lenvatinib and Endometrial-Neoplasms

Endometrial cancer is the most common gynecological disease in developed countries. Although it is considered an indolent disease, advanced and recurrent endometrial carcinomas are characterized by poor prognosis. In the metastatic setting, after the failure of first-line platinum-based chemotherapy, patients have limited therapeutic options. However, endometrial cancer should not be considered as a single entity but as a group of heterogeneous diseases with specific genomic, molecular, and biological features by suggested the analysis of The Cancer Genome Atlas (TCGA). Accumulating data highlighted the effectiveness and safety of the adoption of immune checkpoint inhibitors (ICIs) for several types of solid tumors. In particular, immunotherapy showed promising results in MSI-H/dMMR solid tumors. Endometrial cancer is not an exception. Endometrial cancer has the highest prevalence of MSI across human cancer types, and approximately 30% of primary endometrial cancers are MSI-H/dMMR and 13% to 30% of recurrent endometrial cancers are MSI-H/dMMR. The preliminary results of the KEYNOTE-158, the Australian NCT03015129 and the GARNET trial strongly supported the adoption of ICIs as monotherapy in patients with advanced or recurrent endometrial cancer, after the failure of first-line treatments. Unfortunately, those impressive results are not achieved in patients with MMR proficient disease. Hence, other combinations were tested. In particular, the adoption of ICIs plus tyrosine kinase inhibitors (TKI) showed very compelling results. Recently, the updated results of the KEYNOTE-775 showed that pembrolizumab plus lenvatinib led to significantly longer progression-free and overall survival than chemotherapy among patients with advanced endometrial cancer, irrespective of MMR status. After EMA approval, pembrolizumab plus lenvatinib represents the new standard second-line treatment in endometrial cancer patients, regardless MMR status. Further studies are investigating the role of ICIs and TKIs in the first line and are testing new combinations (e.g. ICIs plus PARP inhibitors).

Topics: Australia; Colorectal Neoplasms; DNA Mismatch Repair; Endometrial Neoplasms; Female; Humans; Immunotherapy; Microsatellite Instability; Neoplasm Recurrence, Local

Advanced and recurrent endometrial carcinoma remains a difficult diagnosis to treat due to the limited and ineffective available treatment options following platinum and taxane chemotherapy. Patients who are microsatellite stable (MSS) or mismatch repair proficient (pMMR) have even poorer outcomes with fewer effective therapies. Fortunately, recent Phase Ib/II and Phase III trials have demonstrated that combination pembrolizumab and lenvatinib resulted in improved ORR, PFS, and OS than currently used therapies in this setting.. In this article, we review the history and notable clinical trials responsible for the advancement and status of treatment options available for advanced endometrial cancer. Most importantly, we review the recently published data on the efficacy, safety, and tolerability of the combination pembrolizumab and lenvatinib in advanced and recurrent endometrial cancer.. The combination pembrolizumab and lenvatinib is an effective treatment regimen for patients with advanced and recurrent endometrial cancer who are MSS or pMMR who have failed prior platinum-based treatment. This combination should be routinely offered to patients following progression or recurrence of systemic platinum and taxane chemotherapy. Although this regimen is safe and effective, clinicians should be aware of the known toxicities and assess patients regularly to determine if dose modifications or interruptions are indicated.

Topics: Antineoplastic Combined Chemotherapy Protocols; Endometrial Neoplasms; Female; Humans; Neoplasm Recurrence, Local; Phenylurea Compounds; Quinolines; Taxoids

The purpose of this article is to review the pharmacology, safety, evidence for current use, and potential futures uses for combination therapy with pembrolizumab and lenvatinib.. A literature review was carried out through PubMed to identify ongoing trials evaluating use, efficacy, and safety of combination pembrolizumab and lenvatinib. NCCN guidelines were utilized to identify current approved uses in therapy and medication package inserts were used to identify pharmacology and preparation requirements.. A total of five completed clinical trials and two ongoing trials were evaluated for use and safety of pembrolizumab with lenvatinib. Data suggests that combination therapy with pembrolizumab and lenvatinib can be used first line for clear cell renal carcinoma in patients with favorable risk or intermediate/poor risk and in endometrial carcinoma as a preferred second-line regimen for recurrent or metastatic disease for biomarker-directed systemic therapy in non-MSI-H/non-dMMR tumors. This combination may have potential for use in unresectable hepatocellular carcinoma and gastric cancer.. Use of non-chemotherapy containing regimens spare patients from extended durations of myelosuppression and reduce the risk of infection. Additionally, pembrolizumab with lenvatinib demonstrates efficacy as first line treatment in clear cell renal carcinoma, second line in endometrial carcinoma, and several potential uses on the horizon.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Endometrial Neoplasms; Female; Humans; Kidney Neoplasms; Phenylurea Compounds; Quinolines

