المؤلفون: Shumaker, Robert, Ren, Min, Aluri, Jagadeesh, Dutcus, Corina E., Rance, Christian, He, Cixin

المصدر: European Journal of Drug Metabolism and Pharmacokinetics; 20240101, Issue: Preprints p1-11, 11p

مستخلص: Background and Objective: Lenvatinib is a multikinase inhibitor that inhibits enzyme activity but induces gene expression of cytochrome P450 3A4 (CYP3A4), an important enzyme for drug metabolism. We evaluated the impact of lenvatinib on CYP3A4 using midazolam as a probe substrate in patients with advanced solid tumors. The primary objective was to determine the pharmacokinetic effects of lenvatinib on midazolam, and the secondary objective was to assess the safety of lenvatinib. Methods: This multicenter, open-label, nonrandomized, phase 1 study involved patients with advanced cancer that progressed after treatment with approved therapies or for which no standard therapies were available. Results: Compared with baseline, coadministration of lenvatinib decreased the geometric mean ratio of the area under the concentration–time curve for midazolam on day 1 to 0.914 (90% confidence interval [CI] 0.850–0.983) but increased it on day 14 to 1.148 (90% CI 0.938–1.404). Coadministration of lenvatinib also decreased the geometric mean ratio of the maximum observed concentration for midazolam on day 1 to 0.862 (90% CI 0.753–0.988) but increased it on day 14 to 1.027 (90% CI 0.852–1.238). There was little change in the terminal elimination phase half-life of midazolam when administered with lenvatinib. The most common treatment-related adverse events were hypertension (20.0%), fatigue (16.7%), and diarrhea (10.0%). Conclusions: Coadministration of lenvatinib had no clinically relevant effect on the pharmacokinetics of midazolam, a CYP3A4 substrate. The adverse events were consistent with the known safety profile of lenvatinib, and no new safety concerns were identified. ClinicalTrials.Gov Identifier: NCT02686164.

المؤلفون: Motzer, Robert, Alekseev, Boris, Rha, Sun-Young, Porta, Camillo, Eto, Masatoshi, Powles, Thomas, Grünwald, Viktor, Hutson, Thomas E, Kopyltsov, Evgeny, Méndez-Vidal, María J, Kozlov, Vadim, Alyasova, Anna, Hong, Sung-Hoo, Kapoor, Anil, Alonso Gordoa, Teresa, Merchan, Jaime R, Winquist, Eric, Maroto, Pablo, Goh, Jeffrey C, Kim, Miso, Gurney, Howard, Patel, Vijay, Peer, Avivit, Procopio, Giuseppe, Takagi, Toshio, Melichar, Bohuslav, Rolland, Frederic, De Giorgi, Ugo, Wong, Shirley, Bedke, Jens, Schmidinger, Manuela, Dutcus, Corina E, Smith, Alan D, Dutta, Lea, Mody, Kalgi, Perini, Rodolfo F, Xing, Dongyuan, Choueiri, Toni K, CLEAR Trial Investigators

المساهمون: Gennigens, Christine

المصدر: New England Journal of Medicine, 384 (14), 1289 - 1300 (2021-04-08)

مصطلحات موضوعية: Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Phenylurea Compounds, Programmed Cell Death 1 Receptor, Protein Kinase Inhibitors, Quinolines, Everolimus, pembrolizumab, lenvatinib, Sunitinib, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized/administration & dosage, Antibodies, Monoclonal, Humanized/adverse effects, Antineoplastic Agents/adverse effects, Antineoplastic Agents/therapeutic use, Antineoplastic Combined Chemotherapy Protocols/adverse effects, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Carcinoma, Renal Cell/drug therapy, Carcinoma, Renal Cell/mortality, Everolimus/administration & dosage, Everolimus/adverse effects, Female, Humans, Kidney Neoplasms/drug therapy, Kidney Neoplasms/mortality, Male, Middle Aged, Phenylurea Compounds/administration & dosage, Phenylurea Compounds/adverse effects, Programmed Cell Death 1 Receptor/antagonists & inhibitors, Progression-Free Survival, Protein Kinase Inhibitors/therapeutic use, Quinolines/administration & dosage, Quinolines/adverse effects, Sunitinib/adverse effects, Sunitinib/therapeutic use, Survival Analysis, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Renal Cell, Kidney Neoplasms, Medicine (all), General Medicine, Human health sciences, Oncology, Sciences de la santé humaine, Oncologie

