Search

Purpose: Lenvatinib and pembrolizumab (LEN+PEMBRO) demonstrated clinically meaningful and statistically significant improvements in efficacy versus treatment of physician's choice (TPC) in patients with advanced endometrial cancer (aEC) in the phase 3 Study 309/KEYNOTE-775. Health-related quality-of-life (HRQoL) is reported. Patients and Methods: Patients were randomly assigned to receive LEN+PEMBRO (n = 411; LEN 20 mg/day; PEMBRO 200 mg Q3W) or TPC (n = 416; doxorubicin 60 mg/m2 Q3W or paclitaxel 80 mg/m2 [weekly, 3 weeks on/1 week off]). Impact of treatment on HRQoL assessed by the global health status/quality of life (GHS/QoL) score of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) was a secondary objective; other scales of the Quality-of-Life Questionnaire (QLQ-C30), EORTC QLQ-Endometrial, 24 questions (EORTC QLQ-EN24), and EuroQoL 5 dimensions, 5 levels (EQ-5D-5L) were exploratory objectives. HRQoL was assessed on day 1 of each cycle. Completion/compliance, change from baseline, time to first and definitive deterioration were assessed. No multiplicity adjustments were applied for HRQoL endpoints. Results: The latest timepoint at which the predefined rates of completion (≥60%) and compliance (≥80%) were met was week 12. HRQoL at week 12 between treatment groups was generally similar. Time to first deterioration symptom scales favoured LEN+PEMBRO for QLQ-C30 dyspnoea, and QLQ-EN24 for poor body image, tingling/numbness, and hair loss; and TPC was favoured for QLQ-C30 pain, appetite loss, and diarrhoea, and QLQ-EN24 muscular pain. While the QLQ-C30 physical functional scale favoured TPC, other functional scales were generally similar between arms. Time to definitive deterioration favoured LEN+PEMBRO on most scales. Conclusion: HRQoL data from Study 309/KEYNOTE-775, with previously published efficacy and safety results, indicate that LEN+PEMBRO has an overall favourable benefit/risk profile versus TPC for the treatment of patients with aEC.

Background We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), define biallelic gPVs within tumors, and describe their associations with clinicopathologic features. Methods Germline assessment of at least 76 cancer predisposition genes was performed in patients with EC undergoing clinical tumor-normal Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing from January 1, 2015, to June 30, 2021. In patients with gPVs, biallelic alterations in ECs were identified through analysis of loss of heterozygosity and somatic PVs. Clinicopathologic variables were compared using nonparametric tests. Results Of 1625 patients with EC, 216 (13%) had gPVs, and 15 patients had 2 gPVs. There were 231 gPVs in 35 genes (75 [32%] high penetrance; 39 [17%] moderate penetrance; and 117 [51%] low, recessive, or uncertain penetrance). Compared with those without gPVs, patients with gPVs were younger (P = .002), more often White (P = .009), and less obese (P = .025) and had differences in distribution of tumor histology (P = .017) and molecular subtype (P Conclusions Of unselected patients with EC, 13% had gPVs, with 63% of gPVs in high-penetrance genes (MMR and homologous recombination) exhibiting biallelic inactivation, potentially driving cancer development. This supports germline assessment in EC given implications for treatment and cancer prevention.

Endometrial cancer (EC) is the most common gynecologic malignancy, with worldwide increasing incidence and disease-associated mortality. Although most patients with EC are diagnosed with early-stage disease, systemic treatment options for patients with advanced or recurrent EC have historically been limited. EC-focused clinical trials and the ensuing therapeutic landscape have expanded since The Cancer Genome Atlas (TCGA) identified 4 distinct EC subgroups associated with differential survival. This endeavor revolutionized our understanding of the genomic characterization of EC as well as molecular drivers of this heterogeneous malignancy, leading to precision oncology approaches to therapeutics and advancement in treatment options. This review describes the current status of and recent advancements in therapeutic options for patients with advanced and recurrent EC. The NCCN Guidelines for Uterine Neoplasms provide detailed recommendations regarding the diagnosis, workup, and management of EC.

