A phase II randomized study of neoadjuvant letrozole plus alpelisib for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer (NeO-ORB)

Ingrid A. Mayer, Aleix Prat, Daniel Egle, Sibel Blau, J. Alejandro Perez Fidalgo, Michael Gnant, Peter A. Fasching, Marco Colleoni, Antonio C Wolff, Eric P. Winer, Christian F. Singer, Sara Hurvitz, Laura García Estevez, Peter A. Van Dam, Sherko Kummel, Christoph Mundhenke, Frankie Holmes, Naveen Babbar, Laure Charbonnier, Ivan Diaz-PadillaFlorian D. Vogl, Dalila Sellami, Carlos L. Arteaga

Research output: Contribution to journalArticle

Abstract

Purpose: Addition of alpelisib to fulvestrant significantly extended progression-free survival in PIK3CA-mutant, hormone receptor–positive (HR þ ) advanced/metastatic breast cancer in the phase III SOLAR-1 study. The combination of alpelisib and letrozole also had promising activity in phase I studies of HR þ advanced/metastatic breast cancer. NEO-ORB aimed to determine whether addition of alpelisib to letrozole could increase response rates in the neoadjuvant setting. Patients and Methods: Postmenopausal women with HR þ , human epidermal growth factor receptor 2-negative, T1c-T3 breast cancer were assigned to the PIK3CA-wild-type or PIK3CA-mutant cohort according to their tumor PIK3CA status, and randomized (1:1) to 2.5 mg/day letrozole with 300 mg/day alpelisib or placebo for 24 weeks. Primary endpoints were objective response rate (ORR) and pathologic complete response (pCR) rate for both PIK3CA cohorts. Results: In total, 257 patients were assigned to letrozole plus alpelisib (131 patients) or placebo (126 patients). Grade 3 adverse events (5% of patients) in the alpelisib arm were hyperglycemia (27%), rash (12%), and maculopapular rash (8%). The primary objective was not met; ORR in the alpelisib versus placebo arm was 43% versus 45% and 63% versus 61% in the PIK3CA-mutant and wild-type cohorts, respectively. pCR rates were low in all groups. Decreases in Ki-67 were similar across treatment arms and cohorts. In PIK3CA-mutant tumors, alpelisib plus letrozole treatment induced a greater decrease in phosphorylated AKT versus placebo plus letrozole. Conclusions: In contrast to initial results in advanced/metastatic disease, addition of alpelisib to 24-week neoadjuvant letrozole treatment did not improve response in patients with HR þ early breast cancer.

Original languageEnglish (US)
Pages (from-to)2975-2987
Number of pages13
JournalClinical Cancer Research
Volume25
Issue number10
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Mayer, I. A., Prat, A., Egle, D., Blau, S., Alejandro Perez Fidalgo, J., Gnant, M., Fasching, P. A., Colleoni, M., Wolff, A. C., Winer, E. P., Singer, C. F., Hurvitz, S., Estevez, L. G., Van Dam, P. A., Kummel, S., Mundhenke, C., Holmes, F., Babbar, N., Charbonnier, L., ... Arteaga, C. L. (2019). A phase II randomized study of neoadjuvant letrozole plus alpelisib for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer (NeO-ORB). Clinical Cancer Research, 25(10), 2975-2987. https://doi.org/10.1158/1078-0432.CCR-18-3160