الوصف: [en] BACKGROUND: Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear.METHODS: In this phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated.RESULTS: A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels.CONCLUSIONS: Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).

العلاقة: http://www.nejm.org/doi/pdf/10.1056/NEJMoa2035716Test; urn:issn:0028-4793; urn:issn:1533-4406

الوصول الحر: https://orbi.uliege.be/handle/2268/300816Test

المؤلفون: Robinson, Bruce, Schlumberger, Martin, Wirth, Lori J., Dutcus, Corina E., Song, James, Taylor, Matthew H., Kim, Sung-Bae, Krzyzanowska, Monika K., Capdevila, Jaume, Sherman, Steven I., Tahara, Makoto

المصدر: The Journal of Clinical Endocrinology & Metabolism; November 2016, Vol. 101 Issue: 11 p4103-4109, 7p

مستخلص: Context:Lenvatinib improved the progression-free survival (PFS) and overall response rate of patients with radioiodine-refractory differentiated thyroid cancer vs placebo in the Phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT).Objective:The objective of the study was to characterize tumor size changes with lenvatinib treatment.Design:SELECT was a phase 3, randomized, double-blind, multicenter study.Setting:In this clinical trial, tumor assessments of lenvatinib (n = 261) and placebo-treated (n = 131) patients were performed by independent radiological review per Response Evaluation Criteria in Solid Tumors version, 1.1 at 8-week intervals.Patients:Patients with complete or partial response were defined as responders to lenvatinib (n = 169). Of the 92 nonresponders, 76 had at least one postbaseline tumor assessment and were included in this analysis.Interventions:Lenvatinib (24 mg once daily) or placebo in 28-day cycles until unacceptable toxicity, disease progression, or death.Main Outcome Measures:This was an exploratory analysis of key end points from SELECT, including PFS, overall response rate, and tumor reduction.Results:The median maximum percentage change in tumor size was −42.9% for patients receiving lenvatinib (responders, −51.9%; nonresponders, −20.2%). Tumor size reduction was most pronounced at first assessment (median, −24.7% at 8 wk after randomization); thereafter, the rate of change was slower but continuous (−1.3% per mo). In a multivariate model, percentage change in tumor size at the first assessment was a marginally significant positive predictor for PFS (P= .06).Conclusions:The change in tumor size conferred by lenvatinib was characterized by two phases: an initial, rapid decline, followed by slower, continuous shrinkage.

المؤلفون: Cortes, Javier, O'Shaughnessy, Joyce, Loesch, David, Blum, Joanne L, Vahdat, Linda T, Petrakova, Katarina, Chollet, Philippe, Manikas, Alexey, Diéras, Veronique, Delozier, Thierry, Vladimirov, Vladimir, Cardoso, Fatima, Koh, Han, Bougnoux, Philippe, Dutcus, Corina E, Seegobin, Seth, Mir, Denis, Meneses, Nicole, Wanders, Jantien, Twelves, Chris

المصدر: The Lancet; March 2011, Vol. 377 Issue: 9769 p914-923, 10p

مستخلص: Treatments with survival benefit are greatly needed for women with heavily pretreated metastatic breast cancer. Eribulin mesilate is a non-taxane microtubule dynamics inhibitor with a novel mode of action. We aimed to compare overall survival of heavily pretreated patients receiving eribulin versus currently available treatments.