Advanced Recurrent Endometrial Cancer Research Articles

Immunotherapy for endometrial cancer.

Advanced recurrent endometrial cancer (EC) has a poor prognosis and new treatment options are needed. In 2013, EC was classified by genomic analysis into four groups: the POLE ultra-mutated group, the MSI-high hypermutated group (MSI-H), the copy number low group, and the copy number high group. The prognosis differs based on the classification, which should enable the individualization of treatment. The MSI-H and POLE types can induce PD-L1 expression in cancer cells. Among the gynecological cancers, EC exhibits the highest levels of PD-1 and PD-L1 expression and has the highest proportion of MSI-H. Thus, an immune checkpoint inhibitor (ICI) is expected to be effective. The first ICI to show efficacy in recurrent EC was the anti-PD1 antibody pembrolizumab, which exhibited efficacy in MSI-H EC. The combination of pembrolizumab and the multi-kinase inhibitor lenvatinib significantly prolongs OS/PFS compared with single-agent chemotherapy in previously treated recurrent EC, regardless of MSI status. ICIs are now moving from second-line and beyond to first-line treatment regimens. The efficacy of paclitaxel plus carboplatin (TC) and ICI combinations compared with TC have been demonstrated, including an ongoing Phase III trial comparing chemotherapy with the combination of pembrolizumab and lenvatinib. Although ICIs are becoming the mainstay of EC, they cause systemic inflammatory side effects known as irAEs. The incidence of irAEs is higher for combination therapy with CT or lenvatinib compared with ICI therapy alone. Even though they are rarely fatal, irAEs should be addressed promptly.

Immune Checkpoint Inhibitors Targeting the PD-1/PD-L1 Pathway in Advanced, Recurrent Endometrial Cancer: A Scoping Review with SWOT Analysis.

Results of recent clinical trials using the immune check point inhibitors (ICI) pembrolizumab or dostarlimab with/without lenvatinib has led to their approval for specific molecular subgroups of advanced recurrent endometrial cancer (EC). Herein, we summarise the clinical data leading to this first tissue-agnostic approval. As this novel therapy is not yet available in the United Kingdom standard care setting, we explore the strengths, weaknesses, opportunities, and threats (SWOT) of ICI treatment in EC. Major databases were searched focusing on clinical trials using programmed cell death protein 1 (PD-1) and its ligand (PD-L1) ICI which ultimately contributed to anti-PD-1 approval in EC. We performed a data quality assessment, reviewing survival and safety analysis. We included 15 studies involving 1609 EC patients: 458 with mismatch repair deficiency (MMRd)/microsatellite instability-high (MSI-H) status and 1084 with mismatch repair proficiency/microsatellite stable (MMRp/MSS) status. Pembrolizumab/dostarlimab have been approved for MMRd ECs, with the addition of lenvatinib for MMRp cases in the recurrent setting. Future efforts will focus on the pathological assessment of biomarkers to determine molecular phenotypes that correlate with response or resistance to ICI in order to identify patients most likely to benefit from this treatment.

548P Progression-free survival (PFS) and overall survival (OS) in advanced/recurrent (AR) mismatch repair deficient/microsatellite instability–high or proficient/stable (dMMR/MSI-H or MMRp/MSS) endometrial cancer (EC) treated with dostarlimab in the GARNET study

