Stand Up to Cancer Phase Ib Study of Pan-Phosphoinositide-3-Kinase Inhibitor Buparlisib With Letrozole in Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer

• Published in: Journal of clinical oncology Vol. 32; no. 12; pp. 1202 - 1209
• Main Authors: MAYER, Ingrid A, ABRAMSON, Vandana G, CANTLEY, Lewis C, WINER, Eric, ARTEAGA, Carlos L, ISAKOFF, Steven J, FORERO, Andres, BALKO, Justin M, KUBA, María Gabriela, SANDERS, Melinda E, YAP, Jeffrey T, VAN DEN ABBEELE, Annick D, YISHENG LI
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 20.04.2014
• Subjects: Adult; Aged; Aminopyridines - administration & dosage; Aminopyridines - adverse effects; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Biological and medical sciences; Breast Neoplasms - diagnostic imaging; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorodeoxyglucose F18; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical sciences; Middle Aged; Morpholines - administration & dosage; Morpholines - adverse effects; Multimodal Imaging; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nitriles - administration & dosage; Nitriles - adverse effects; ORIGINAL REPORTS; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Positron-Emission Tomography; Protein Kinase Inhibitors - administration & dosage; Radiopharmaceuticals; Receptor, ErbB-2 - metabolism; Receptors, Estrogen - biosynthesis; Tomography, X-Ray Computed; Triazoles - administration & dosage; Triazoles - adverse effects; Tumors; Antineoplastic agent; Buparlisib; Estrogen receptor; Breast disease; Azole derivatives; Antiestrogen; Estrogen; Antihormone; Estrogen synthase; Metastasis; Cancerology; Advanced stage; Non steroid compound; Aromatase inhibitor; Enzyme; Transferases; Enzyme inhibitor; Breast cancer; Malignant tumor; Ovarian hormone; Human Epidermal growth factor Receptor 2; 1-Phosphatidylinositol 3-kinase; Mammary gland diseases; Triazole derivatives; Sex steroid hormone; Letrozole; Cancer; Hormonal receptor
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2013.54.0518

Buparlisib, an oral reversible inhibitor of all class I phosphoinositide-3-kinases, has shown antitumoral activity against estrogen receptor (ER)-positive breast cancer cell lines and xenografts, alone and with endocrine therapy. This phase Ib study evaluated buparlisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER-positive breast cancer refractory to endocrine therapy. Patients received letrozole and buparlisib in two different administration schedules. Outcomes were assessed by standard solid-tumor phase I methods. [(18)F]fluorodeoxyglucose-positron emission tomography/computed tomography ([(18)F]FDG-PET/CT) scans were done at baseline and 2 weeks after treatment initiation. Tumor blocks were collected for phosphoinositide-3-kinase pathway mutation analysis. Fifty-one patients were allocated sequentially to continuous or intermittent (five on/two off days) buparlisib administration on an every-4-week schedule. Buparlisib's maximum-tolerated dose (MTD) was 100 mg/d. Common drug-related adverse events included ≤ grade 2 hyperglycemia, nausea, fatigue, transaminitis, and mood disorders. The clinical benefit rate (lack of progression ≥ 6 months) among all patients treated at the MTD was 31%, including two objective responses in the continuous dose arm. Of seven patients remaining on treatment ≥ 12 months, three had tumors with PIK3CA hot-spot mutation. Patients exhibiting metabolic disease progression by [(18)F]FDG-PET/CT scan at 2 weeks progressed rapidly on therapy. The letrozole and buparlisib combination was safe, with reversible toxicities regardless of schedule administration. Clinical activity was observed independent of PIK3CA mutation status. No metabolic response by [(18)F]FDG-PET/CT scan at 2 weeks was associated with rapid disease progression. Phase III trials of buparlisib and endocrine therapy in patients with ER-positive breast cancer are ongoing.