosis of endometrial cancer (1–2 prior regimens) were randomized to 28-day cycles on four treatment arms: 1) weekly paclitaxel 80 mg/m2 (days 1, 8, and 15); 2) weekly paclitaxel 80 mg/m2 + oral sapanisertib 4 mg on days 2–4, 9–11, 16–18, and 23–25; 3) weekly sapanisertib 30 mg, or 4) sapanisertib 4 mg + TAK-117 200 mg on days 1–3, 8–10, 15–17, and 22–24. ResultsOf 241 patients randomized, 234 received treatment (paclitaxel, n = 87 [3 ongoing]; paclitaxel+sapanisertib, n = 86 [3 ongoing]; sapanisertib, n = 41; sapanisertib+TAK-117, n = 20). The sapanisertib and sapanisertib+TAK-117 arms were closed to enrollment after futility analyses. After a median follow-up of 14.4 (paclitaxel) versus 17.2 (paclitaxel+sapanisertib) months, median progression-free survival (PFS; primary endpoint) was 3.7 versus 5.6 months (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.58–1.15; p = 0.139); in patients with endometrioid histology (n = 116), median PFS was 3.3 versus 5.7 months (HR 0.66; 95% CI 0.43–1.03). Grade ≥ 3 treatment-emergent adverse event rates were 54.0% with paclitaxel versus 89.5% paclitaxel+sapanisertib. ConclusionsOur findings support inclusion of chemotherapy combinations with investigational agents for advanced or metastatic disease. The primary endpoint was not met and toxicity was manageable.Trial registration:ClinicalTrials.gov number, NCT02725268

AFT-50 EndoMAP: A phase IB/II multicohort study of targeted agents with atezolizumab (Atezo) for patients with recurrent or persistent endometrial cancer (EC) (1303)

AFT-50 EndoMAP: A phase IB/II multicohort study of targeted agents with atezolizumab (Atezo) for patients with recurrent or persistent endometrial cancer (EC) (1303)

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 .

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>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 .

Phase 2, two-stage study of letrozole and abemaciclib in estrogen receptor (ER) positive recurrent or persistent endometrial cancer (072)

Phase 2, two-stage study of letrozole and abemaciclib in estrogen receptor (ER) positive recurrent or persistent endometrial cancer (072)

A phase II trial of IDO-inhibitor, BMS-986205 (IDO), and PD-1 inhibitor, nivolumab (NIVO), in recurrent or persistent endometrial cancer (EC; CA017-056).

5589 Background: Indoleamine 2,3-dioxygenase 1 (IDO1) allows tumor escape through kynurenine production, which induces regulatory T cells and suppresses effector T-cell proliferation. NIVO, an anti-PD-1 inhibitor can upregulate IDO1, supporting the rationale for combining NIVO with IDO. We report results of NIVO as monotherapy and in combination with IDO inhibitor BMS-986205 in the treatment of pts with recurrent EC. Methods: In this single-institution, randomized phase 2 study, eligible pts must have received 1-4 prior lines of chemotherapy and have measurable disease by RECIST v 1.1. All EC histologies, including carcinosarcoma, were allowed. Pts with microsatellite insufficient (MSI-H) or mismatch repair (MMR)-deficient tumors were excluded. Pts were randomized to NIVO 480mg IV every 4 weeks (wks) with or without IDO 100mg orally daily. Primary endpoints were Overall Response Rate [ORR = Complete Response (CR) + Partial Response (PR)] by RECIST v 1.1. Secondary objectives were duration of response (DOR), median progression free survival (mPFS), PFS rate at 24 wks (PFS24wks) and safety. Overall survival (OS) was also evaluated. Results: Between 10/2019 and 11/2021, pts were randomized to receive either NIVO (n = 12) or NIVO + IDO (n = 12). Median age was 67 years (range 48-82) and median number of prior lines of therapy was 2 (range 1-3). Histologies included serous (n = 5, 21%), endometrioid (n = 10, 42%), clear cell (n = 1, 4.2%), carcinosarcoma (n = 6, 25%), undifferentiated (n = 1, 4.2%), and mucinous (n = 1, 4.2%). In the NIVO + IDO arm, 1 pt achieved partial response (8.3%, CI: 0.9-100%) with DOR of 17.6 months. In the NIVO arm, no responses were observed. Efficacy outcomes are summarized in the table. Treatment-related adverse events (TRAEs) grade ≥ 3 in the NIVO arm included acute kidney injury (n = 1, 8.3%), hypokalemia (n = 1, 8.3%), and thromboembolic event (n = 1, 8.3%). In the NIVO + IDO arm, TRAEs grade ≥ 3 included fatigue (n = 1, 8.3%), and elevated liver function (n = 1, 8.3%). No TRAEs led to study-drug interruption or dose reductions. Conclusions: NIVO monotherapy and in combination with IDO showed acceptable safety in pts with recurrent EC. NIVO in combination with IDO showed ORR of 8.3%. No responses were observed with NIVO monotherapy. The trial closed to accrual due to lack of observed clinical efficacy. Clinical trial information: NCT04106414. [Table: see text]

