B Pistilli1,2, T Pluard3, A Urruticoechea4,5, D Farci6, A Kong7,8, T Bachelot9, S Chan10, H S Han11, G Jerusalem12, P Urban13, D Robinson14, S L Mouhaër15, E D Tomaso14,16, C Massacesi15, C Saura17. 1. Breast Cancer Unit, Institut Gustave Roussy, 114 Rue Edouard-Vaillant, 94800, Villejuif, France. barbara.pistilli@gustaveroussy.fr. 2. Macerata Hospital, Macerata, Italy. barbara.pistilli@gustaveroussy.fr. 3. Saint Luke's Health System, Kansas City, MO, USA. 4. Onkologikoa Foundation, San Sebastian, Spain. 5. Catalan Institute of Oncology, Barcelona, Spain. 6. Ospedale Oncologico, Cagliari, Italy. 7. University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. 8. University of Oxford and Oxford University Hospitals NHS Trust, Oxford, UK. 9. Centre Léon Bérard et Inserm U1052, Lyon, France. 10. Nottingham University Hospitals NHS Trust, Nottingham, UK. 11. Moffitt Cancer Center, Tampa, FL, USA. 12. CHU Sart Tilman Liège and University of Liège, Liège, Belgium. 13. Novartis Pharma AG, Basel, Switzerland. 14. Novartis Institutes for BioMedical Research, Cambridge, MA, USA. 15. Novartis Pharmaceuticals Corporation, Rueil-Malmaison, France. 16. Syros Pharmaceuticals, Watertown, MA, USA. 17. Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
Abstract
PURPOSE: A Phase Ib study in patients with trastuzumab-resistant, human epidermal growth factor receptor-2- (HER2)-positive advanced breast cancer defined the recommended Phase II dose of buparlisib as 100 mg/day in combination with 2 mg/kg weekly trastuzumab, and reported preliminary signs of clinical activity. Here we present results from the Phase II portion. METHODS: Patients with trastuzumab-resistant, HER2-positive advanced breast cancer received buparlisib plus trastuzumab. Study endpoints included safety/tolerability and antitumour activity. The study was extended to include a Phase Ib dose-escalation phase, in which patients with progressive brain metastases also received capecitabine. RESULTS: In the Phase II portion, of 50 patients treated with buparlisib and trastuzumab, the most common (≥ 30%) all-grade adverse events (AEs) were diarrhoea (54%), nausea (48%), decreased appetite, increased alanine aminotransferase (36% each), increased aspartate aminotransferase (34%), fatigue, rash (32% each), cough and hyperglycemia (30% each). One (2%) patient achieved complete response and four (8%) patients had confirmed partial responses [PR; including two patients with phosphatidylinositol 3-kinase (PI3 K) pathway-activated tumours]. Overall response rate (ORR) was 10%: the primary endpoint (ORR ≥ 25%) was therefore not met. In the Phase Ib portion, all patients with measurable brain lesions at baseline showed tumour shrinkage to some degree; due to low enrollment, maximum tolerated dose of buparlisib in combination with trastuzumab and capecitabine was not determined. CONCLUSION: Buparlisib plus trastuzumab, as a chemotherapy-free regimen, demonstrated an acceptable safety profile but limited efficacy in patients with heavily pretreated, trastuzumab-resistant HER2-positive breast cancer, and in patients with progressive brain metastases also receiving capecitabine.
PURPOSE: A Phase Ib study in patients with trastuzumab-resistant, human epidermal growth factor receptor-2- (HER2)-positive advanced breast cancer defined the recommended Phase II dose of buparlisib as 100 mg/day in combination with 2 mg/kg weekly trastuzumab, and reported preliminary signs of clinical activity. Here we present results from the Phase II portion. METHODS:Patients with trastuzumab-resistant, HER2-positive advanced breast cancer received buparlisib plus trastuzumab. Study endpoints included safety/tolerability and antitumour activity. The study was extended to include a Phase Ib dose-escalation phase, in which patients with progressive brain metastases also received capecitabine. RESULTS: In the Phase II portion, of 50 patients treated with buparlisib and trastuzumab, the most common (≥ 30%) all-grade adverse events (AEs) were diarrhoea (54%), nausea (48%), decreased appetite, increased alanine aminotransferase (36% each), increased aspartate aminotransferase (34%), fatigue, rash (32% each), cough and hyperglycemia (30% each). One (2%) patient achieved complete response and four (8%) patients had confirmed partial responses [PR; including two patients with phosphatidylinositol 3-kinase (PI3 K) pathway-activated tumours]. Overall response rate (ORR) was 10%: the primary endpoint (ORR ≥ 25%) was therefore not met. In the Phase Ib portion, all patients with measurable brain lesions at baseline showed tumour shrinkage to some degree; due to low enrollment, maximum tolerated dose of buparlisib in combination with trastuzumab and capecitabine was not determined. CONCLUSION:Buparlisib plus trastuzumab, as a chemotherapy-free regimen, demonstrated an acceptable safety profile but limited efficacy in patients with heavily pretreated, trastuzumab-resistant HER2-positive breast cancer, and in patients with progressive brain metastases also receiving capecitabine.
Authors: Lucía Zhu; Diana Retana; Pedro García-Gómez; Laura Álvaro-Espinosa; Neibla Priego; Mariam Masmudi-Martín; Natalia Yebra; Lauritz Miarka; Elena Hernández-Encinas; Carmen Blanco-Aparicio; Sonia Martínez; Cecilia Sobrino; Nuria Ajenjo; Maria-Jesus Artiga; Eva Ortega-Paino; Raúl Torres-Ruiz; Sandra Rodríguez-Perales; Riccardo Soffietti; Luca Bertero; Paola Cassoni; Tobias Weiss; Javier Muñoz; Juan Manuel Sepúlveda; Pedro González-León; Luis Jiménez-Roldán; Luis Miguel Moreno; Olga Esteban; Ángel Pérez-Núñez; Aurelio Hernández-Laín; Oscar Toldos; Yolanda Ruano; Lucía Alcázar; Guillermo Blasco; José Fernández-Alén; Eduardo Caleiras; Miguel Lafarga; Diego Megías; Osvaldo Graña-Castro; Carolina Nör; Michael D Taylor; Leonie S Young; Damir Varešlija; Nicola Cosgrove; Fergus J Couch; Lorena Cussó; Manuel Desco; Silvana Mouron; Miguel Quintela-Fandino; Michael Weller; Joaquín Pastor; Manuel Valiente Journal: EMBO Mol Med Date: 2022-02-17 Impact factor: 12.137
Authors: Flávia Melo Cunha de Pinho Pessoa; Caio Bezerra Machado; Emerson Lucena da Silva; Laudreísa da Costa Pantoja; Rodrigo Monteiro Ribeiro; Maria Elisabete Amaral de Moraes; Manoel Odorico de Moraes Filho; Raquel Carvalho Montenegro; André Salim Khayat; Caroline Aquino Moreira-Nunes Journal: Int J Mol Sci Date: 2022-03-30 Impact factor: 5.923