Francoise Borson-Chazot1, Emmanuelle Dantony2, Frederic Illouz3, Jonathan Lopez4, Patricia Niccoli5, Johanna Wassermann6, Christine Do Cao7, Sophie Leboulleux8, Marc Klein9, Antoine Tabarin10, Marie-Claude Eberle11, Danielle Benisvy12, Christelle de la Fouchardière13, Claire Bournaud14, Helene Lasolle1, Armelle Delahaye1, Muriel Rabilloud2, Véronique Lapras15, Myriam Decaussin-Petrucci16, Martin Schlumberger8. 1. 1 Fédération d'Endocrinologie, Hospices Civils de Lyon, Université Claude Bernard Lyon 1 , Lyon, France . 2. 2 Service de Biostatistique-Bioinformatique, Hospices Civils de Lyon, Université Lyon 1 , Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France . 3. 3 Service d'Endocrinologie, Centre de Référence de la Thyroïde et des Récepteurs Hormonaux , Centre Hospitalier Universitaire d'Angers, France . 4. 4 Service de Biochimie et Biologie moléculaire, Centre Hospitalier Lyon-Sud , Hospices Civils de Lyon, Université Lyon 1, France . 5. 5 Departement d'Oncologie Médicale, Institut Paoli Calmette , Marseille, France . 6. 6 Département d'oncologie Médicale, Hôpital Pitié Salpêtrière, Assistance Publique-Hôpitaux de Paris, Université Sorbonne , Paris, France . 7. 7 Service d'Endocrinologie, Centre Hospitalier Regional et Universitaire Lille , France . 8. 8 Service de Médecine Nucléaire et de Cancérologie Endocrinienne, Institut Gustave Roussy , Villejuif et Université Paris Saclay, France . 9. 9 Service d'Endocrinologie, Centre Hospitalier Universitaire et Université de Nancy , France . 10. 10 Service d'Endocrinologie, Centre Hospitalier Universitaire et Université de Bordeaux , France . 11. 11 Service de Médecine Nucléaire, Institut du Cancer de Montpellier , France . 12. 12 Service de Médecine Nucléaire, Centre Antoine Lacassagne , Nice, France . 13. 13 Département d'Oncologie Médicale, Centre Léon Bérard , Lyon, France . 14. 14 Centre de Médecine Nucléaire, Groupement Hospitalier Est , Hospices Civils de Lyon, France . 15. 15 Service de Radiologie, Centre Hospitalier Lyon-Sud , Hospices Civils de Lyon, France . 16. 16 Service d'Anatomie et Cytologie Pathologiques, Groupement Hospitalier Lyon Sud , Hospices Civils de Lyon, et Université Lyon 1, France .
Abstract
BACKGROUND: Dysregulation of the phosphatidylinositol 3-kinase (PI3K) pathway is frequent in advanced follicular (FTC) and poorly differentiated thyroid (PDTC) carcinomas and has been implicated in oncogenesis and tumor progression. This study investigated the efficacy and safety of buparlisib, a pan-PI3K inhibitor in radioiodine refractory FTC and PDTC. METHODS: The primary endpoint of this open-label, multicenter, phase 2 pilot study was progression-free survival (PFS) at 6 months. The sample size was determined considering that a PFS ≤50% at 6 months would denote an absence of benefits (null hypothesis). Secondary endpoints were objective response rate, PFS at 12 months, overall survival at 6 and 12 months, and safety based on the frequency and severity of adverse events (AEs). RESULTS: Forty-three patients (19M/24 F; median age: 67 years) with metastatic, radioiodine refractory, progressive disease received buparlisib, 100 mg, daily. Histology was PDTC in 25 (58%), FTC in 17 (40%), and Hürthle cell carcinoma in 1 (2%). RAS mutation was found in 44% (12/27) and activation of the PI3K pathway in 35% (8/23) of tested tumors. The probability of PFS was 41.7% [95% confidence interval (CI) 7.7-55.5] at 6 months and 20.9% [CI 0-35.7] at 12 months, lower than the 50% expected PFS. At 6 months, 25.6% patients had stable disease, 48.8% were progressive and 25.6% had stopped treatment due to AE. The response to therapy was not influenced by age, sex, histology, or genetic alterations. The overall survivals at 6 and 12 months were 85.9% [CI 76-97] and 78.7 % [CI 67-92], respectively. The mean tumor growth rate decreased from 3.78 mm/month [CI 2.61-4.95] before treatment to 0.8 mm/month [CI -0.2-1.88] during treatment (p < 0.02). Severe grade 3-4 AEs occurred in 27 patients (63%), including hepatitis (25%), hyperglycemia (21%), mood disorders (12%), and skin toxicity (12%), with favorable outcome after temporary or permanent treatment discontinuation or dose reduction. CONCLUSIONS: Buparlisib did not result in significant efficacy in advanced FTC and PDTC. However, the decrease in tumor growth rate may suggest incomplete inhibition of oncogenic pathways and/or escape mechanisms. This should lead to evaluate combined therapy associating inhibitors of both the PI3K and mitogen-activated protein kinase pathways.