Dostarlimab is a programmed death 1 (PD-1) inhibitor approved in the EU as a monotherapy in patients (pts) with dMMR/MSI-H AR EC that has progressed on or after platinum-based chemotherapy; and in the US as a monotherapy in pts with dMMR AR EC that has progressed on or after platinum-based chemotherapy or dMMR solid tumors that have progressed on or after prior treatment, with no satisfactory alternative treatment options. We report on PFS and OS in 2 expansion cohorts of the GARNET trial that enrolled pts with EC. GARNET is a multicenter, open-label, single-arm phase 1 study. Pts were assigned to cohort A1 (dMMR/MSI-H EC) or A2 (MMRp/MSS EC) based on local immunohistochemistry assessment. Pts received 500 mg of dostarlimab IV every 3 weeks for 4 cycles, then 1000 mg every 6 weeks until disease progression, discontinuation, or withdrawal. PFS and OS are secondary efficacy endpoints. 153 pts with dMMR/MSI-H and 161 pts with MMRp/MSS EC were enrolled and treated. The efficacy-evaluable population included 143 pts with dMMR/MSI-H EC and 156 pts with MMRp/MSS EC with measurable disease at baseline and ≥6 mo of follow-up. Median follow-up was 27.6 mo for dMMR/MSI-H and 33.0 mo for MMRp/MSS EC (Table). For pts with dMMR/MSI-H EC, median PFS (mPFS) was 6.0 mo, with 3-year estimated PFS rate of 40.1%. With 37.3% of pts experiencing an event, mOS was not reached; estimated 3-year OS was >50%. For pts with MMRp/MSS EC, mPFS was 2.7 mo. mOS was 16.9 mo with 68.9% of pts experiencing an event. Safety has been previously reported.Table: 548PdMMR/MSI-H ECN=143MMRp/MSS ECN=156Median follow-up, mo27.633.0mPFS (95% CI), mo6.0 (4.1–18.0)2.7 (2.6–2.8)Estimated probability of PFS, %12 mo24 mo36 mo46.440.140.113.39.46.8N=153N=161mOS (95% CI), moNR (25.7–NR)16.9 (13.0–21.8)Estimated probability of survival, %12 mo24 mo36 mo73.360.558.460.638.422.2Datacut: 1 Nov 2021. NR, not reached Open table in a new tab Datacut: 1 Nov 2021. NR, not reached Dostarlimab demonstrated durable antitumor activity in dMMR/MSI-H and MMRp/MSS AR EC. dMMR/MSI-H was associated with longer PFS and OS than MMRp/MSS as expected.

Dostarlimab in advanced/recurrent (AR) mismatch repair deficient/microsatellite instability–high or proficient/stable (dMMR/MSI-H or MMRp/MSS) endometrial cancer (EC): The GARNET study.

5509 Background: Dostarlimab is a programmed death 1 (PD-1) inhibitor approved in the U.S. as a monotherapy in patients (pts) with dMMR AR EC that has progressed on or after treatment with a platinum-containing regimen or dMMR solid tumors that have progressed on or after prior treatment, with no satisfactory alternative treatment options; and in the E.U. as a monotherapy in pts with dMMR/MSI-H AR EC that has progressed on or after treatment with a platinum-containing regimen. Here, we report on efficacy and safety in the 2 expansion cohorts of the GARNET trial that enrolled pts with EC. Methods: GARNET is a multicenter, open-label, single-arm phase 1 study. Pts were assigned to cohort A1 (dMMR/MSI-H EC) or cohort A2 (MMRp/MSS EC) based on local assessment. Pts received 500 mg of dostarlimab IV Q3W for 4 cycles, then 1,000 mg Q6W until disease progression, discontinuation, or withdrawal. The primary endpoints are ORR and DOR by blinded independent central review using RECIST v1.1. Results: For this third interim analysis, 153 dMMR/MSI-H and 161 MMRp/MSS pts were enrolled and dosed. Of these, 143 dMMR/MSI-H and 156 MMRp/MSS pts had measurable disease at baseline and ≥ 6 mo of follow-up and were included in the efficacy-evaluable population. ORRs were 45.5% (dMMR/MSI-H) and 15.4% (MMRp/MSS; Table). Median (m) DORs were not reached (NR; dMMR/MSI-H) and 19.4 mo (MMRp/MSS). Probability of PFS at 6, 9, and 12 mo was 49.5%, 48.0%, and 46.4% in dMMR/MSI-H EC and 35.8%, 31.3%, and 29.4% in MMRp/MSS EC, respectively. mOS was NR (dMMR/MSI-H) and 16.9 mo (MMRp/MSS). Overall, 27 pts (8.6%) discontinued treatment because of a treatment-related adverse event (TRAE; 13 dMMR/MSI-H, 14 MMRp/MSS). The majority of TRAEs were grade 1 or 2. The most common any-grade TRAEs were fatigue (56; 17.8%), diarrhea (46; 14.6%), and nausea (43; 13.7%). No deaths were attributed to dostarlimab in the EC cohorts. Hypothyroidism (12; 8%) was the most common any-grade immune-related TRAE. Conclusions: Dostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H and MMRp/MSS AR EC. dMMR/MSI-H was associated with better outcomes: a higher response rate and longer PFS and OS. Safety was consistent with other PD-1 antibodies. Clinical trial information: NCT02715284. [Table: see text]

Efficacy and safety of dostarlimab in patients (pts) with mismatch repair deficient (dMMR) solid tumors: Analysis of 2 cohorts in the GARNET study.

