Phase II Randomized Preoperative Window-of-Opportunity Study of the PI3K Inhibitor Pictilisib Plus Anastrozole Compared With Anastrozole Alone in Patients With Estrogen Receptor-Positive Breast Cancer.

Abstract

PURPOSE:

Preclinical data support a key role for the PI3K pathway in estrogen receptor-positive breast cancer and suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance. This preoperative window study assessed whether adding the PI3K inhibitor pictilisib (GDC-0941) can increase the antitumor effects of anastrozole in primary breast cancer and aimed to identify the most appropriate patient population for combination therapy.

PATIENTS AND METHODS:

In this randomized, open-label phase II trial, postmenopausal women with newly diagnosed operable estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers were recruited. Participants were randomly allocated (2:1, favoring the combination) to 2 weeks of preoperative treatment with anastrozole 1 mg once per day (n = 26) or the combination of anastrozole 1 mg with pictilisib 260 mg once per day (n = 49). The primary end point was inhibition of tumor cell proliferation as measured by change in Ki-67 protein expression between tumor samples taken before and at the end of treatment.

RESULTS:

There was significantly greater geometric mean Ki-67 suppression of 83.8% (one-sided 95% CI, ≥ 79.0%) for the combination and 66.0% (95% CI, ≤ 75.4%) for anastrozole (geometric mean ratio [combination:anastrozole], 0.48; 95% CI, ≤ 0.72; P = .004). PIK3CA mutations were not predictive of response to pictilisib, but there was significant interaction between response to treatment and molecular subtype (P = .03); for patients with luminal B tumors, the combination:anastrozole geometric mean ratio of Ki-67 suppression was 0.37 (95% CI, ≤ 0.67; P = .008), whereas no significant Ki-67 response was observed for pictilisib in luminal A tumors (1.01; P = .98). Multivariable analysis confirmed Ki-67 response to the combination treatment of patients with luminal B tumors irrespective of progesterone receptor status or baseline Ki-67 expression.

CONCLUSION:

Adding pictilisib to anastrozole significantly increases suppression of tumor cell proliferation in luminal B primary breast cancer.

• Authors: Peter Schmid, Sarah E Pinder, Duncan Wheatley, Jane Macaskill, Charles Zammit, Jennifer Hu, Robert Price, Nigel Bundred, Sirwan Hadad, Alice Shia, Shah-Jalal Sarker, Louise Lim, Patrycja Gazinska, Natalie Woodman, Darren Korbie, Matt Trau, Paul Mainwaring, Steven Gendreau, Mark R Lackner, Mika Derynck, Timothy R Wilson, Hannah Butler, Gemma Earl, Peter Parker, Arnie Purushotham, Alastair Thompson
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 34 Issue 17 Pg. 1987-94 (06 10 2016) ISSN: 1527-7755 [Electronic] United States
• PMID: 26976426 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial)
• Copyright: © 2016 by American Society of Clinical Oncology.

Chemical References

• 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
• Biomarkers, Tumor
• Indazoles
• Nitriles
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Receptors, Estrogen
• Sulfonamides
• Triazoles
• Anastrozole
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Aged
• Aged, 80 and over
• Anastrozole
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor (metabolism)
• Breast Neoplasms (drug therapy, metabolism, surgery)
• Combined Modality Therapy
• Drug Synergism
• Female
• Humans
• Indazoles (administration & dosage)
• Middle Aged
• Neoplasms, Hormone-Dependent (drug therapy, metabolism, surgery)
• Nitriles (administration & dosage, therapeutic use)
• Phosphoinositide-3 Kinase Inhibitors
• Postmenopause
• Preoperative Care (methods)
• Protein Kinase Inhibitors (administration & dosage)
• Receptor, ErbB-2 (biosynthesis)
• Receptors, Estrogen (biosynthesis)
• Sulfonamides (administration & dosage)
• Triazoles (administration & dosage, therapeutic use)