Study 309/KEYNOTE-775 is a phase 3 open-label, randomized trial of lenvatinib plus pembrolizumab versus treatment of physician's choice (TPC) in patients with advanced endometrial cancer with progression after platinum-based therapy. Primary endpoints of superiority for lenvatinib plus pembrolizumab were met for progression-free survival (PFS) and overall survival (OS) in all-comers (ie, regardless of mismatch repair [MMR] status) and patients with MMR proficiency (pMMR). We present results for the Japanese subset. Patients were randomized to oral lenvatinib 20 mg/day plus intravenous pembrolizumab 200 mg every 3 weeks (Q3W; up to 35 cycles of pembrolizumab) or TPC (intravenous doxorubicin 60 mg/m

A complex relationship between adipose tissue and malignancy, involving an inflammatory response, has been reported. The goal of this work was to assess the prevalence of white adipose tissue (WAT) inflammation in patients with endometrial cancer (EC), and the association with circulating inflammation markers. Furthermore, the aim was to characterize the pathways activated in and the cell type composition of adipose tissue in patients with EC.Adipose tissue and blood samples were prospectively collected from 101 patients with EC at initial surgery. WAT inflammation was determined based on adipocytes surrounded by macrophages forming crown-like structures. Circulating levels of metabolic syndrome-associated and inflammatory markers were quantified. RNA-sequencing was performed on adipose samples (n = 55); differential gene expression, pathway, and cellular decomposition analyses were performed using state-of-the-art bioinformatics methods.WAT inflammation was identified in 46 (45.5%) of 101 EC patients. Dyslipidemia, hypertension, and diabetes mellitus were significantly associated with WAT inflammation (p .05). WAT inflammation was associated with greater body mass index (p .001) and higher circulating levels of leptin, high-sensitivity C-reactive protein, and interleukin-6, as well as lower levels of adiponectin and sex hormone-binding globulin (p .05). Transcriptomic analysis demonstrated increased levels of proinflammatory and pro-neoplastic-related gene expression in inflamed omental adipose tissue.WAT inflammation is associated with metabolic syndrome, obesity, and inflammatory markers, as well as increased expression of proinflammatory and proneoplastic genes.

Supplementary Fig 3

Supplementary Fig 2

Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody–drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy.Significance:T-DM1 is clinically effective in lung cancers with amplification of or mutations in ERBB2. This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy.See related commentary by Rolfo and Russo, p. 643.This article is highlighted in the In This Issue feature, p. 627

Supplementary Fig 5

Supplementary Table 1

Supplementary Fig 6

Supplementary Fig 4

Supplementary Legend

Progression-free survival and hazard ratios by histology

Table S1. Plasma pharmacokinetic sampling times Table S2. Identified Alterations, Listed by Patient Table S3. Adverse events reported in {greater than or equal to}10% of patients (safety cohort) Table S4. Grade 3 to 5 adverse events reported in >1 patient (safety cohort) Table S5. Evaluation of Best Overall Response in Patients with Initial Measurable Disease and Evaluable by CA-125 Figure S1. Geometric mean (standard deviation) plasma concentrations of binimetinib (top) and its metabolite AR00426032 (bottom) on cycle 1 days 7, 8, and 15: semi-logarithmic scale (pharmacokinetic set [30 mg BID binimetinib continuous]) Figure S2. Geometric mean (standard deviation) plasma concentrations of binimetinib (top) and its metabolite AR00426032 (bottom) on cycle 1 days 7, 8, and 15: semi-logarithmic scale (pharmacokinetic set [45 mg BID binimetinib continuous]) Figure S3. Geometric mean (standard deviation) plasma concentrations of binimetinib (top) and its metabolite AR00426032 (bottom) on cycle 1 days 1, 8, and 15: semi-logarithmic scale (pharmacokinetic set [45 mg BID binimetinib intermittent]) Figure S4. Representative CT Resolution of Implant in a Complete Responder

SUPPLEMENTARY TABLES Supplementary Table 1. Treatment-emergent grade 3/4 adverse events in the safety population (n=116) Supplementary Table 2. MEDI3617 pharmacokinetic parameters Supplementary Table 3. Treatment outcome: objective response and progression-free survival, by cohort

Development of diffuse telangiectasias (highlighted by blue arrows) occurred on the upper chest, back, and face in a patient with ovarian granulosa cell tumor treated at the 0.75 mg/kg Q2W dose of STM 434.

