Mathilde Guerin1, Keyvan Rezai2, Nicolas Isambert3, Mario Campone4, Aurélie Autret5, Jihane Pakradouni5, Magali Provansal1, Jacques Camerlo1, Renaud Sabatier1, François Bertucci1, Emmanuelle Charafe-Jauffret6, Alice Hervieu3, Jean-Marc Extra1, Patrice Viens1, François Lokiec2, Jean-Marie Boher7, Anthony Gonçalves8. 1. Aix-Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France. 2. Institut Curie - Hôpital René Huguenin, Saint-Cloud, France. 3. Centre Georges-Francois Leclerc, Dijon, France. 4. Institut de Cancérologie de L'Ouest, Nantes, France. 5. Institut Paoli-Calmettes, Department of Clinical Research and Innovations, Marseille, France. 6. Aix-Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, Department of Biopathology, CRCM, Marseille, France. 7. Institut Paoli-Calmettes, Department of Clinical Research and Innovations, Marseille, France; Aix Marseille University, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de La Santé & Traitement de L'Information Médicale, Marseille, France. 8. Aix-Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France. Electronic address: goncalvesa@ipc.unicancer.fr.
Abstract
BACKGROUND: Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms. PATIENTS AND METHODS: PIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments. RESULTS: A total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug-drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57-92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12-51%]). CONCLUSION: Combining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population. TRIAL REGISTRATION ID: NCT01589861.
BACKGROUND:Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms. PATIENTS AND METHODS: PIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments. RESULTS: A total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug-drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57-92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12-51%]). CONCLUSION: Combining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population. TRIAL REGISTRATION ID: NCT01589861.
Authors: Maria Mitsogianni; Ioannis P Trontzas; Georgia Gomatou; Stephanie Ioannou; Nikolaos K Syrigos; Elias A Kotteas Journal: Oncol Lett Date: 2021-02-12 Impact factor: 2.967
Authors: Autumn J McRee; Paul K Marcom; Dominic T Moore; William C Zamboni; Zachary A Kornblum; Zhiyuan Hu; Rachel Phipps; Carey K Anders; Katherine Reeder-Hayes; Lisa A Carey; Karen E Weck; Charles M Perou; E Claire Dees Journal: Clin Breast Cancer Date: 2017-10-28 Impact factor: 3.225
Authors: Ariella B Hanker; Benjamin P Brown; Jens Meiler; Arnaldo Marín; Harikrishna S Jayanthan; Dan Ye; Chang-Ching Lin; Hiroaki Akamatsu; Kyung-Min Lee; Sumanta Chatterjee; Dhivya R Sudhan; Alberto Servetto; Monica Red Brewer; James P Koch; Jonathan H Sheehan; Jie He; Alshad S Lalani; Carlos L Arteaga Journal: Cancer Cell Date: 2021-06-24 Impact factor: 38.585