2587 Background: Dostarlimab is a programmed death 1 (PD-1) inhibitor approved in the US as a monotherapy in pts with dMMR solid tumors that have progressed on or after prior treatment, with no satisfactory alternative treatment options; or dMMR advanced/recurrent (AR) endometrial cancer (EC) that has progressed on or after treatment with a platinum-based chemo; and in the EU as a monotherapy in pts with dMMR/ microsatellite instability–high (MSI-H) AR EC that has progressed on or after treatment with a platinum-based chemo. Here we report on efficacy and safety in 2 expansion cohorts that enrolled pts with dMMR solid tumors. Methods: GARNET is a multicenter, open-label, single-arm phase 1 study. Cohort A1 enrolled pts with dMMR/MSI-H AR EC; cohort F enrolled pts with dMMR/MSI-H/POLε-mut non-EC solid tumors. Pts received 500 mg of IV dostarlimab Q3W for 4 cycles, then 1000 mg Q6W until PD, discontinuation, or withdrawal. Primary endpoints were ORR and DOR by BICR per RECIST v1.1. Biomarker status was based on local assessment. Results: For this third interim analysis, 153 pts with dMMR/MSI-H EC and 210 pts with dMMR/MSI-H/POLε-mut non-EC solid tumors (56% colorectal cancer, 11% gastric) were enrolled and treated. Efficacy analysis was performed for 143 dMMR/MSI-H EC and 204 dMMR/MSI-H/POLε-mut non-EC pts who had measurable disease at baseline and ≥6 mo of follow-up. ORRs were 45.5% (dMMR/MSI-H EC) and 43.1% (dMMR/POLε-mut non-EC solid tumors; Table). Probability of PFS at 6, 9, and 12 mo was 49.5%, 48.0%, and 46.4% in dMMR/MSI-H EC and 51.8%, 48.1%, and 46.4% in dMMR/MSI-H/POLε-mut non-EC. Median (m) DOR and mOS were not reached for either cohort. A total of 13 pts (8.5%) with dMMR/MSI-H EC and 12 pts (5.7%) with dMMR/MSI-H/POLε-mut non-EC solid tumors discontinued owing to a treatment-related adverse event (TRAE). TRAEs occurring in ≥12% of pts were diarrhea, asthenia, fatigue, nausea, and pruritis (dMMR/MSI-H EC) and diarrhea, asthenia, and pruritus (dMMR/MSI-H/POLε-mut non-EC solid tumors). 2 deaths (1 hepatic ischemia, 1 suicide) were attributed by investigators to dostarlimab in pts with non-EC solid tumors. Conclusions: Dostarlimab demonstrated durable antitumor activity across 16 tumor types in pts with dMMR solid tumors, confirming efficacy in a larger sample size with extended follow-up. The safety profile was acceptable, with manageable toxicities. Clinical trial information: NCT02715284. [Table: see text]

Real-world outcomes in patients with advanced endometrial cancer: A retrospective cohort study of US electronic health records

ObjectivesTo characterize clinical outcomes of women with advanced/recurrent endometrial cancer (AEC) in routine practice using electronic health records from a real-world database. MethodsAdult women diagnosed with AEC (stage III/IV, or early stage with locoregional/distant recurrence) between January 1, 2013 and September 30, 2020, inclusive, were eligible provided they received platinum-based chemotherapy at any time following diagnosis and had ≥2 clinical visits. Follow-up was from initiation of systemic treatment after advanced diagnosis (index) until March 30, 2021, last available follow-up, or death, whichever occurred first. Outcomes, by histological subtype, included Kaplan–Meier estimates of overall survival (OS) and time to first subsequent therapy or death (TFST). ResultsOf the 2202 women with AEC, most were treated in a community setting (82.7%) and presented with stage III/IV disease at initial diagnosis (74.0%). The proportion with endometrioid carcinoma, uterine serous carcinoma (USC), and other AEC subtypes was 59.8%, 25.0%, and 15.2%, respectively. The most common first systemic treatment following advanced/recurrent diagnosis was platinum-based combination chemotherapy (82.0%). Median OS (95% CI) from initiation of first systemic treatment was shorter with USC (31.3 [27.7–34.3] months) and other AECs (29.4 [21.4–43.9] months) versus endometrioid carcinoma (70.8 [60.5–83.2] months). Similar results were observed for TFST. Black/African American women had worse OS and TFST than white women. ConclusionsWomen with AEC had poor survival outcomes, demonstrating the requirement for more effective therapies. To our knowledge, this is the most comprehensive evaluation of contemporary treatment of AEC delivered in a community setting to date.