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

TPS5609 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. Activity of pembrolizumab and lenvatinib was demonstrated in a phase 2 trial in MMR-P EC (NCT02501096). By inhibiting VEGF receptor (VEGFR) and PD-L1 signaling, immunologically “cold” tumors may become inflamed. However, there are concerns regarding the toxicity of pembrolizumab/lenvatinib and alternatives are sought. 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. Methods: This is an investigator-initiated, phase 2, two-stage single cohort trial evaluating avelumab with axitinib in recurrent or persistent EC. Participants must have MMR-P EC of any histology and have received at least one chemotherapeutic regimen, with no upper limit on the number of prior lines received. Prior use of immune checkpoint (IC) inhibitors is excluded. Treatment consists of avelumab 800mg IV every 2 weeks and axitinib 5mg orally twice daily. Co-primary endpoints are progression-free survival at 6 months (PFS6) and objective response rate by RECIST 1.1. Translational objectives include characterization of tumor-infiltrating lymphocytes, infiltrating myeloid cells, expression of IC markers, and whole exome sequencing to evaluate mutations in genes related to DNA repair and immunologic response. This is a two-stage design in the method of Sill et al, with 16 participants anticipated in stage 1 and 19 participants in stage 2, for a total of 35 participants. Accrual is ongoing. Clinical trial information: NCT02912572.

A phase II trial of bevacizumab and rucaparib in recurrent carcinoma of the cervix or endometrium.

5527 Background: Treatment options for patients with recurrent cervical and endometrial cancer remain limited. Even with optimum care, median survival has stalled at 12-17 months. The PARP inhibitor rucaparib has demonstrated activity in both BRCA wild-type and mutant cancers. Furthermore, preclinical studies suggest a synergistic effect of PARP inhibitors and antiangiogenic agents. We hypothesized that the combination of rucaparib and the VEGF inhibitor bevacizumab would yield a clinically-significant anti-cancer effect in patients with persistent or recurrent cervical or endometrial carcinoma. Methods: NCT03476798 is a phase II trial of adults with histologically-documented carcinoma of the cervix or endometrium. Patients with evaluable lesions who had undergone at least one prior line of systemic therapy, had adequate performance status and organ function, with a life expectancy of at least three months were eligible. Biopsies were obtained prior to treatment initiation for assessment of baseline tumor biomarkers, including ARID1A mutation status. Each cycle comprised 21 days. Rucaparib was administered orally at 600 mg, twice daily. Bevacizumab was administered by IV at 15 mg/kg on day 1 of each cycle. The primary objective was to estimate the proportion of patients with persistent or recurrent cervical or endometrial cancer who survive progression-free for at least six months (PFS6). Kaplan-Meier analysis was used to estimate progression-free survival. Results: There were 28 evaluable patients; six had cervical and 22 had endometrial cancer. Median age was 60.5 years (range, 30-74). Self-reported patient races were White (82.1%), Black (10.7%), and Native American (7.1%). Self-identified Hispanic or Latina patients comprised 3.6% of the cohort. Twenty-two of 28 patients had progressive disease by six months [survival distribution function estimate = 0.214 (lower CI, 0.087; upper CI, 0.378)]. Of the six patients who achieved PFS6, one had cervical and five had endometrial cancer. Six patients had a mutation in the ARID1A gene and those patients achieved PFS6 at a rate of 66.7%. Conclusions: The study hypothesis was evaluated in a two-stage design, and the interim analysis occurred once 28 evaluable patients were enrolled. In order to move on to the second stage, at least seven patients needed to remain progression-free at six months, but only six did. Thus, the study was ended after the interim analysis. The combination of rucaparib and bevacizumab did not provide the expected clinical benefit in this cohort of patients, but may warrant further exploration in patients with ARID1A mutations. Clinical trial information: NCT03476798.

