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Tyrosine kinase inhibitors have shown activity in osteosarcoma and might enhance the efficacy of chemotherapy. We aimed to determine the recommended phase 2 dose and antitumour activity of lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma. This multicentre, open-label, multicohort, phase 1/2 trial was done at 17 hospitals in six countries. Eligible patients were aged 2–25 years, had relapsed or refractory osteosarcoma, measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors version 1.1, Lansky play–performance score or Karnofsky performance score of 50% or higher, up to one previous VEGF or VEGF receptor-targeted therapy, and a life expectancy of at least 3 months. This study includes a combination dose-finding phase 1 part (cohort 3A) and a phase 2 combination expansion in patients with osteosarcoma (cohort 3B). Lenvatinib was administered orally at a starting dose of 11 mg/m2 per day, capped at 24 mg per day, and etoposide (100 mg/m2 per day) plus ifosfamide (3000 mg/m2 per day) were administered intravenously on days 1–3 of each 21-day cycle for a maximum of five cycles. Lenvatinib monotherapy continued after these five cycles until disease progression, toxic effects, or patient choice to discontinue. The phase 1 primary endpoint was to determine the recommended phase 2 dose by evaluating dose-limiting toxicity and the phase 2 primary endpoint was progression-free survival at 4 months. Progression-free survival was measured in the full analysis set, which included all patients enrolled for efficacy outcomes; safety was assessed in all patients who received any study drug. This study is registered with ClinicalTrials.gov, NCT02432274. 30 patients were screened for enrolment into cohort 3A between May 9, 2016, and June 3, 2019, and 22 patients for enrolment into cohort 3B between Sept 13, 2018, and July 18, 2019. Eight patients from cohort 3A and two from cohort 3B were ineligible for enrolment in the study. In phase 1, dose-limiting toxicities were observed in three patients (one in the lenvatinib 11 mg/m2 combination group and two in the 14 mg/m2 combination group) and the recommended phase 2 dose was determined as lenvatinib 14 mg/m2 per day (with daily dose cap of 24 mg) and etoposide 100 mg/m2 per day plus ifosfamide 3000 mg/m2 per day administered intravenously on days 1–3 of each 21-day cycle for a maximum of five cycles. 35 patients from phase 1 (cohort 3A; n=15) and phase 2 (cohort 3B; n=20) were treated at the recommended phase 2 dose and their results were pooled. Progression-free survival at 4 months was 51% (95% CI 34–69) in 18 of 35 patients per the binomial estimate. The most common grade 3–4 treatment-emergent adverse events were neutropenia (27 [77%] of 35), thrombocytopenia (25 [71%]), anaemia (19 [54%]), and decreased white blood cell count (19 [54%]). 26 [74%] of 35 patients had serious treatment-emergent adverse events and no treatment-related deaths occurred. Lenvatinib with etoposide plus ifosfamide shows promising antitumour activity with no new safety signals in patients with refractory and relapsed osteosarcoma. These findings warrant further investigation in an ongoing randomised phase 2 study (NCT04154189). Eisai and Merck Sharp & Dohme.

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/m2 Q3W or paclitaxel 80 mg/m2 QW [3 weeks on/1 week off]). Primary endpoints were PFS by blinded independent central review per RECIST version 1.1 and OS. One hundred four patients were randomized in Japan (data cutoff, October 26, 2020; median follow‐up, 11.8 [range, 1.1–26.9] months). Hazard ratios (HRs) for PFS with lenvatinib plus pembrolizumab versus TPC were 1.04 (95% CI, 0.63–1.73) in patients with pMMR and 0.81 (0.50–1.31) in all‐comers. Hazard ratios for OS were 0.74 (0.41–1.34) with pMMR and 0.59 (0.33–1.04) for all‐comers. Adverse events were manageable and led to discontinuation of one/both study drugs in 36.5% of patients in the lenvatinib plus pembrolizumab group versus 7.8% in the TPC group. Similar to the global Study 309/KEYNOTE‐775 results, this analysis suggested favorable efficacy and manageable safety with lenvatinib plus pembrolizumab after platinum‐based chemotherapy in Japanese patients with advanced endometrial cancer and supports this combination as a new standard of care in this population. Study 309/KEYNOTE‐775 is a phase 3 open‐label, randomized trial of lenvatinib plus pembrolizumab versus treatment of physician’s choice in patients with advanced endometrial cancer with progression after platinum‐based therapy. We present results for the Japanese subset of this clinical trial. Similar to results from the global study, this analysis suggested favorable efficacy and manageable safety with lenvatinib plus pembrolizumab after platinum‐based chemotherapy in Japanese patients with advanced endometrial cancer and supports this combination as a new standard of care in this population.