Purpose:Advanced-stage endometrial cancers have limited treatment options and poor prognosis, highlighting the need to understand genetic drivers of therapeutic vulnerabilities and/or prognostic predictors. We examined whether prospective molecular characterization of recurrent and metastatic disease can reveal grade and histology-specific differences, facilitating enrollment onto clinical trials.Experimental Design:We integrated prospective clinical sequencing and IHC data with detailed clinical and treatment histories for 197 tumors, profiled by MSK-IMPACT from 189 patients treated at Memorial Sloan Kettering Cancer Center.Results:Patients had advanced disease and high-grade histologies, with poor progression-free survival on first-line therapy (PFS1). When matched for histology and grade, the genomic landscape was similar to that of primary untreated disease profiled by TCGA. Using multiple complementary genomic and mutational signature-based methods, we identified patients with microsatellite instability (MSI), even when standard MMR protein IHC staining failed. Tumor and matched normal DNA sequencing identified rare pathogenic germline mutations in BRCA2 and MLH1. Clustering the pattern of DNA copy-number alterations revealed a novel subset characterized by heterozygous losses across the genome and significantly worse outcomes compared with other clusters (median PFS1 9.6 months vs. 17.0 and 17.4 months; P = 0.006). Of the 68% of patients harboring potentially actionable mutations, 27% were enrolled to matched clinical trials, of which 47% of these achieved clinical benefit.Conclusions:Prospective clinical sequencing of advanced endometrial cancer can help refine prognosis and aid treatment decision making by simultaneously detecting microsatellite status, germline predisposition syndromes, and potentially actionable mutations. A small overall proportion of all patients tested received investigational, genomically matched therapy as part of clinical trials.

Additional clinical information for patients in MSKCC cohort

Purpose:STM 434 is a soluble receptor ligand trap targeting activin A, a protein in the TGFβ family that plays important roles in growth, differentiation, and cancer cachexia. This study evaluated the safety, antitumor activity, and metabolic effects of STM 434 in a first-in-human, multicenter, phase I clinical trial (NCT02262455).Patients and Methods:Patients with advanced solid tumors were enrolled in 8 dose cohorts ranging from 0.25 mg/kg every 4 weeks to 8 mg/kg every 2 weeks via a 3 + 3 dose-escalation design. The primary endpoint was maximum tolerated dose (MTD). Secondary endpoints included safety, pharmacokinetics, and response. As activin A is implicated in metabolism and muscle function, changes in key metabolic parameters, including lean body mass and 6-minute walk test, were serially measured.Results:Thirty-two patients were treated on study. The most common treatment-related adverse events were fatigue (41%) and mucocutaneous bleeding complications including epistaxis (34%) and gingival bleeding (22%), likely related to off-target inhibition of bone morphogenetic protein 9 (BMP9). STM 434 treatment resulted in the expected follicle-stimulating hormone level decreases in most patients and in metabolic parameter changes, including an increase in total lean body mass and 6-minute walk test distance. No responses were observed in the 30 evaluable patients, but the stable disease rate in patients with granulosa cell ovarian cancer was 10 of 12 (80%).Conclusions:Although no direct antitumor efficacy was documented, potentially clinically meaningful dose-related metabolic effects, including treatment of cancer cachexia, were observed that support further exploration of activin A inhibitors that limit BMP9 blockade.See related commentary by Bonilla and Oza, p. 5432

Change and end of treatment values for albumin, hemoglobin, and absolute lymphocytes among the 32 patients are summarized below. Abbreviations: SD, stable disease.

Purpose: This first-in-human study aimed to determine the MTD and safety of MEDI3617, a selective anti–angiopoietin-2 (Ang2) mAb, alone and combined with bevacizumab or cytotoxic chemotherapy.Patients and Methods: This phase I/Ib, multicenter, open-label, dose-escalation and dose-expansion study evaluated patients with advanced solid tumors. Patients received intravenous MEDI3617 as monotherapy [5–1,500 mg every 3 weeks (Q3W)] or with bevacizumab every 2 weeks (Q2W) or Q3W, weekly paclitaxel, or carboplatin plus paclitaxel Q3W. Dose expansions included a monotherapy cohort in platinum-resistant ovarian cancer and a bevacizumab combination cohort in bevacizumab-refractory malignant glioma. Safety/tolerability, pharmacokinetics, pharmacodynamics, and clinical activity were assessed.Results: We enrolled 116 patients. No formal MTD was identified (monotherapy or combination therapy). MEDI3617 demonstrated linear pharmacokinetics and maximal accumulation of peripheral Ang2 binding at doses above 300 mg Q3W. MEDI3617 monotherapy safety profile was acceptable, except in advanced ovarian cancer [prolonged grade 3 edema-associated adverse events (AE) occurred]. Otherwise, MEDI3617 combined with chemotherapy or bevacizumab was well tolerated. The AE profiles of MEDI3617 and bevacizumab were largely non-overlapping. Overall response rates in ovarian cancer and glioma monotherapy dose-expansion arms were 6% and 0%, respectively.Conclusions: Recommended MEDI3617 monotherapy dosage is 1,500 mg Q3W or 1,000 mg Q2W, except in ovarian cancer. Although peripheral edema has occurred with other Ang2 inhibitors, the severity and duration seen here in ovarian cancer potentially identifies a new, clinically significant safety signal for this class of agents. On the basis of limited clinical activity, MEDI3617 development was discontinued. Clin Cancer Res; 24(12); 2749–57. ©2018 AACR.