Lenvatinib plus pembrolizumab in advanced recurrent endometrial cancer: a cost-effectiveness analysis

Objectives: To determine the cost-effectiveness of lenvatinib plus pembrolizumab (LP) in patients with endometrial cancer without microsatellite instability who failed first-line chemotherapy. Methods: A decision analysis model was created to evaluate the cost-effectiveness of LP relative to doxorubicin, pegylated liposomal doxorubicin (PLD), and bevacizumab in patients with recurrent microsatellite stable endometrial cancer who failed first-line chemotherapy. Clinical estimates were obtained from published data and drug cost estimates were obtained using average wholesale prices. Additional cost estimates were utilized to estimate cost of grade 3-4 toxicity treatment. The measure of effectiveness was quality-adjusted life years (QALYs). Due to the high rate of toxicity in the LP group, a health state utility (HSU) penalty of -0.05 was applied to this group. Incremental cost-effectiveness ratios (ICERs) were calculated to determine the cost per QALY. The willingness to pay threshold (WTP) was set at $100,000 per QALY saved. Sensitivity analyses were performed on cost, effectiveness, and HSU penalty for LP. Results: Costs of treatment with doxorubicin, PLD, and bevacizumab are $26.7 million (M), $51.1 M, and $225.1 M respectively. Cost of treatment with LP is $856.5M. Relative to doxorubicin, the ICER for PLD, bevacizumab, and LP are $46,279, $345,824, and $726,483 respectively. Two-way sensitivity analysis varying the cost of LP show that if the combined cost of these two drugs decreases from over $34,000 per cycle to less than $9,000 per cycle, this strategy would be cost-effective. At the current cost, even if the median overall survival was double the 16.7 months used in the base model, the ICER for LP remains above the WTP threshold. Eliminating the HSU penalty for LP decreased the ICER $567,000 while increasing the penalty to 0.10 increased the ICER to over $1M. Conclusions: LP is not cost-effective in patients with recurrent, MSS endometrial cancer who have failed first line therapy. A dramatic reduction in cost of LP is required for this novel strategy to be cost-effective. To determine the cost-effectiveness of lenvatinib plus pembrolizumab (LP) in patients with endometrial cancer without microsatellite instability who failed first-line chemotherapy. A decision analysis model was created to evaluate the cost-effectiveness of LP relative to doxorubicin, pegylated liposomal doxorubicin (PLD), and bevacizumab in patients with recurrent microsatellite stable endometrial cancer who failed first-line chemotherapy. Clinical estimates were obtained from published data and drug cost estimates were obtained using average wholesale prices. Additional cost estimates were utilized to estimate cost of grade 3-4 toxicity treatment. The measure of effectiveness was quality-adjusted life years (QALYs). Due to the high rate of toxicity in the LP group, a health state utility (HSU) penalty of -0.05 was applied to this group. Incremental cost-effectiveness ratios (ICERs) were calculated to determine the cost per QALY. The willingness to pay threshold (WTP) was set at $100,000 per QALY saved. Sensitivity analyses were performed on cost, effectiveness, and HSU penalty for LP. Costs of treatment with doxorubicin, PLD, and bevacizumab are $26.7 million (M), $51.1 M, and $225.1 M respectively. Cost of treatment with LP is $856.5M. Relative to doxorubicin, the ICER for PLD, bevacizumab, and LP are $46,279, $345,824, and $726,483 respectively. Two-way sensitivity analysis varying the cost of LP show that if the combined cost of these two drugs decreases from over $34,000 per cycle to less than $9,000 per cycle, this strategy would be cost-effective. At the current cost, even if the median overall survival was double the 16.7 months used in the base model, the ICER for LP remains above the WTP threshold. Eliminating the HSU penalty for LP decreased the ICER $567,000 while increasing the penalty to 0.10 increased the ICER to over $1M. LP is not cost-effective in patients with recurrent, MSS endometrial cancer who have failed first line therapy. A dramatic reduction in cost of LP is required for this novel strategy to be cost-effective.