Abstract B18: Single-arm, open-label, phase II study of LY3023414 for the treatment of recurrent or persistent endometrial cancer

Abstract Background: Activating mutations of the PI3K/mTOR pathway are highly prevalent in endometrial cancers (EC), but monotherapy targets of this pathway have shown modest activity and are associated with poor tolerance. LY3023414 is a selective inhibitor of class I PI3K isoforms, mTOR, and DNA-PK. Building on phase I experience of LY3023414, we sought to evaluate the efficacy and safety of LY3023414 in PI3K pathway activated advanced EC. Methods: Eligible patients (pts) had PI3K pathway activation defined as (1) loss of PTEN function including whole or partial gene deletion, frame shift mutations, or non-sense mutations (PTEN missense mutations excluded) or (2) activating mutation in PIK3CA, AKT1, PIK3R1, PIK3R2, or mTOR. Up to 4 prior lines of therapy were allowed. Each cycle was 21 days. Efficacy assessments were performed every 2 cycles and treatment-related adverse events (AEs) were assessed per CTCAE v. 4.03. The primary objective was best overall response rate by RECIST 1.1. Results: Of the 28 pts enrolled, 25 (89%) had 1-2 lines of therapy and 3 pts (11%) had 3-4 prior lines of therapy. LY3023414 was dosed at the RP2D of 200 mg orally twice daily. Three pts were excluded from efficacy assessment due to toxicity, noncompliance or early patient withdrawal. The clinical benefit rate (CBR), defined as the percentage of pts with complete response (CR) + partial response (PR) + stable disease (SD) ≥12 weeks, was 56% (14/25). Five patients achieved PR; 9 pts achieved SD at best response. Three of the 5 PRs were sustained from 44-52 weeks; 1 pt with PR is still on therapy > 84 weeks. The median PFS and median OS were 2.53 (CI 1.18-2.99) months and 9.24 (CI 5-NR) months, respectively. Twenty-one pts underwent further genomic sequencing; 16 pts (76%) had a PIK3CA mutation, 6 pts (29%) had a PIK3R1 and 10 pts (48%) had a PTEN mutation. There were no significant co-mutations identified and a correlation of molecular alterations with response was not identified. Across all cycles, the most common grade 3 LY3023414-related adverse events (AEs) were lymphopenia (n=10), hypokalemia (n=5), hypophosphatemia (n=4), hyponatremia (n=3), and anemia (n=3). There were 3 LY3023414-related grade 4 AEs: allergic reaction (n=1), CPK rise (n=1) and hyponatremia (n=1). There were no LY3023414-related G5 AEs. Conclusions: In PI3K pathway-altered, heavily pretreated advanced EC, LY3023414 demonstrated a manageable safety profile and promising single-agent efficacy. Enrollment is now complete and updated response data will be presented. Citation Format: Maria M. Rubinstein, David Hyman, Imogen Caird, Roisin O'Cearbhaill, Rachel Grisham, William Tew, Martee Hensley, Paul Sabbatini, Carol Aghajanian, Alexia Iasonos, Helen Won, Duygu Selcuklu, Catherine Zimel, Vicky Makker. Single-arm, open-label, phase II study of LY3023414 for the treatment of recurrent or persistent endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B18.