BackgroundLenvatinib plus pembrolizumab demonstrated clinically meaningful benefit in patients with previously treated advanced endometrial carcinoma in Study 111/KEYNOTE-146 (NCT02501096). In these exploratory analyses from this study, we evaluated the associations between clinical outcomes and gene expression signature scores and descriptively summarized response in biomarker subpopulations defined by tumor mutational burden (TMB) and DNA variants for individual genes of interest.MethodsPatients with histologically confirmed metastatic endometrial carcinoma received oral lenvatinib 20 mg once daily plus intravenous pembrolizumab 200 mg every 3 weeks for 35 cycles. Archived formalin-fixed paraffin-embedded tissue was obtained from all patients. T-cell–inflamed gene expression profile (TcellinfGEP) and 11 other gene signatures were evaluated by RNA sequencing. TMB, hotspot mutations in PIK3CA (oncogene), and deleterious mutations in PTEN and TP53 (tumor suppressor genes) were evaluated by whole-exome sequencing (WES).Results93 and 79 patients were included in the RNA-sequencing-evaluable and WES-evaluable populations, respectively. No statistically significant associations were observed between any of the RNA-sequencing signature scores and objective response rate or progression-free survival. Area under the receiver operating characteristic curve values for response ranged from 0.39 to 0.54; all 95% CIs included 0.50. Responses were seen regardless of TMB (≥175 or <175 mutations/exome) and mutation status. There were no correlations between TcellinfGEP and TMB, TcellinfGEP and microvessel density (MVD), or MVD and TMB.ConclusionsThis analysis demonstrated efficacy for lenvatinib plus pembrolizumab regardless of biomarker status. Results from this study do not support clinical utility of the evaluated biomarkers. Further investigation of biomarkers for this regimen is warranted.Trial registration numberNCT02501096.

BackgroundLenvatinib is a multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT. Pembrolizumab is an anti-programmed death-1 monoclonal antibody. We previously reported results from a cohort of 108 patients with metastatic EC (data cutoff date, January 10, 2019) who received lenvatinib + pembrolizumab as part of an ongoing multicenter, open-label, phase 1b/2 study evaluating the combination treatment in patients with selected solid tumors (NCT02501096). Lenvatinib + pembrolizumab showed a tolerable safety profile and promising antitumor activity per immune-related (ir) Response Evaluation Criteria In Solid Tumors (RECIST) by investigator assessment, including an objective response rate (ORR) of 38.9% (95% confidence interval [CI], 29.7–48.7), median progression-free survival (PFS) of 7.4 months (95% CI, 5.3–8.7), and median overall survival (OS) of 16.7 months (95% CI, 15.0-not estimable).1 Here we present updated efficacy and safety data (data cutoff date: August 18, 2020).MethodsPatients included in the EC cohort had histologically confirmed, measurable metastatic EC and had received ≤2 prior chemotherapies (unless discussed with the sponsor). Patients received lenvatinib (20 mg orally once daily) and pembrolizumab (200 mg intravenously once every 3 weeks). The phase 2 efficacy endpoints included ORR, PFS, OS, and duration of response. Tumor assessments for primary and secondary endpoints were evaluated by investigators per irRECIST.ResultsThe 108 patients from the key efficacy analysis set for the previously reported results were all included in these updated analyses. Median follow-up duration for the study was 34.7 months. Efficacy outcomes are summarized in table 1. Treatment-related adverse events (TRAEs) occurred in 104 (96%) patients (94 [87%] grade ≤3, 10 [9%] grade ≥4). TRAEs led to study-drug interruption of 1 or both drugs in 80 (74.1%) patients and dose reductions of lenvatinib in 73 (67.6%) patients; 23 (21.3%) patients discontinued 1 or both drugs due to a TRAE. The most common grade ≥3 TRAEs were hypertension (33.3%), lipase increased (9.3%), fatigue (8.3%), and diarrhea (7.4%).Abstract 354 Table 1ConclusionsWith extended follow-up, our updated efficacy analysis continued to show clinical benefit in patients with metastatic EC who received lenvatinib + pembrolizumab. Moreover, the combination had a manageable safety profile that was generally consistent with the established safety profiles of the individual monotherapies. No new safety signals were detected. A phase 3 study of lenvatinib + pembrolizumab versus treatment of physician’s choice in advanced endometrial cancer further supports the lasting clinical benefits observed in our study.2 Trial Registration www.clinicaltrials.gov NCT02501096ReferencesMakker V, Taylor MH, Aghajanian C, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol 2020;38(26):2981–2992.Makker V, Colombo N, Casado Herráez A, et al. A multicenter, open-label, randomized, phase 3 study to compare Ethics ApprovalThis study was approved by the following ethics committees/institutional review boards (IRBs): Oregon Health & Sciences University IRB, IntegReview IRB, Memorial Sloan Kettering Cancer Center IRB, University of Pennsylvania Office of Regulatory Affairs IRB, Dana-Farber Cancer Institute IRB, The University of Chicago Biological Sciences Division IRB, University of Texas MD Anderson Cancer Center IRB, Western IRB, Quorum Review IRB, US Oncology, Inc. IRB, CEIm - Comité de Ética de la Investigación con Medicamentos, Regional Komite for Medisinsk og Helsefagli Forskningsetikk, and REC - Regional Committees for Medical and Health Research Ethics. All participants gave informed consent before taking part in this study.ConsentNo identifying information is contained in this abstract so no permission from participants is considered necessary.

