Peter Schmid
Capivasertib Plus Paclitaxel Versus Placebo Plus Paclitaxel As First-Line Therapy for Metastatic Triple-Negative Breast Cancer: The PAKT Trial
Schmid, Peter; Abraham, Jacinta; Chan, Stephen; Wheatley, Duncan; Murray Brunt, Adrian; Nemsadze, Gia; D. Baird, Richard; Hee Park, Yeon; S. Hall, Peter; Perren, Timothy; C. Stein, Robert; Mangel, László; Ferrero, Jean-Marc; Phillips, Melissa; Conibear, John; Cortes, Javier; Foxley, Andrew; C. de Bruin, Elza; McEwen, Robert; Stetson, Daniel; Dougherty, Brian; Sarker, Shah-Jalal; Prendergast, Aaron; McLaughlin-Callan, Max; Burgess, Matthew; Lawrence, Cheryl; Cartwright, Hayley; Mousa, Kelly; C. Turner, Nicholas
Authors
Jacinta Abraham
Stephen Chan
Duncan Wheatley
Professor Adrian Brunt m.brunt@keele.ac.uk
Gia Nemsadze
Richard D. Baird
Yeon Hee Park
Peter S. Hall
Timothy Perren
Robert C. Stein
László Mangel
Jean-Marc Ferrero
Melissa Phillips
John Conibear
Javier Cortes
Andrew Foxley
Elza C. de Bruin
Robert McEwen
Daniel Stetson
Brian Dougherty
Shah-Jalal Sarker
Aaron Prendergast
Max McLaughlin-Callan
Matthew Burgess
Cheryl Lawrence
Hayley Cartwright
Kelly Mousa
Nicholas C. Turner
Abstract
PURPOSE: The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is frequently activated in triple-negative breast cancer (TNBC). The AKT inhibitor capivasertib has shown preclinical activity in TNBC models, and drug sensitivity has been associated with activation of PI3K or AKT and/or deletions of PTEN. The PAKT trial was designed to evaluate the safety and efficacy of adding capivasertib to paclitaxel as first-line therapy for TNBC. PATIENTS AND METHODS: This double-blind, placebo-controlled, randomized phase II trial recruited women with untreated metastatic TNBC. A total of 140 patients were randomly assigned (1:1) to paclitaxel 90 mg/m2 (days 1, 8, 15) with either capivasertib (400 mg twice daily) or placebo (days 2-5, 9-12, 16-19) every 28 days until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), PFS and OS in the subgroup with PIK3CA/AKT1/PTEN alterations, tumor response, and safety. RESULTS: Median PFS was 5.9 months with capivasertib plus paclitaxel and 4.2 months with placebo plus paclitaxel (hazard ratio [HR], 0.74; 95% CI, 0.50 to 1.08; 1-sided P = .06 [predefined significance level, 1-sided P = .10]). Median OS was 19.1 months with capivasertib plus paclitaxel and 12.6 months with placebo plus paclitaxel (HR, 0.61; 95% CI, 0.37 to 0.99; 2-sided P = .04). In patients with PIK3CA/AKT1/PTEN-altered tumors (n = 28), median PFS was 9.3 months with capivasertib plus paclitaxel and 3.7 months with placebo plus paclitaxel (HR, 0.30; 95% CI, 0.11 to 0.79; 2-sided P = .01). The most common grade = 3 adverse events in those treated with capivasertib plus paclitaxel versus placebo plus paclitaxel, respectively, were diarrhea (13% v 1%), infection (4% v 1%), neutropenia (3% v 3%), rash (4% v 0%), and fatigue (4% v 0%). CONCLUSION: Addition of the AKT inhibitor capivasertib to first-line paclitaxel therapy for TNBC resulted in significantly longer PFS and OS. Benefits were more pronounced in patients with PIK3CA/AKT1/PTEN-altered tumors. Capivasertib warrants further investigation for treatment of TNBC.
Journal Article Type | Article |
---|---|
Acceptance Date | Sep 25, 2019 |
Online Publication Date | Dec 16, 2019 |
Publication Date | Feb 10, 2020 |
Publicly Available Date | May 26, 2023 |
Journal | Journal of Clinical Oncology |
Print ISSN | 0732-183X |
Electronic ISSN | 1527-7755 |
Publisher | American Society of Clinical Oncology |
Peer Reviewed | Peer Reviewed |
Volume | 38 |
Issue | 5 |
Pages | 423 - 433 |
DOI | https://doi.org/10.1200/JCO.19.00368 |
Publisher URL | https://ascopubs.org/doi/pdf/10.1200/JCO.19.00368 |
Files
jco.19.00368.pdf
(1 Mb)
PDF
Publisher Licence URL
https://creativecommons.org/licenses/by-nc/4.0/
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