On September 17, 2019, FDA granted accelerated approval to pembrolizumab plus lenvatinib for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation. The submission and review of this application was conducted through an FDA Oncology Center of Excellence initiative named Project Orbis whereby the FDA, the Australian Therapeutic Goods Administration, and Health Canada were able to simultaneously review and collaborate, rendering simultaneous approval decisions in all countries. Accelerated approval of the pembrolizumab plus lenvatinib combination was based on a single-arm trial of 94 patients, with previously treated metastatic endometrial cancer whose tumors were not MSI-H/dMMR. Efficacy was demonstrated on the basis of an objective response rate of 38.3% (95% confidence interval, 28.5%-48.9%) with 10 complete responses (10.6%) accompanied by supportive durations of response. Trials to confirm clinical benefit of this combination are ongoing. Here, we summarize the benefit-risk analysis supporting accelerated approval of the pembrolizumab plus lenvatinib combination and describe the methodology for the first Project Orbis review.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Australia; Canada; Drug Approval; Endometrial Neoplasms; Female; Humans; Microsatellite Instability; Phenylurea Compounds; Quinolines; United States; United States Food and Drug Administration

Changes in molecular classification together with a deeper knowledge of both immune disregulation and phosphatidylinositol-3 kinase (PI3K) pathway alterations are leading to a new endometrial cancer treatment paradigm. This review will address the cutting-edge data in this field.. This article will cover the updated data in endometrial cancer molecular classification and its correlation with the outcomes in randomized clinical trials (e.g., PORTEC-3). Moreover, we will review the latest data regarding checkpoint blockade molecules (CPB) in the recurrent setting and how they are changing the treatment landscape. In addition, the role of the PI3K inhibitors, their activity, and toxicity profile will be described.. As result of the incorporation of molecular classification in our daily practice, the adjuvant treatment in endometrial cancer is rapidly evolving and leading to a new paradigm. The promising data observed with CPB in the recurrent setting have led to the food and drug administration approval of pembrolizumab as monotherapy and in combination with lenvatinib. Additionally, the current outcomes achieved with PI3K inhibitor agents encourage us to continue our clinical research to identify those patients who may benefit the most.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Class I Phosphatidylinositol 3-Kinases; Clinical Trials as Topic; Endometrial Neoplasms; Female; Humans; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Randomized Controlled Trials as Topic; Signal Transduction

Topics: Antibodies, Monoclonal, Humanized; Endometrial Neoplasms; Female; Humans; Phenylurea Compounds

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

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Carcinoma; Clinical Trials, Phase III as Topic; Endometrial Neoplasms; Female; Humans; Neoplasm Recurrence, Local; Phenylurea Compounds; Quinolines; Randomized Controlled Trials as Topic

