Publication: Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer
Authors
André, Fabrice ; Ciruelos, Eva ; Rubovszky, Gabor ; Campone, Mario ; Loibl, Sibylle ; Rugo, Hope S. ; Iwata, Hiroji ; Conte, Pierfranco ; Mayer, Ingrid A. ; Kaufman, Bella ; Yamashita, Toshinari ; Lu, Yen-Shen ; Inoue, Kenichi ; Takahashi, Masato ; Pápai, Zsuzsanna ; Longin, Anne-Sophie ; Mills, David ; Wilke, Celine ; Hirawat, Samit ; Juric, Dejan ; Alonso Romero, José Luis
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Publisher
Massachusetts Medical Society
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DOI
https://doi.org/10.1056/NEJMoa1813904
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info:eu-repo/semantics/article
Description
© 2019 Massachusetts Medical Society. All rights reserved. This document is the Published version of a Published Work that appeared in final form in New England Journal of Medicine.To access the final edited and published work see https://doi.org/10.1056/NEJMoa1813904
Abstract
Background: PIK3CA mutations occur in approximately 40% of patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer. The PI3Kα-specific inhibitor alpelisib has shown antitumor activity in early studies. Methods: In a randomized, phase 3 trial, we compared alpelisib (at a dose of 300 mg per day) plus fulvestrant (at a dose of 500 mg every 28 days and once on day 15) with placebo plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status. The primary end point was progression-free survival, as assessed by the investigator, in the cohort with PIK3CA-mutated cancer; progression-free survival was also analyzed in the cohort without PIK3CA-mutated cancer. Secondary end points included overall response and safety.
Results: A total of 572 patients underwent randomization, including 341 patients with confirmed tumor-tissue PIK3CA mutations. In the cohort of patients with PIK3CA-mutated cancer, progression-free survival at a median follow-up of 20 months was 11.0 months (95% confidence interval [CI], 7.5 to 14.5) in the alpelisib–fulvestrant group, as compared with 5.7 months (95% CI, 3.7 to 7.4) in the placebo–fulvestrant group (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001); in the cohort without PIK3CA-mutated cancer, the hazard ratio was 0.85 (95% CI, 0.58 to 1.25; posterior probability of hazard ratio <1.00, 79.4%). Overall response among all the patients in the cohort with PIK3CA-mutated cancer was greater with alpelisib–fulvestrant than with placebo–fulvestrant (26.6% vs. 12.8%); among patients with measurable disease in this cohort, the percentages were 35.7% and 16.2%, respectively. In the overall population, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the alpelisib–fulvestrant group vs. 0.7% in the placebo–fulvestrant group) and rash (9.9% vs. 0.3%). Diarrhea of grade 3 occurred in 6.7% of patients in the alpelisib–fulvestrant group, as compared with 0.3% of those in the placebo–fulvestrant group; no diarrhea of grade 4 was reported. The percentages of patients who discontinued alpelisib and placebo owing to adverse events were 25.0% and 4.2%, respectively. Conclusions: Treatment with alpelisib–fulvestrant prolonged progression-free survival among patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. (Funded by Novartis Pharmaceuticals; SOLAR-1 ClinicalTrials.gov number, NCT02437318.)
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Citation
N Engl J Med 2019 380:1929-1940
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