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J Clin Oncol. 2020 Feb 10;38(5):423-433. doi: 10.1200/JCO.19.00368. Epub 2019 Dec 16.

Capivasertib Plus Paclitaxel Versus Placebo Plus Paclitaxel As First-Line Therapy for Metastatic Triple-Negative Breast Cancer: The PAKT Trial.

Author information

1
Barts ECMC, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
2
Barts Hospital NHS Trust, London, United Kingdom.
3
Velindre National Health Service (NHS) Trust, Cardiff, United Kingdom.
4
Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
5
Royal Cornwall Hospitals NHS Trust, Truro, United Kingdom.
6
University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, United Kingdom.
7
Institute of Clinical Oncology, Tbilisi, Georgia.
8
Cancer Research UK Cambridge Centre, Cambridge, United Kingdom.
9
Samsung Medical Centre, Seoul, Republic of Korea.
10
Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom.
11
Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.
12
National Institute for Health Research Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, University College London, London, United Kingdom.
13
Institute of Oncology, Medical University of Pécs, Pecs, Hungary.
14
Centre Antoine Lacassagne, Nice, France.
15
Ramon y Cajal University Hospital, Madrid, Spain.
16
AstraZeneca, Cambridge, United Kingdom.
17
AstraZeneca, Waltham, MA.
18
Institute of Cancer Research, London, United Kingdom.
19
Royal Marsden Hospital, London, United Kingdom.

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.

PMID:
31841354
DOI:
10.1200/JCO.19.00368

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