BACKGROUND: Dysregulation of the phosphatidylinositol 3-kinase (PI3K) pathway is frequent in advanced follicular (FTC) and poorly differentiated thyroid (PDTC) carcinomas and has been implicated in oncogenesis and tumor progression. This study investigated the efficacy and safety of buparlisib, a pan-PI3K inhibitor in radioiodine refractory FTC and PDTC. METHODS: The primary endpoint of this open-label, multicenter, phase 2 pilot study was progression-free survival (PFS) at 6 months. The sample size was determined considering that a PFS ≤50% at 6 months would denote an absence of benefits (null hypothesis). Secondary endpoints were objective response rate, PFS at 12 months, overall survival at 6 and 12 months, and safety based on the frequency and severity of adverse events (AEs). RESULTS: Forty-three patients (19M/24 F; median age: 67 years) with metastatic, radioiodine refractory, progressive disease received buparlisib, 100 mg, daily. Histology was PDTC in 25 (58%), FTC in 17 (40%), and Hürthle cell carcinoma in 1 (2%). RAS mutation was found in 44% (12/27) and activation of the PI3K pathway in 35% (8/23) of tested tumors. The probability of PFS was 41.7% [95% confidence interval (CI) 7.7-55.5] at 6 months and 20.9% [CI 0-35.7] at 12 months, lower than the 50% expected PFS. At 6 months, 25.6% patients had stable disease, 48.8% were progressive and 25.6% had stopped treatment due to AE. The response to therapy was not influenced by age, sex, histology, or genetic alterations. The overall survivals at 6 and 12 months were 85.9% [CI 76-97] and 78.7 % [CI 67-92], respectively. The mean tumor growth rate decreased from 3.78 mm/month [CI 2.61-4.95] before treatment to 0.8 mm/month [CI -0.2-1.88] during treatment (p < 0.02). Severe grade 3-4 AEs occurred in 27 patients (63%), including hepatitis (25%), hyperglycemia (21%), mood disorders (12%), and skin toxicity (12%), with favorable outcome after temporary or permanent treatment discontinuation or dose reduction. CONCLUSIONS:Buparlisib did not result in significant efficacy in advanced FTC and PDTC. However, the decrease in tumor growth rate may suggest incomplete inhibition of oncogenic pathways and/or escape mechanisms. This should lead to evaluate combined therapy associating inhibitors of both the PI3K and mitogen-activated protein kinase pathways.
Authors: Eric L Bolf; Noelle E Gillis; Cole D Davidson; Princess D Rodriguez; Lauren Cozzens; Jennifer A Tomczak; Seth Frietze; Frances E Carr Journal: Mol Cancer Res Date: 2020-06-17 Impact factor: 5.852
Authors: William G Herrick; Casey L Kilpatrick; Melinda G Hollingshead; Dominic Esposito; Geraldine O'Sullivan Coyne; Andrea M Gross; Barry C Johnson; Alice P Chen; Brigitte C Widemann; James H Doroshow; Ralph E Parchment; Apurva K Srivastava Journal: Mol Cancer Ther Date: 2021-02-03 Impact factor: 6.009