Standard therapy for advanced endometrial cancer after failure of platinum-based chemotherapy remains unclear.. In this phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced endometrial cancer who had previously received at least one platinum-based chemotherapy regimen to receive either lenvatinib (20 mg, administered orally once daily) plus pembrolizumab (200 mg, administered intravenously every 3 weeks) or chemotherapy of the treating physician's choice (doxorubicin at 60 mg per square meter of body-surface area, administered intravenously every 3 weeks, or paclitaxel at 80 mg per square meter, administered intravenously weekly [with a cycle of 3 weeks on and 1 week off]). The two primary end points were progression-free survival as assessed on blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival. The end points were evaluated in patients with mismatch repair-proficient (pMMR) disease and in all patients. Safety was also assessed.. A total of 827 patients (697 with pMMR disease and 130 with mismatch repair-deficient disease) were randomly assigned to receive lenvatinib plus pembrolizumab (411 patients) or chemotherapy (416 patients). The median progression-free survival was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 6.6 vs. 3.8 months; hazard ratio for progression or death, 0.60; 95% confidence interval [CI], 0.50 to 0.72; P<0.001; overall: 7.2 vs. 3.8 months; hazard ratio, 0.56; 95% CI, 0.47 to 0.66; P<0.001). The median overall survival was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 17.4 vs. 12.0 months; hazard ratio for death, 0.68; 95% CI, 0.56 to 0.84; P<0.001; overall: 18.3 vs. 11.4 months; hazard ratio, 0.62; 95% CI, 0.51 to 0.75; P<0.001). Adverse events of grade 3 or higher occurred in 88.9% of the patients who received lenvatinib plus pembrolizumab and in 72.7% of those who received chemotherapy.. Lenvatinib plus pembrolizumab led to significantly longer progression-free survival and overall survival than chemotherapy among patients with advanced endometrial cancer. (Funded by Eisai and Merck Sharp and Dohme [a subsidiary of Merck]; Study 309-KEYNOTE-775 ClinicalTrials.gov number, NCT03517449.).

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Endometrial Neoplasms; Female; Humans; Middle Aged; Phenylurea Compounds; Quinolines; Survival Analysis

The combination of lenvatinib plus pembrolizumab has shown efficacy in treatment of advanced endometrial carcinoma (that is not microsatellite instability-high or mismatch repair deficient) following prior systemic therapy in any setting in the open-label, single-arm, phase Ib/II Study 111/KEYNOTE-146. With the exception of hypothyroidism, the safety profile of the combination was comparable to that of each monotherapy. Given the medical complexity and fragility of patients with endometrial carcinoma, further characterization of adverse reactions (ARs) associated with treatment will help health care professionals to optimize treatment with lenvatinib plus pembrolizumab combination therapy.. In Study 111/KEYNOTE-146, patients received lenvatinib at a starting dose of 20 mg orally once daily and pembrolizumab 200 mg intravenously every 3 weeks. Selected ARs (hypertension, fatigue, nausea/vomiting, diarrhea, decreased appetite/weight loss, hypothyroidism, palmar-plantar erythrodysesthesia syndrome, musculoskeletal pain, stomatitis, and proteinuria) were chosen for detailed post hoc analyses.. Median times to first onset of the selected ARs in this analysis all occurred within the first 10 weeks of treatment. Of the selected ARs, grade ≥3 severity of fatigue, hypertension, and nausea occurred in ≥5% of patients. Overall incidence of hypothyroidism was 51%, primarily of grade 2 severity (46%). Most of the ARs assessed were managed with a combination of study drug dose modifications and concomitant medications.. No new safety signals were identified and the toxicity profile in this study was manageable with supportive medications, dose interruptions, and/or lenvatinib dose reductions. This analysis provides AR management guidance for patients with endometrial cancer receiving lenvatinib plus pembrolizumab combination therapy.. Lenvatinib plus pembrolizumab has shown efficacy in the treatment of patients with advanced endometrial carcinoma (that is, not microsatellite instability-high or mismatch repair deficient) following at least one prior systemic therapy in any setting. Patients may experience toxicity associated with this combination, including adverse reactions of hypertension, fatigue, nausea/vomiting, diarrhea, decreased appetite/weight loss, hypothyroidism, palmar-plantar erythrodysesthesia syndrome, musculoskeletal pain, stomatitis, and proteinuria. These adverse reactions may be managed with a combination of concomitant supportive care medications and judicious lenvatinib dose modifications. This article provides context and guidance for the recognition and management of adverse reactions in patients receiving lenvatinib plus pembrolizumab.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Endometrial Neoplasms; Female; Humans; Phenylurea Compounds; Quinolines