Women with advanced endometrial cancer that progressed during platinum-containing therapy were randomly assigned to lenvatinib plus pembrolizumab or physician’s choice of chemotherapy (doxorubicin or paclitaxel). The median progression-free survival was 7.2 months with lenvatinib plus pembrolizumab and 3.8 months with chemotherapy; the median overall survival was 18.3 months and 11.4 months, respectively.

Lenvatinib plus either pembrolizumab or everolimus was compared with sunitinib as first-line therapy for advanced renal cell cancer. Progression-free survival was significantly longer with lenvatinib plus pembrolizumab than with sunitinib. Lenvatinib plus everolimus was also more effective than sunitinib, but the difference was smaller.

Lenvatinib plus everolimus is approved for the treatment of advanced renal cell carcinoma (RCC) after one prior vascular endothelial growth factor-targeted therapy. Lenvatinib plus pembrolizumab demonstrated promising antitumor activity in a Phase I/II trial of RCC. We describe the rationale and design of the CLEAR study, a three-arm Phase III trial comparing lenvatinib plus everolimus and lenvatinib plus pembrolizumab versus sunitinib monotherapy for first-line treatment of RCC. Eligible patients must have advanced clear cell RCC and must not have received any prior systemic anticancer therapy. The primary end point is progression-free survival; secondary end points include objective response rate, overall survival, safety, health-related quality of life and pharmacokinetics. Biomarker evaluations are included as exploratory end points.

Abstract BACKGROUND Rising incidence and prevalence of inflammatory bowel disease (IBD) observed historically in early-industrialized regions now also appear in newly-industrialized and emerging regions. The epidemiology of IBD has been proposed to progress across epidemiologic stages: 1. Emergence (low incidence and prevalence); 2. Acceleration in Incidence (rapid rising incidence); and 3. Compounding Prevalence (stabilizing incidence, rapid rising prevalence). AIM To gather real-world data on the incidence and prevalence of IBD and characterize global regions in each epidemiologic stage by meta-analyses. METHODS Two previous systematic reviews (database inception–2010; 2010–2016) were updated with a search of MEDLINE, Embase, PubMed, and Web of Science (2017–2023) to identify all population-based studies reporting the incidence or prevalence of Crohn’s disease (CD) or ulcerative colitis (UC). International partners provided a secondary review of the included studies from their local regions. Incidence and prevalence rates (per 100,000 population), stratified by epidemiologic stage, were meta-analyzed to determine pooled rates with associated 95% confidence intervals (95%CI). A Cochrane Q test was used to investigate differences between epidemiologic stages for both CD and UC. RESULTS After assessing 1,250 manuscripts, a total of 491 studies (439 incidence, 228 prevalence) from 80 global regions spanning 1920-2022 were identified by the systematic review (Figure 1). All data identified with our search strategy are available to view in an open-access, online interactive data repository (https://gives21.shinyapps.io/dashboard/) created with Shiny for R. The pooled incidence of CD and UC per 100,000 person-years rose from 0.28 (95%CI: 0.21, 0.36) and 0.57 (95%CI: 0.47, 0.69) in Stage 1 to 2.13 (95%CI: 1.88, 2.42) and 4.05 (95%CI: 3.65, 4.50) in Stage 2 to 9.34 (95%CI: 8.73, 9.99) and 14.07 (95%CI: 13.09, 15.12) in Stage 3 (Table 1). Similarly, the pooled prevalence of CD and UC per 100,000 persons rose from 1.96 (95%CI: 1.41, 2.74) and 6.35 (95%CI: 4.45, 9.07) in Stage 1 to 22.18 (95%CI: 17.96, 27.38) and 45.36 (95%CI: 37.84, 54.38) in Stage 2 to 186.18 (95%CI: 163.18, 212.42) and 255.92 (95%CI: 230.60, 284.02) in Stage 3 (Table 1). Subgroup analysis confirmed differences in both incidence and prevalence for CD and UC between epidemiologic stages (p<0.001). DISCUSSION This is the most comprehensive systematic review on the incidence and prevalence of IBD. The amalgamated real-world data from this study highlight the rising global burden of IBD across three distinct epidemiologic stages: 1. Emergence, 2. Acceleration in Incidence, and 3. Compounding Prevalence. Figure 1 Systematic review study selection flowchart including a brief overview of two previous systematic reviews: Molodecky, N.A. et al. Gastroenterology. 2012;142(1):46-54 and Ng, S.C. et al. Lancet. 2017;390(10114):2769-78. Table 1 Pooled incidence and prevalence rates per 100,000 population for Crohn’s disease and ulcerative colitis. Cochrane Q subgroup analysis for difference in estimates between epidemiologic stages. † Represents the number of study-subregion groups used in the calculation of pooled rates and their 95% confidence intervals.