Supplementary Table and Figure Legends

Purpose: Epithelial ovarian cancer (EOC) is a molecularly diverse disease. MEK inhibition targets tumors harboring MAPK pathway alterations and enhances paclitaxel-induced apoptosis in EOC. This phase Ib study evaluated the MEK inhibitor binimetinib combined with paclitaxel in patients with platinum-resistant EOC.Patients and Methods: Patients received intravenous weekly paclitaxel with oral binimetinib in three different administration schedules. Outcomes were assessed by RECIST and CGIC CA-125 response criteria. Tumor samples were analyzed using next-generation sequencing.Results: Thirty-four patients received ≥1 binimetinib dose. A 30-mg twice-a-day continuous or 45-mg twice-a-day intermittent binimetinib dose was deemed the recommended phase II dose (RP2D) in combination with 80 mg/m2 i.v. weekly paclitaxel. Rate of grade 3/4 adverse events was 65%. The best overall response rate was 18%—one complete (CR) and four partial responses (PR)—among 28 patients with RECIST-measurable disease. Eleven patients achieved stable disease (SD), yielding a clinical benefit rate (CR+PR+SD) of 57%. Response rates, per both RECIST and CA-125 criteria, were highest in the 45-mg twice-a-day continuous cohort and lowest in the 45-mg twice-a-day intermittent cohort. All four evaluable patients with MAPK pathway–altered tumors experienced clinical benefit.Conclusions: The combination of binimetinib and intravenous weekly paclitaxel was tolerable in this patient population. The RP2D of binimetinib in combination with paclitaxel was 30 mg twice a day as a continuous or 45 mg twice a day as an intermittent dose. Although response rates were modest, a higher clinical benefit rate was seen in patients harboring alterations affecting the MAPK pathway. Clin Cancer Res; 24(22); 5525–33. ©2018 AACR.

OBJECTIVE: To assess survival among patients diagnosed with uterine carcinosarcoma (CS) who underwent sentinel lymph node (SLN) biopsy alone vs. systematic lymph node dissection (LND). METHODS: We identified newly diagnosed CS patients who underwent primary surgical management from January 1996–December 2019. The SLN cohort underwent SLN biopsy alone with bilateral SLNs identified. The systematic LND cohort did not undergo SLN biopsy. RESULTS: Ninety-nine patients underwent SLN biopsy, and 100 patients underwent systematic LND. There was no difference by age, stage, body mass index, myoinvasion (

