3 juni 2022: Bron: JAMA Oncol. Published online May 12, 2022.
Vistusertib aanvullend gegeven aan arimidex - anastrozol geeft betere resultaten op response en ziekteprogressievrije tijd met beheersbare bijwerkingen bij patiënten met een recidief van of uitgezaaide buikvlieskanker - endometriumkanker. Ziekteprogressievrije tijd verdubbelde bijna in vergelijking met arimidex - Anastrasol. In de Vistusertib + Anastrozolgroep, was de 8 weken-PFR (ziekteprogressievrije tijd) 67.3% (unilateral 95% CI, 54.7%) en in de Anastrozolgroep alleen, 39.1% (unilateral 95% CI, 22.2%).
Dit blijkt uit Victoria, een fase I/II gerandomiseerde klinische studie bij totaal 73 patiënten De onderzoekers evalueerden de werkzaamheid en veiligheid van vistusertib, een zogeheten mTOR-remmer, in combinatie met arimidex - anastrozol bij patiënten met hormoonreceptor positieve recidiverende of gemetastaseerde endometriumkanker - buikvlieskanker.
Het progressievrije percentage na 8 weken verdubbelde bijna met vistusertib plus anastrozol vergeleken met alleen anastrozol. De meest voorkomende graad 3 en 4 bijwerkingen geassocieerd met vistusertib plus anastrozol waren lymfocytopenie, hyperglykemie en vermoeidheid.
Het is wel vreemd dat Astrazeneca gestopt is met de productie van Vistusertib terwijl er dus nog studies lopen en vistusertib bij o.a. eierstokkanker en longkanker goede resultaten heeft laten zien. Zie bv. deze studie: Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer
De Victoria, een fase I/II gerandomiseerde klinische studie bij endometriumkanker - buikvlieskanker is 12 mei gepubliceerd in JAMA. Hier het abstract. Klik op de titel voor het volledige studierapport dat gratis is in te zien:
May 12, 2022
JAMA Oncol. Published online May 12, 2022. doi:10.1001/jamaoncol.2022.1047
Key Points
Question Does combining an mTOR inhibitor (vistusertib) with anastrozole therapy help control disease in patients with recurrent or metastatic hormone receptor−positive endometrial cancer?
Findings This multicenter open-label phase 1/2 randomized clinical trial of 75 women found that the progression-free rate at 8 weeks was 67.3% among the patients receiving vistusertib with anastrozole in the combination arm compared with 39.1% in the anastrozole alone arm.
Meaning Treatment combining vistusertib with anastrozole demonstrated clinically meaningful improvement with manageable adverse events for patients with recurrent or metastatic endometrial cancer; further research on the selection of patients with endometrial cancer for endocrine treatment should be encouraged.
Importance Endometrial cancer is often hormone-dependent and treated with aromatase inhibitors. The PI3K-AKT-mTOR pathway deregulation observed in endometrial cancer drives hormonal resistance, thus supporting the rationale of combining mTOR inhibitor with endocrine therapy.
Objective To evaluate the safety and efficacy of vistusertib in combination with anastrozole in the treatment of women with hormone receptor−positive recurrent or metastatic endometrial cancer.
Design, Settings, and Participants The VICTORIA study was a multicenter, open-label, randomized clinical trial that accrued 75 patients with hormone receptor−positive recurrent or metastatic endometrial cancer from 12 cancer centers in France in April 2016 to October 2019. After a safety run-in period, a Simon 2-stage design was used. Data analyses were performed from December 11, 2020, to March 11, 2021.
Interventions Patients were randomized in a 2:1 ratio to oral vistusertib (125 mg twice daily 2 days per week) and oral anastrozole (1 mg daily) in the combination vistusertib with anastrozole arm (V+A arm) or oral anastrozole alone (A arm).
Main Outcomes and Measures The primary end point was serious adverse events for the safety run-in period and progression-free rate at 8 weeks (8wk-PFR)—assessed with a blinded independent central review in phase 2. The secondary end points were objective response rate, duration of response, progression-free survival (PFS), overall survival, and incidence of adverse events.
Results Of the 75 patients who were randomized, 73 (median age, 69.5 [37-88] y; all female) were treated: V+A arm, 49 patients; A arm, 24 patients. In the V+A arm, the 8wk-PFR was 67.3% (unilateral 95% CI, 54.7%) and in the A arm, 39.1% (unilateral 95% CI, 22.2%). No significant serious adverse events were reported during the safety run-in period (n = 6 in V+A arm). The overall response rate was 24.5% (95% CI, 13.3%-38.9%) in the V+A arm vs 17.4% (95% CI, 5.0%-38.8%) in the A arm. With a median follow-up of 27.7 months, median PFS was 5.2 (95% CI, 3.4-8.9) in the V+A arm and 1.9 (95% CI, 1.6-8.9) months in the A arm. Fatigue, lymphopenia, hyperglycemia, and diarrhea were the most common (grade ≥2) adverse events associated with vistusertib.