To estimate the maximally tolerated dose (MTD) and describe toxicities associated with lenvatinib and weekly paclitaxel in patients with recurrent endometrial and platinum resistant epithelial ovarian cancer.. Using a 3 + 3 design patients were given weekly paclitaxel 80 mg/m2 IV day 1, 8, 15 and oral levantinib daily on a 28-day cycle. Lenvatinib dose levels were 8 mg, 12 mg, 16 mg, 20 mg. Toxicities were recorded using CTCAE v4.03 and response was determined with imaging after cycle 2, then every 3rd cycle, using RECIST 1.1 criteria.. 26 patients were enrolled; 19 with ovarian cancer (14 high grade serous, 1 low grade serous, 2 clear cell, 1 endometrioid, and 1 carcinosarcoma), and 7 with endometrial cancer (3 serous, and 4 endometrioid). The MTD was established at lenvatinib 16 mg and weekly paclitaxel 80 mg/m2. Toxicities (all grades) occurring in ≥25% of patients included anemia, neutropenia, lymphopenia, mucositis, nausea, diarrhea, anorexia, hypertension, fatigue, proteinuria, epistaxis, hoarseness. Twenty-three patients were evaluable for response and PFS; 15 (65%) had a partial response, 7 (30%) stable, 1 (4%) progressive disease with an objective response rate of 65%; 71% in ovarian and 50% in endometrial cancer. Median progression free survival (PFS) is 12.4 months; 14.0 months in endometrial cancer, 7.2 months in ovarian cancer; 54% had a PFS > 6 months. The median duration of response for PR patients (n = 15) was 10.9 months.. The regimen was tolerable with manageable side effects. Encouraging activity was observed in endometrial and ovarian cancer, and warrants further development.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Ovarian Epithelial; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Endometrial Neoplasms; Fallopian Tube Neoplasms; Female; Genital Neoplasms, Female; Humans; Middle Aged; Ovarian Neoplasms; Paclitaxel; Peritoneal Neoplasms; Phenylurea Compounds; Quinolines

This study assessed the efficacy of lenvatinib, a multitargeted tyrosine kinase inhibitor, as second-line therapy in patients with unresectable endometrial cancer. The primary end point was the objective response rate (ORR) as assessed by independent radiologic review (IRR). Secondary end points included median progression-free survival (PFS), overall survival (OS), and clinical benefit rate. Exploratory end points examined the association of baseline levels of plasma biomarkers (50 circulating cytokine and/or angiogenic factors measured by immunoassays) with efficacy outcomes.. An international, open-label, single-arm, multicenter, phase 2 trial was conducted. Eligible patients had histologically confirmed unresectable endometrial cancer that relapsed after 1 prior systemic platinum-based chemotherapy. Patients received once-daily oral lenvatinib 24 mg in a 28-day dosing cycle.. There were 133 patients in the study. By IRR, 19 patients had a confirmed objective response for an ORR of 14.3% (95% CI: 8.8-21.4). Durable stable disease (≥23 weeks) was observed in 31 patients (23.3%) and the clinical benefit rate was 37.6% (95% CI: 29.3-46.4). Median PFS was 5.6 months (95% CI: 3.7-6.3), and median OS was 10.6 months (95% CI: 8.9-14.9). The most common (any grade) treatment-related adverse events were fatigue/asthenia (48%), hypertension (49%), nausea/vomiting (32%), decreased appetite (32%), and diarrhea (31%). Lower baseline levels of angiopoietin-2 were associated with longer PFS, OS, and a higher ORR.. Patients with recurrent endometrial cancer treated with second-line lenvatinib experienced modest antitumor activity and treatment was generally well tolerated, with a safety profile consistent with previous studies.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Endometrial Neoplasms; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Neoplasm Recurrence, Local; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Survival Rate

Modulation of vascular endothelial growth factor-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. We report results from the dose-finding and initial phase II expansion of a phase Ib/II study of lenvatinib plus pembrolizumab in patients with selected advanced solid tumors.. Eligible patients had metastatic renal cell carcinoma (RCC), endometrial cancer, squamous cell carcinoma of the head and neck (SCCHN), melanoma, non-small-cell lung cancer (NSCLC), or urothelial cancer. The primary objective of phase Ib was to determine the maximum tolerated dose (MTD) for lenvatinib plus pembrolizumab (200 mg intravenously every 3 weeks). In the preplanned phase II cohort expansion, the primary objective was objective response rate at week 24 (ORR. Lenvatinib plus pembrolizumab demonstrated a manageable safety profile and promising antitumor activity in patients with selected solid tumor types.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cohort Studies; Endometrial Neoplasms; Female; Humans; Kidney Neoplasms; Male; Maximum Tolerated Dose; Melanoma; Middle Aged; Neoplasms; Phenylurea Compounds; Quinolines