Lenvatinib is an oral multitargeted tyrosine kinase inhibitor that has shown efficacy and manageable safety across multiple cancer types. The recommended starting doses for lenvatinib differ across cancer types and indications based on whether it is used as monotherapy or as combination therapy.This review covers clinical trials that established the dosing paradigm and efficacy of lenvatinib and defined its adverse-event profile as a monotherapy; or in combination with the mTOR inhibitor, everolimus; or the anti-PD-1 antibody, pembrolizumab; and/or chemotherapy.Lenvatinib has been established as standard-of-care either as a monotherapy or in combination with other anticancer agents for the treatment of radioiodine-refractory differentiated thyroid carcinoma, hepatocellular carcinoma, renal cell carcinoma, and endometrial carcinoma, and is being investigated further across several other tumor types. The dosing and adverse-event management strategies for lenvatinib have been developed through extensive clinical trial experience. Collectively, the data provide the rationale to start lenvatinib at the recommended doses and then interrupt or dose reduce as necessary to achieve required dose intensity for maximized patient benefit. The adverse-event profile of lenvatinib is consistent with that of other tyrosine kinase inhibitors, and clinicians are encouraged to review and adopt relevant symptom-management strategies.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The open-label phase Ib/II Study 111/KEYNOTE-146 of daily lenvatinib 20 mg plus pembrolizumab 200 mg once every 3 weeks showed promising efficacy and tolerable safety in patients with previously treated advanced endometrial carcinoma (EC; primary data cutoff date: January 10, 2019). This updated analysis reports long-term follow-up efficacy and safety data from 108 patients with previously treated EC included in the primary analysis. End points included objective response rate, duration of response, progression-free survival, overall survival, and safety. Investigators performed tumor assessments per immune-related RECIST. At the updated data cutoff date (August 18, 2020), the median study follow-up duration was 34.7 months (95% CI, 30.9 to 41.2), the objective response rate was 39.8% (95% CI, 30.5 to 49.7), and the median duration of response was 22.9 months (95% CI, 10.2 to not estimable). The median progression-free survival and overall survival were 7.4 months (95% CI, 5.2 to 8.7) and 17.7 months (95% CI, 15.5 to 25.8), respectively. Treatment-related treatment-emergent adverse events of any grade occurred in 104 (96.3%) patients. The most common grade ≥ 3 treatment-related treatment-emergent adverse events were hypertension (33.3%), elevated lipase (9.3%), fatigue (8.3%), and diarrhea (7.4%). The results demonstrate extended efficacy and tolerability of lenvatinib plus pembrolizumab in this cohort of patients with previously treated advanced EC.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We report the final prespecified analysis for overall survival (OS), along with updated progression-free survival (PFS) and objective response rate (ORR), and safety from the open-label, randomized, phase III Study 309/KEYNOTE-775. In total, 827 patients with advanced, recurrent, or metastatic endometrial cancer (EC) were randomly assigned to receive lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously once every 3 weeks (n = 411) or chemotherapy of the treating physician's choice (doxorubicin 60 mg/m2 intravenously once every 3 weeks or paclitaxel 80 mg/m2 intravenously once weekly [3 weeks on; 1 week off] [n = 416]). Efficacy was reported for patients with mismatch repair proficient (pMMR) tumors and all-comers, and by subgroups (histology, prior therapy, MMR status). Updated safety was also reported. Lenvatinib plus pembrolizumab showed benefits in OS (pMMR HR, 0.70; 95% CI, 0.58 to 0.83; all-comer HR, 0.65; 95% CI, 0.55 to 0.77), PFS (pMMR HR, 0.60; 95% CI, 0.50 to 0.72; all-comer HR, 0.56; 95% CI, 0.48 to 0.66), and ORR (pMMR patients, 32.4% v 15.1%; all-comers, 33.8% v 14.7%) versus chemotherapy. OS, PFS, and ORR favored lenvatinib plus pembrolizumab in all subgroups of interest. No new safety signals were observed. Lenvatinib plus pembrolizumab continued to show improved efficacy versus chemotherapy and manageable safety in patients with previously treated advanced EC.

Endometrial carcinosarcoma is a rare and aggressive high-grade endometrial carcinoma with secondary sarcomatous trans-differentiation (conversion theory). The clinical presentation and diagnostic work-up roughly align with those of the more common endometrioid counterpart, although endometrial carcinosarcoma is more frequently diagnosed at an advanced stage. Endometrial carcinosarcoma is not a single entity but encompasses different histological subtypes, depending on the type of carcinomatous and sarcomatous elements. The majority of endometrial carcinosarcomas are characterized by p53 abnormalities. The proportion ofPOLEand microsatellite instablity-high (MSI-H) is directly related to the epithelial component, being approximately 25% and 3% in endometrioid and non-endometrioid components.The management of non-metastatic disease is based on a multimodal approach with optimal surgery followed by (concomitant or sequential) chemotherapy and radiotherapy, even for early stages. Palliative chemotherapy is recommended in the metastatic or recurrent setting, with carboplatin/paclitaxel doublet being the first-line regimen. Although the introduction of immunotherapy plus/minus a tyrosine kinase inhibitor shifted the paradigm of treatment of patients with recurrent endometrial cancer, patients with endometrial carcinosarcoma were excluded from most studies evaluating single-agent immunotherapy or the combination. However, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved the use of pembrolizumab and lenvatinib in endometrial cancer (all histotypes) after progression on chemotherapy and single-agent immunotherapy in MSI-H cancers. In the era of precision medicine, emerging knowledge on molecular endometrial carcinosarcoma is opening new promising therapeutic options for more personalized treatment. The present review outlines state-of-the-art knowledge and future directions for patients with endometrial carcinosarcoma.