Randomized phase II study of sapanisertib (SAP) + paclitaxel (PAC) versus PAC alone in patients (pts) with advanced, recurrent, or persistent endometrial cancer.

6087 Background: SAP (TAK-228, MLN0128) is a selective dual inhibitor of mammalian target of rapamycin complexes 1 and 2. In endometrial tumor xenograft models, SAP+PAC exhibited stronger antitumor efficacy than PAC alone. Methods: Female pts with histologic/cytologic diagnosis of endometrial cancer were randomized to receive SAP 4 mg by mouth (days [d] 2–4, 9–11, 16–18, 23–25) plus PAC 80 mg/m2 intravenously (d 1, 8, 15), or PAC alone, in 28-day cycles until unacceptable toxicity or disease progression. Randomization was stratified by histologic subtype, lines of prior chemotherapy (1 vs. 2), and prior taxane therapy. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR; ORR + stable disease), and safety. Additional treatment arms of SAP alone (weekly dosing) and SAP+TAK-117 were closed after futility analyses. Results: 180 pts were randomized to SAP+PAC (n=90) or PAC (n=90); 86 and 87 pts received SAP+PAC and PAC, respectively; 3 pts from each arm were ongoing on treatment at data cut (30 July 2019). Baseline characteristics were balanced between arms. After a median follow-up of 17.2 vs. 14.4 mos with SAP+PAC vs. PAC, median PFS was 5.6 mos vs. 3.7 mos (hazard ratio [HR] 0.82; 95% CI 0.58–1.15). In pts with endometrioid histology (n=116), median PFS was 5.7 mos with SAP+PAC vs 3.3 mos with PAC (HR 0.66; 95% CI 0.43–1.03). In pts with nonendometrioid histology (n=64), median PFS was 3.6 mos with SAP+PAC vs. 5.4 mos with PAC (HR 1.09; 95% CI 0.62–1.90). Median OS was 13.7 mos with SAP+PAC vs. 14.6 mos with PAC (HR 1.01; 95% CI 0.67–1.53). Confirmed ORR was 24% with SAP+PAC vs. 18% with PAC (endometrioid, 23% vs. 16%; nonendometrioid, 28% vs. 22%); CBR was 80% vs. 58% (endometrioid, 84% vs. 55%; nonendometrioid, 72% vs. 63%). Median number of cycles received was 5 (range 1–23) with SAP+PAC and 4 (range 1–37) with PAC. Rates of grade ≥3 treatment-emergent adverse events (TEAEs) were 90% with SAP+PAC vs. 54% with PAC; the most common included anemia (21% vs.12%), neutropenia (12% vs. 3%), fatigue (12% vs. 5%), hypophosphatemia (12% vs. 1%), and pulmonary embolism (11% vs. 3%). Conclusions: Median PFS was longer with SAP+PAC vs. PAC in pts with endometrial cancer but did not reach statistical significance. PFS was particularly longer in the endometrioid subtype but again was not significant, and further studies are warranted. Incidence of grade ≥3 TEAEs was higher with SAP+PAC vs. PAC, but SAP+PAC toxicity was manageable, with no new safety signals. Clinical trial information: NCT02725268.

Phase II, two-stage study of avelumab in patients with microsatellite stable (MSS), microsatellite instable (MSI) and polymerase epsilon (POLE) mutated recurrent or persistent endometrial cancer

Phase II, two-stage study of avelumab in patients with microsatellite stable (MSS), microsatellite instable (MSI) and polymerase epsilon (POLE) mutated recurrent or persistent endometrial cancer

Phase 2, two-group, two-stage, open-label study of avelumab in patients with microsatellite stable, microsatellite instable and POLE-mutated recurrent or persistent endometrial cancer.