Patients with advanced endometrial carcinoma have limited treatment options. We report final primary efficacy analysis results for a patient cohort with advanced endometrial carcinoma receiving lenvatinib plus pembrolizumab in an ongoing phase Ib/II study of selected solid tumors.. Patients took lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks, in 3-week cycles. The primary end point was objective response rate (ORR) at 24 weeks (ORR. Lenvatinib plus pembrolizumab showed promising antitumor activity in patients with advanced endometrial carcinoma who have experienced disease progression after prior systemic therapy, regardless of tumor MSI status. The combination therapy had a manageable toxicity profile.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Endometrial Neoplasms; Female; Humans; Microsatellite Instability; Middle Aged; Phenylurea Compounds; Progression-Free Survival; Quinolines; Time Factors

Lenvatinib is a multikinase inhibitor of VEGFR1, VEGFR2, and VEGFR3, and other receptor tyrosine kinases. Pembrolizumab, an antibody targeting PD-1, has moderate efficacy in biomarker-unselected endometrial cancer. We aimed to assess the combination of lenvatinib plus pembrolizumab in patients with advanced endometrial carcinoma, after establishing the maximum tolerated dose in a phase 1b study.. In this open-label, single-arm, phase 2 study done at 11 centres in the USA, eligible patients were aged 18 years or older and had metastatic endometrial cancer (unselected for microsatellite instability or PD-L1), had an Eastern Cooperative Oncology Group performance status of 0 or 1, had received no more than two previous systemic therapies, had measurable disease according to the immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and had a life expectancy of 12 weeks or longer. Patients received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks. Treatment continued until disease progression, development of unacceptable toxic effects, or withdrawal of consent. The primary endpoint of this interim analysis was the proportion of patients with an objective response at week 24 as assessed by investigators according to irRECIST in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT02501096.. Between Sept 10, 2015, and July 24, 2017, 54 patients were enrolled, 53 of whom were included in the analysis. At the cutoff date for anti-tumour activity data (Dec 15, 2017), median study follow-up was 13·3 months (IQR 6·7-20·1). 21 (39·6% [95% CI 26·5-54·0]) patients had an objective response at week 24. Serious treatment-related adverse events occurred in 16 (30%) patients, and one treatment-related death was reported (intracranial haemorrhage). The most frequently reported any-grade treatment-related adverse events were hypertension (31 [58%]), fatigue (29 [55%]), diarrhoea (27 [51%]), and hypothyroidism (25 [47%]). The most common grade 3 treatment-related adverse events were hypertension (18 [34%]) and diarrhoea (four [8%]). No grade 4 treatment-related adverse events were reported. Five (9%) patients discontinued study treatment because of treatment-related adverse events.. Lenvatinib plus pembrolizumab showed anti-tumour activity in patients with advanced recurrent endometrial cancer with a safety profile that was similar to those previously reported for lenvatinib and pembrolizumab monotherapies, apart from an increased frequency of hypothyroidism. Lenvatinib plus pembrolizumab could represent a new potential treatment option for this patient population, and is being investigated in a randomised phase 3 study.. Eisai and Merck.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Endometrial Neoplasms; Female; Humans; Middle Aged; Phenylurea Compounds; Progression-Free Survival; Protein Kinase Inhibitors; Quinolines; Time Factors; United States

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.