Lenvatinib plus pembrolizumab in advanced recurrent endometrial cancer: A cost-effectiveness analysis

ObjectiveTo determine the cost-effectiveness of lenvatinib plus pembrolizumab (LP) in patients with microsatellite stable (MSS), recurrent, pretreated endometrial cancer (EC). MethodsA decision analysis model was created to evaluate the cost-effectiveness of LP relative to doxorubicin, pegylated liposomal doxorubicin (PLD), and bevacizumab in patients with recurrent pretreated MSS EC. Published data was used to estimate quality adjusted life years (QALYs) and drug cost estimates were obtained using average wholesale prices. A health state utility (HSU) penalty of −0.10 was applied to the LP group to account for treatment toxicity. Incremental cost-effectiveness ratios (ICERs) were calculated to determine cost/QALY. The willingness to pay threshold (WTP) was set at $100,000 per QALY saved. Sensitivity analyses were performed on cost, effectiveness, and HSU penalty for LP. ResultsCosts of treatment with doxorubicin, PLD, and bevacizumab are $23.7 million (M), $56.9 M, and $250.8 M respectively. Cost of treatment with LP is $1.8 billion. Relative to doxorubicin, the ICERs for PLD, bevacizumab, and LP are $56,808, $345,824, and $1.6 M respectively. A sensitivity analysis varying the cost of LP shows that if the combined drug cost decreases from over $58,000 to less than $11,000 per cycle, this strategy would be cost-effective. Eliminating the HSU penalty for LP decreased the ICER $1.0 M while increasing the penalty to −0.20 increased the ICER to $3.7 M. ConclusionsLP is not cost-effective in patients with recurrent pretreated, MSS EC. A dramatic reduction in cost of LP is required for this novel strategy to be cost-effective.

Pembrolizumab in advanced recurrent endometrial cancer: A cost-effectiveness analysis

ObjectiveTo determine the cost-effectiveness of pembrolizumab in patients with recurrent endometrial cancer that have failed first-line chemotherapy. MethodsWe created a model to evaluate the cost-effectiveness of pembrolizumab compared to pegylated liposomal doxorubicin (PLD) or bevacizumab for the treatment of women with recurrent endometrial cancer who have failed carboplatin and paclitaxel. Microsatellite instability-high (MSI-H) and non-microsatellite instability-high (non-MSI-H) tumors were evaluated. We included 4400 patients in the model; 800 patients were assumed to have MSI-H tumors. Drug costs were calculated using 2016–2017 wholesale acquisition costs, and cost of Grade III-IV toxicities was estimated from clinical experience. Effectiveness was calculated as 2-year overall survival (OS). We calculated incremental cost-effectiveness ratios (ICERs) to determine the cost per 2-year survivor. Univariate sensitivity analyses were performed. The willingness to pay threshold was $100,000 per year of OS. ResultsThe cost of therapy with PLD and bevacizumab were $33.2 million (M) and $167.9 M, respectively. The cost of pembrolizumab therapy was $318.3 M for non-MSI-H patients compared to $57.9 M for MSI-H patients. For non-MSI-H patients, bevacizumab was cost-effective relative to PLD with an ICER of $153,028, while pembrolizumab was not cost-effective relative to bevacizumab with an ICER of $341,830. For MSI-H patients, pembrolizumab was cost-effective compared to PLD with an ICER of $147,249, while bevacizumab was subjected to extended dominance. Sensitivity analysis revealed that for non-MSI-H patients, one cycle of pembrolizumab would need to cost $7253 or less to be cost-effective. ConclusionsFor patients with MSI-H recurrent endometrial cancers who have failed first-line chemotherapy, pembrolizumab is cost-effective relative to other single agent drugs. To be cost-effective in non-MSI-H patients, the cost of pembrolizumab should decrease substantially.