Abstract BACKGROUND Epidemiologic stages of inflammatory bowel disease (IBD) have been proposed: 1. Emergence (low incidence and prevalence); 2. Acceleration in Incidence (rapidly rising incidence, low prevalence); and 3. Compounding Prevalence (stabilizing incidence, rapidly rising prevalence). To date, these stages have been theoretical without quantified definitions of incidence and prevalence. AIM To use machine learning to determine incidence and prevalence ranges corresponding to the epidemiologic stages and provide stage classifications across time for global regions. METHODS We built a supervised random forest classifier in R to determine epidemiologic stages of IBD from population-based studies (n=340), a subset derived from a systematic review on the incidence and prevalence of IBD. A labelled training data set comprising rates of incidence and prevalence of Crohn’s disease (CD) and ulcerative colitis (UC) extracted from the systematic review was used to predict classifications of stage 1, stage 2, or stage 3 for each region, stratified by decade (1960–2019). Model accuracy was measured using a blind validation data set. The validated model was then used to predict stage classifications for regions in the data set. Interquartile ranges for incidence and prevalence of CD and UC were calculated on the random forest output, and the distributions were compared using negative binomial regression. RESULTS The random forest’s classification accuracy on the blinded validation data was 93.7% (95%CI: 90.6, 96.1) indicating an appropriate model fit and performance. Significant differences between all stages for the incidence and prevalence of CD and UC (p<0.001) were found. The clear distinction across stages defines the incidence and prevalence ranges (25th–75th, per 100,000) for IBD as: CD incidence 0.0–0.3, UC incidence 0.2–0.7, CD prevalence 0.3–2.2, and UC prevalence 1.7–8.1 for stage 1; CD incidence 1.0–4.4, UC incidence 2.3–6.3, CD prevalence 9.0–33.9, and UC prevalence 22.8–73.3 for stage 2; and CD incidence 6.6–14.0, UC incidence 10.1–18.1, CD prevalence 163.2–274.7, and UC prevalence 189.1–323.2 for stage 3 (Figure 1). A decade-by-decade analysis shows global regions transitioning across the epidemiologic stages (Figure 2). By the 2010s, North America, Scandinavia, Western Europe, Australia, and New Zealand were in stage 3. Most regions in Asia and Latin America were in stage 1 in the last half of the 20th century, with many transitioning to stage 2 in the 2010s. DISCUSSION Temporal incidence and prevalence data show that regions transition across epidemiologic stages. Numerical definitions of the epidemiologic stages can be used to establish the anticipated burden growth of IBD by providing estimated rates of the number of incident and prevalent IBD cases a region can expect as it transitions between IBD epidemiologic stages in the future. Figure 1 Coalescing ranges for incidence (panel A) and prevalence (panel B) by Crohn’s disease and ulcerative colitis at epidemiologic stage 1, stage 2, and stage 3. Data were categorized by data type (incidence or prevalence), disease type (Crohn’s disease or ulcerative colitis), and epidemiologic stage, as per results from the random forest classifier. The 25th and 75th percentiles were calculated using the rates across all regions included in the analysis for all available time points for each box group. Figure 2 Global maps depicting epidemiologic stages of IBD evolution from 1960 to 2019 broken down by decade, as predicted by the random forest model. Panel A contains stage classifications from 1960 to 1969; panel B contains stage classifications from 1970 to 1979; panel C contains stage classifications from 1980 to 1989; panel D contains stage classifications from 1990 to 1999; panel E contains stage classifications from 2000 to 2009; and panel F contains stage classifications from 2010 to 2019.