TPS5615 Background: The Cancer Genome Atlas project identified 2 groups of hypermutated endometrial cancers (ECs): an ultramutated group that harbored mutations in the exonuclease domain of polymerase e ( POLE), and a hypermutated group with microsatellite instability (MSI), the majority of which harbored MLH1 promoter methylation. We (Howitt, JAMA Onc 2015) and others have shown that POLE and MSI ECs are associated with higher number of predicted neoepitopes and tumor infiltrating lymphocytes, which is counterbalanced by overexpression of PD-1/PD-L1, suggesting that they may be excellent candidates for PD-1/PD-L1 blockade. Anti-PD-1 therapy has also demonstrated promising activity in mismatch repair deficient colorectal cancers and collectively in non-colorectal cancers (Le, NEJM 2015). Methods: This is an open-label, two-cohort, two-stage, phase 2 trial, of avelumab, a fully human IgG1 antibody directed against PD-L1, in two cohorts: i) a MSI/ POLE cohort including ECs with immunohistochemical (IHC) complete loss of expression of at least one of the mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE and ii) a MSS cohort including ECs with normal IHC expression of all MMR proteins. Key eligibility criteria include measurable disease, no upper limit of prior therapies, and any EC histology. Co-primary objectives include objective response rate and rate of progression-free survival at 6 months. Avelumab is administered at 10 mg/kg as 1-hour IV infusion every 2 weeks until disease progression or unacceptable toxicity; therapy may continue at the investigator’s discretion while awaiting radiologic confirmation of disease progression 4 weeks later. Maximum target enrollment is 70 patients (35 for each cohort). In the first stage, 16 patients will be enrolled in each cohort; if there are at least two objective responses or two patients progression-free at 6 months, accrual will continue to the second stage where 19 more patients will be enrolled for each cohort. Thus far, 16 patients have been enrolled, 13 on the MSS cohort and 3 on the MSI/ POLE cohort. Clinical trial information: NCT02912572.

Limited access safety lead-in of the MEK inhibitor trametinib in combination with GSK2141795, an AKT inhibitor, in patients with recurrent or persistent endometrial cancer: A Gynecologic Oncology Group study

Limited access safety lead-in of the MEK inhibitor trametinib in combination with GSK2141795, an AKT inhibitor, in patients with recurrent or persistent endometrial cancer: A Gynecologic Oncology Group study

Preliminary results of a phase II study: PD-1 blockade in mismatch repair–deficient, recurrent or persistent endometrial cancer

Preliminary results of a phase II study: PD-1 blockade in mismatch repair–deficient, recurrent or persistent endometrial cancer

Characterizing bevacizumab use in endometrial cancer in a community medical setting

Objectives: Given that 85% of cancer patients are treated in community settings and the role of bevacizumab in the treatment of endometrial cancer is undefined, we sought to characterize the practice patterns of bevacizumab use in recurrent or persistent endometrial cancer in a community based integrated health care system. Methods: Following IRB approval, patients with endometrial cancer and prior treatment with bevacizumab were identified within the cancer registry database from our regional medical institution. Patients were excluded if they had a concurrent or prior cancer. A chart reviewof the eligible patients was performed to extract traditional clinical variables. Bevacizumab side effects were also recorded to assess tolerability. Results: Twenty-two patients were identified with recurrent or persistent endometrial cancer treated with bevacizumab. The average age was 64 years (range 38–79). Twenty-seven percent were Stage 1, 50% were Stage 3, and 23% were Stage 4. Histology types included 36% papillary serous, 32% endometriod, 9% clear cell, 5% adenosquamous, 5% carcinosarcoma, and 13% with mixed histologic components. The average time period for bevacizumab treatment was 134 days (range 22–374). The average number of chemotherapy treatments prior to bevacizumab use was 2 treatments (range 0–5). Fifty percent of patients received bevacizumab as part of a multidrug treatment regimen, 27% received it as monotherapy, and 22% received additional therapeutic agents during part of their treatment regimen with bevacizumab. Chemotherapy treatments were overseen by 13 medical oncologist and 3 gyn oncologists. Progressive diseasewas seen in 64% of patients using bevacizumab, while 27% had stable disease and 9% has partial or complete regression. Five patients (23%) had Grade 3/4 bevacizumab side effects, including three patients with hypertension, one subarachnoid hemorrhage, and one fistula. No deaths were attributed to bevacizumab. Conclusion: Bevacizumab is well tolerated in this heavily pretreated population, and utilized in varied combinations with clinical benefit. Further studies are needed to elucidate a standard treatment regimen which may optimize patient outcomes in this population with poor prognosis. Learning objective: Learners will be able to describe the role of bevacizumab in recurrent endometrial cancer in patientswho are treated in a community setting.