Topics: Antineoplastic Combined Chemotherapy Protocols; Endometrial Neoplasms; Female; Humans; Neoplasm Recurrence, Local; Platinum; Retrospective Studies

Recommendations for clinical practice Nice/Saint-Paul-de-Vence 2022-2023 : Management of advanced/relapsing endometrial cancer Since the first recommendations in 2020 concerning metastatic and/or relapsed endometrial cancer, new treatment options have shown a benefit on patients' life expectancy, justifying their update. In first line, the choice will be made between chemotherapy with carboplatin/paclitaxel or hormone therapy with progestin, depending on tumor characteristics (histological type, grade, expression of hormone receptors, rate of progression). In case of a dMMR tumors, the use of immunotherapy within the framework of a therapeutic trial is an option. Beyond first-line chemotherapy, current standard treatment consists of the combination of pembrolizumab and lenvatinib, regardless of MMR status. Close clinical and biological monitoring is however necessary given the potential toxicity. Chemotherapy retains its place either as monotherapy (paclitaxel or doxorubicin) in the event of failure or contraindication to pembrolizumab-lenvatinib, or in combination with carboplatin in the event of a long free interval and pMMR tumor. The numerous ongoing clinical trials evaluating new therapeutic targets or strategies adapted to molecular or histological types should allow further improvements the prognosis of patients with metastatic endometrial cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Clinical Trials as Topic; Endometrial Neoplasms; Female; Hormones; Humans; Paclitaxel

To evaluate adverse events (AEs) of combination lenvatinib plus pembrolizumab for the treatment of recurrent endometrial cancer (EC) and to assess outcomes by lenvatinib starting dose.. We retrospectively reviewed patients with recurrent EC treated with lenvatinib plus pembrolizumab at our institution between 10/1/2019-11/30/2021. Starting dose of lenvatinib was defined as standard (20 mg) or reduced (10 mg/14 mg). AEs were manually extracted through chart review and graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. PFS, overall survival (OS), and duration of response (DOR) were analyzed.. Forty-three patients were identified; median age was 67 years (range, 54-85). The most common histologies were serous (35%), endometrioid (23%), and carcinosarcoma (21%). Starting lenvatinib doses were 10 mg (n = 10), 14 mg (n = 10), and 20 mg (n = 23). Median number of cycles received was 8 (range, 1-42). Twenty-four patients (56%) required ≥1 lenvatinib dose reduction; 3 (7%) discontinued lenvatinib, and 1 (2%) discontinued pembrolizumab for intolerance or AE. Thirty-six patients (84%) experienced grade ≥ 3 AEs; hypertension, weight loss, anemia, fatigue, and thrombocytopenia were most common. The standard dose group experienced significantly shorter observed PFS vs the reduced dose group (P = .02). There was no difference in DOR (P = .09) or OS (P = .27) between the groups.. In clinical practice, AEs associated with combination lenvatinib plus pembrolizumab were common and comparable to Study 309/KEYNOTE-775 findings. AEs were similar regardless of starting lenvatinib dose. Further dose optimization studies of lenvatinib plus pembrolizumab may be indicated in recurrent EC. Clinical trial data remain the gold standard to guide starting lenvatinib dosing.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Endometrial Neoplasms; Female; Humans; Neoplasm Recurrence, Local; Phenylurea Compounds; Retrospective Studies

Topics: Antibodies, Monoclonal, Humanized; Endometrial Neoplasms; Female; Humans; Phenylurea Compounds; Quinolines

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Endometrial Neoplasms; Female; Humans; Phenylurea Compounds; Quinolines

To investigate the effectiveness and safety of pembrolizumab and lenvatinib (PEMBRO+LEN) for recurrent endometrial cancer (EC) in a real-world setting.. This multicenter retrospective cohort study included patients with recurrent EC who received PEMBRO+LEN between March 2020 and May 2021 at three tertiary hospitals in Korea. We summarized patient characteristics and evaluated the response rates, survival outcomes, and treatment-related adverse events (AEs).. In total, 48 patients were included in the study. The median age of the patients was 62.5 (range, 42-78) years. The most common histologic subtype was endometrioid adenocarcinoma (43.8%), followed by serous adenocarcinoma (25.0%). Most patients (91.7%) had mismatch repair-proficient tumors. Patients received PEMBRO+LEN for a median of 4.5 cycles, during which the best objective response rate and disease control rate were 23.8% (95% CI, 11.9-38.1) and 76.2% (95% CI, 61.9-88.1), respectively. Overall, 56.2% of patients experienced LEN dose reduction once or more and 16.7% experienced LEN interruption. The most common treatment-related AEs were fatigue (18.8%), hypertension (16.7%), and hypothyroidism (14.6%). Total of 8 patients (16.7%) discontinued LEN during the treatment because of treatment-related AEs. Serum CA-125 level was the only prognostic factor for progression-free survival (adjusted hazard ratio, 4.41; 95% confidence interval, 1.19-16.36; p = 0.03).. In our real-world study, Korean patients with recurrent EC who received PEMBRO+LEN showed lower treatment response rate and similar treatment discontinuation rate, compared to clinical trials.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Endometrial Neoplasms; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Phenylurea Compounds; Quinolines; Retrospective Studies