Pembrolizumab in advanced recurrent endometrial cancer: A cost-effectiveness analysis

Objective: To determine the cost-effectiveness of pembrolizumab, a PD-L1 antibody, in recurrent endometrial cancer that has failed first-line chemotherapy in women with (MSI-H) and without (MSI-L) microsatellite instability.

Long-term remission of an advanced recurrent endometrial cancer in a heavily pretreated patient using a combined regimen with bevacizumab and metronomic cyclophosphamide

The treatment of advanced endometrial cancer remains a challenge and the range of valuable treatments remains limited. Recently, the monoclonal vascular endothelial growth factor--antibody bevacizumab as a single-agent regimen or in combination with different chemotherapeutic approaches has been approved as a therapeutic option for several solid tumors. First, clinical trials evaluating the use of bevacizumab in endometrial cancers have been completed, but the results have not been published yet. A 59-year-old patient with advanced recurrent endometrial cancer presented at our institution suffering from increasing abdominal discomfort. She had been extensively pretreated using radiotherapeutic approaches and multiple chemotherapeutic regimens. The level of cancer antigen 125 (CA 125) was rising and a cystic pelvic mass was detected, consistent with a persistent local tumor relapse. As several cytotoxic treatment attempts had failed, we decided to induce a combined therapy with bevacizumab (intravenously) and metronomic cyclophosphamide (orally) as an individual treatment option. After 6 weeks of treatment, the patient's abdominal complaints had completely disappeared, CA 125 had decreased significantly to nearly baseline levels, and the previously detected cystic pelvic mass could no longer be seen. No significant side effects could be observed besides a mild fatigue. During the following weeks, CA 125 levels continued to decrease, and the patient experienced a long-time remission in fine condition for 10 months before PD. Bevacizumab in combination with metronomic cyclophophamide can be a well-tolerated salvage treatment option for patients with advanced, heavily pretreated recurrent endometrial cancer that exacts further evaluation within clinical trials.

Phase II study of oral ridaforolimus in patients with metastatic and/or locally advanced recurrent endometrial cancer: NCIC CTG IND 192.

5013 Background: Loss of PTEN function occurs in 26-83% of endometrial carcinomas (EC) leading to deregulation of PI3K/AKT/mTOR signaling. Intravenous (IV) inhibitors of mTOR have demonstrated activity in advanced EC. Ridaforolimus is an orally administered analog of rapamycin that inhibits mTOR. Methods: NCIC CTG conducted a 2-stage phase II study to assess the activity (objective response) of ridaforolimus in women with measurable EC. Prior hormonal therapy, radiotherapy and adjuvant chemotherapy were allowed. Patients (pts) received ridaforolimus 40 mg PO daily x 5 days per week in 4 week cycles. Tumor response was assessed every 2 cycles. Results: 35 pts were enrolled; 1 pt cancelled without receiving treatment. Of the remaining 34, 33 are now evaluable for safety and 26 for response. Follow-up is ongoing. 11 pts had received prior chemo-, 7 hormonal and 22 radio-therapy. Median age was 63 (range 43-89) yrs; 7 pts had adenocarcinoma, 21 endometrioid, 4 serous and 2 mixed histology. 113 (range 1-13) cy...

A phase II study of temsirolimus (CCI-779) in patients with metastatic and/or locally advanced recurrent endometrial cancer previously treated with chemotherapy: NCIC CTG IND 160b

5516 Background: Loss of PTEN function occurs in 26–80% of endometrial carcinomas and leads to deregulated PI3K/Akt/mTOR signalling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation and cell cycle progression. Inhibition of mTOR with temsirolimus, an ester derivative of rapamycin, has demonstrated promising activity, irrespective of PTEN loss, in chemotherapy naive endometrial cancer with an objective response rate of 21% and prolonged stable disease in 48%. This trial was designed to assess the level of activity in patients who had previously received chemotherapy. Methods: A single stage phase II study of temsirolimus in women with chemotherapy treated, recurrent or metastatic endometrial cancer has been completed, at a dose of 25mg i.v. weekly. 27 eligible patients have been enrolled and archival specimens of tumour have been collected for PTEN immunohistochemistry analysis. Thirteen had received prior radiation and 10 hormonal therapy...