Conclusions and Relevance This multicenter, open-label, phase 1/2 randomized clinical trial demonstrated that adding vistusertib to anastrozole improved 8wk-PFR, overall response rate, and PFS for patients with endometrial cancer and had manageable adverse events. Identification of molecular subgroups would allow for more precise selection of patients who may be most likely to experience favorable outcomes.
Trial Registration ClinicalTrials.gov Identifier: NCT02730923
Accepted for Publication: February 3, 2022.
Published Online: May 12, 2022. doi:10.1001/jamaoncol.2022.1047
Corresponding Author: Pierre Heudel, MD, MSc, LLM, Department of Medical Oncology, Centre Léon Bérard, 28 Rue Laennec, 69008, Lyon, France (pierre-etienne.heudel@lyon.unicancer.fr).
Author Contributions: Dr Heudel and Ms Dalban had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Heudel, Frenel, Arnaud, You, Garin, Diaz, Pérol, Ray-Coquard.
Acquisition, analysis, or interpretation of data: Heudel, Frenel, Dalban, Bazan, Joly, Abdeddaim, Chevalier-Place, Augereau, Pautier, Chakiba, You, Lancry-Lecomte, Marcel, Treilleux, Pérol, Fabbro, Ray-Coquard.
Drafting of the manuscript: Heudel, Frenel, Arnaud, You, Lancry-Lecomte, Garin, Ray-Coquard.
Critical revision of the manuscript for important intellectual content: Frenel, Dalban, Bazan, Joly, Abdeddaim, Chevalier-Place, Augereau, Pautier, Chakiba, You, Lancry-Lecomte, Marcel, Diaz, Treilleux, Pérol, Fabbro, Ray-Coquard.
Statistical analysis: Dalban, You, Pérol.
Obtained funding: Heudel, Bazan, Garin, Marcel, Diaz.
Administrative, technical, or material support: Joly, Garin, Treilleux.
Supervision: Heudel, Frenel, Bazan, Treilleux, Pérol, Ray-Coquard.
Other - screening and patient inclusion: Fabbro.
Conflict of Interest Disclosures: Dr Heudel reported personal fees from Seagen, Novartis, and AstraZeneca, and nonfinancial support from Lilly, Pfizer, and Roche outside the submitted work. Dr Frenel reported personal fees from AstraZeneca during the conduct of the study and personal fees from Pfizer, Lilly, Novartis, AstraZeneca, Clovis Oncology, GlaxoSmithKline, Daiichi-Sankyo, and Roche outside the submitted work. Dr Bazan reported personal fees from Roche, Novartis, Pierre-Fabre, AstraZeneca, Clovis Oncology, Daiichi-Sankyo, Seagen, and Pfizer outside the submitted work. Dr Joly reported personal fees from GlaxoSmithKline for the scientific board and coordination of an international study in endometrial cancer, and from the scientific board of Merck Sharp & Dohme/Eisai, both outside the submitted work. Dr Abdeddaim reported personal fees from GlaxoSmithKline outside the submitted work. Dr Augereau reported nonfinancial support from AstraZeneca, GlaxoSmithKline, Clovis, Novartis, and Pfizer outside the submitted work. Dr Pautier reported grants from PharmaMar, Merck Sharp & Dohme, and personal fees from AstraZeneca and GlaxoSmithKline outside the submitted work. Dr You reported consulting fees from Merck Sharp & Dohme, AstraZeneca, GlaxoSmithKline−Tesaro, Bayer, Roche-Genentech, ECS Progastrine, Novartis, Lek, Amgen, Clovis Oncology, Merck Serono, Bristol Myers Squibb, Seagen, and Myriad outside the submitted work. Dr Pérol reported grants from the National Cancer Institute, France, during the conduct of the study; and honoraria and consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Ipsen, Janssen, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Pfizer, Roche, and Takeda outside the submitted work. Dr Fabbro reported serving on the boards of AstraZeneca and GlaxoSmithKline outside the submitted work. Dr Ray-Coquard reported personal fees from PharmaMar, Immunogen, Genmab, Bristol Myers Squibb, Deciphera, Mersana, Clovis, AstraZeneca, Agenus, Novartis, Roche, Macrogenics, GlaxoSmithKline, and grants from Merck Sharp & Dohme, all outside the submitted work. No other disclosures were reported.
Funding/Support: This study was funded by a grant from the National Cancer Institute of France (No. INCa-ARC 9223).
Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Meeting Presentation: The study results were presented in part during the fully online American Society of Clinical Oncology conference on June 4-8, 2021.
Additional Contributions: We thank the patients and their families for their participation, and the researchers, nurses, and study staff for their contributions to the VICTORIA trial. We also thank the Independent Data Monitoring Committee members (Paul Cottu, MD; Anne-Claire Hardy-Bessard, MD; Audrey Dugué, MSc) and the Biosample Management Platform for logistics and laboratory support of the Centre Léon Bérard. We also thank the GINECO group for participation in the VICTORIA trial and the Sites de Recherche Intégrée Sur le Cancer program (INCa-DGOS-Inserm 12563 LYriCAN) for its involvement.
Data Sharing Statement: See Supplement 3.
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endometriumkanker, buikvlieskanker, arimidex, anastrosol, vistusertib, ziekteprogressie vrije tijd
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