In the international, randomized, open-label, phase 3 study 309-KEYNOTE-775 trial, lenvatinib plus pembrolizumab (LP) showed improved progression-free survival (PFS) and overall survival (OS) compared with chemotherapy in pretreated patients with advanced endometrial cancer. This study aimed to investigate whether LP is cost-effective compared with chemotherapy.. The clinical data for this model was derived from the 309-KEYNOTE-775 trial. Costs and utilities were either derived from the standard fee database or extracted from previously published literature. A three-state Markov model was developed to simulate the disease process of patients with advanced endometrial cancer. One-way sensitivity analyses were conducted to investigate the impact of variables in the analysis model. Probabilistic sensitivity analysis was performed based on 10,000 Monte-Carlo simulations. A subgroup analysis was performed to test whether LP is cost-effective in patients with mismatch repair-proficient (pMMR) disease.. Lenvatinib plus pembrolizumab provided an incremental 0.64 quality-adjusted life years (QALYs) with an incremental cost of $241,278.18, compared with chemotherapy, resulting in the incremental cost-effectiveness ratio (ICER) of $378,251.44/QALY, which exceeded the willingness to pay (WTP) threshold. While in the pMMR subgroup, the ICER increased to $413,256.68/QALY. The variance of the utility of PFS state, the cost of LP, and the utility of the progressive disease state were the most influential factors in the sensitivity analysis.. Under the current WTP threshold, LP is not cost-effective compared with chemotherapy in pretreated patients with advanced endometrial cancer.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Cost-Benefit Analysis; Endometrial Neoplasms; Female; Humans; Phenylurea Compounds; Quinolines

In 2022, the KEYNOTE-775 (NCT03517449) study showed that pembrolizumab plus lenvatinib (PL) has more benefits than traditional chemotherapy as a first-line regimen to treat patients with mismatch repair-proficient (pMMR) advanced endometrial cancer (aEC). However, given the high cost of immuno-targeted therapy, the widespread use among patients remains uncertain. Therefore, we conducted a cost-effectiveness comparison between PL and chemotherapy.. We evaluated the cost-effectiveness of PL versus chemotherapy over 7 years by developing a comprehensive Markov model, included 697 patients, that calculated total cost, life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) at a willingness-to-pay (WTP) threshold of $150,000 per QALY. The robustness of the model was evaluated by one-way, two-way, and probabilistic sensitivity analyses. In addition, we also performed subgroup analyses.. Chemotherapy yielded a mean survival of 0.705 QALYs (0.901 LYs) per patient and was associated with a mean cost of $163,777. PL was associated with an incremental cost of $38,582 and an additional 0.349 QALYs, leading to an ICER of $110,401 per QALY as compared to chemotherapy. The cost of pembrolizumab had a significant impact on ICER. At the assumed WTP threshold of $150,000 per QALY, approximately 79.2% of simulations show cost-effectiveness occurs in PL. Results of the subgroup analysis showed that PL was the most cost-effective regimen for patients who had previously received 1-line of therapy.. For patients with pMMR aEC, the PL strategy may be the most cost-effective strategy at a WTP of $150,000 from the economic perspective of the United States.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; DNA Mismatch Repair; Endometrial Neoplasms; Female; Humans; Phenylurea Compounds; Quality-Adjusted Life Years; Quinolines; United States

Topics: Aged; Air; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Endometrial Neoplasms; Female; Humans; Phenylurea Compounds; Quinolines; Uterine Neoplasms