A phase II evaluation of cediranib in the treatment of recurrent or persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study

PurposeCediranib is a multi-tyrosine kinase inhibitor targeting vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This phase II study was conducted to assess activity and tolerability of single-agent cediranib in recurrent/persistent endometrial cancer. Patients and methodsEligible patients had recurrent or persistent endometrial cancer after receiving one or two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group (GOG) performance status of ≤2 (≤1 if two prior cytotoxic regimens given). Cediranib 30mg orally daily for a 28daycycle was administered until disease progression or prohibitive toxicity. Microvessel density (MVD) was measured in tumor tissue from initial hysterectomy specimens and correlated with clinical outcome. Primary endpoints were tumor response and surviving progression-free for six months without subsequent therapy (6-month event-free survival [EFS]). ResultsOf 53 patients enrolled, 48 were evaluable for cediranib efficacy and toxicity. Median age was 65.5years, 52% of patients had received prior radiation, and 73% of patients received only one prior chemotherapy regimen. A partial response was observed in 12.5%. Fourteen patients (29%) had six-month EFS. Median progression-free survival (PFS) was 3.65months and median overall survival (OS) 12.5months. No grade 4 or 5 toxicities were observed. A trend towards improved PFS was found in patients whose tumors expressed high MVD. ConclusionCediranib as a monotherapy treatment for recurrent or persistent endometrial cancer is well tolerated and met protocol set objectives for sufficient activity to warrant further investigation. MVD may be a useful biomarker for activity.

A phase II evaluation of cediranib in the treatment of recurrent or persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group (GOG) study

A phase II evaluation of cediranib in the treatment of recurrent or persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group (GOG) study

Phase II evaluation of dalantercept, a soluble recombinant activin receptor-like kinase 1 (ALK1) receptor fusion protein, for the treatment of recurrent or persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group Study 0229N

ObjectiveThis two-stage phase II study assessed activity of single agent dalantercept in patients with recurrent/persistent endometrial carcinoma (EMC). MethodsEligible patients had persistent/recurrent EMC after 1–2 prior cytotoxic regimens, measurable disease (RECIST 1.1), and GOG performance≤2. Dalantercept 1.2mg/kg subcutaneous was administered once every 3weeks until disease progression (PD)/development of prohibitory toxicity. Primary objectives were to estimate the proportion of patients with persistent/recurrent EMC, who survive progression-free without receiving non-protocol therapy (TPFS) for at least 6months and to estimate the proportion having objective tumor response. ResultsAll 28 enrolled patients were eligible and evaluable. Median age: 62years. Most common histologies: 32% Grade 1/2 endometrioid and 54% serous tumors. Prior treatment: 1 or 2 regimens in 82% and 18% of patients, respectively. Eighteen patients received prior radiation therapy. Patients received 1–12 cycles of dalantercept, and 46% of patients received ≤2cycles. The most common adverse events (AE) were fatigue, anemia, constipation and peripheral edema. Grade 3/4 AEs occurred in 39% and 4% of patients. One grade 5 gastric hemorrhage in a patient with a history of radiation fibrosis/small bowel obstruction was deemed possibly dalantercept-related. All patients are off study: 86% for PD. No ORs were observed; 57% had stable disease and 11% had TPFS>6 mos. Median progression-free and overall survival: 2.1months (90% CI: 1.4–3.2) and 14.5months (90% CI: 7.0–17.5), respectively. ConclusionsDalantercept has insufficient single agent activity in recurrent EMC to warrant further investigation at this dose level and schedule.