We reviewed our institutional data to evaluate toxicity and efficacy outcomes of pembrolizumab/lenvatinib in recurrent endometrial cancer in a "real-world" clinical setting and to compare the impact of reduced lenvatinib starting dose on outcomes.. Retrospectively, we reviewed toxicity, treatment responses, and survival outcomes of patients with recurrent endometrial cancer who received ≥1 cycle of pembrolizumab/lenvatinib. We compared subgroups based on lenvatinib starting dose (recommended [20 mg] vs reduced [<20 mg]) and histologic type.. We analyzed 70 patients (recommended dose cohort, n = 16; reduced dose cohort, n = 54). The most common starting dose was 14 mg daily. Compared to the reduced dose cohort, the recommended dose cohort had a significantly higher mean number of lenvatinib dose reductions due to side effects (1.1 vs. 0.4; p = 0.003) and significantly shorter median time to treatment toxicity (1.3 vs. 3.7 days; p = 0.0001). Response rates did not differ significantly between the recommended and reduced dose cohorts (28.6% vs. 38.3%, respectively; p = 0.752). Two patients, both in the reduced dose cohort, had complete responses. Patients with carcinosarcoma histology had response and clinical benefit rates of 25% (3 of 12) and 58.3% (7 of 12), respectively. There were no differences between the 2 dose cohorts with respect to progression-free (p = 0.245) or overall survival (p = 0.858).. In clinical practice, a lower starting dose of lenvatinib (14 mg daily) in combination with pembrolizumab was safe and efficacious in recurrent endometrial cancer. The combination produced responses in endometrial carcinosarcomas. Larger studies are required to validate these findings.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinosarcoma; Cohort Studies; Endometrial Neoplasms; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Neoplasm Recurrence, Local; Phenylurea Compounds; Quinolines; Retrospective Studies

To determine the cost effectiveness of pembrolizumab/lenvatinib (P/L) versus standard-of-care carboplatin/paclitaxel (C/T) as first-line systemic therapy for patients with advanced/recurrent endometrial cancer.. We designed a Markov model to simulate treatment outcomes for advanced/recurrent endometrial cancer patients whose tumors are either microsatellite stable (MSS) or have high microsatellite instability (MSI-high). We adopted a healthcare sector perspective for the analysis. Model inputs for costs, health utility, and clinical estimates were obtained from the literature including data from GOG0209 and KEYNOTE-146. Primary outcomes included costs of care, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER). The time-horizon was three years and the discount rate was 3% annually.. In a MSS cohort, compared to C/T, first-line treatment with P/L increased treatment costs by $212,670 and decreased QALYs by 0.28 per patient. In a MSI-high cohort, compared to C/T, P/L increased costs by $313,487 and increased QALYs by 0.11 per patient, representing an ICER of $2,849,882 per QALY. Sensitivity analyses found that the price of the new drugs was the most important determinant of the ICER and that the price of the new drugs would need to decrease by 85% to $2817 per cycle to reach a $150,000/QALY threshold.. In the MSS model, we found that first-line therapy for advanced or recurrent endometrial cancer with P/L increased costs and worsened outcomes compared to C/T. In the MSI-high model, P/L improved survival and QALYs compared to C/T but was not cost-effective at the current cost of the drugs.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cost-Benefit Analysis; Decision Trees; Drug Costs; Endometrial Neoplasms; Female; Humans; Markov Chains; Microsatellite Instability; Neoplasm Recurrence, Local; Neoplasm Staging; Paclitaxel; Phenylurea Compounds; Progression-Free Survival; Quality of Life; Quality-Adjusted Life Years; Quinolines

To determine the cost-effectiveness of lenvatinib plus pembrolizumab (LP) in patients with microsatellite stable (MSS), recurrent, pretreated endometrial cancer (EC).. 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 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.. Costs 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.. LP 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.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cost-Benefit Analysis; Decision Support Techniques; Doxorubicin; Drug Costs; Endometrial Neoplasms; Female; Humans; Microsatellite Repeats; Neoplasm Recurrence, Local; Phenylurea Compounds; Quinolines; United States

Topics: Antibodies, Monoclonal, Humanized; Endometrial Neoplasms; Female; Humans; Microsatellite Repeats; Phenylurea Compounds; Programmed Cell Death 1 Receptor; Quinolines; Vascular Endothelial Growth Factor A