PMID- 28800861
OWN - NLM
STAT- MEDLINE
DCOM- 20171012
LR  - 20181002
IS  - 1474-5488 (Electronic)
IS  - 1470-2045 (Linking)
VI  - 18
IP  - 10
DP  - 2017 Oct
TI  - Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy 
      for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, 
      double-blind, placebo-controlled, phase 2 trial.
PG  - 1360-1372
LID - S1470-2045(17)30450-3 [pii]
LID - 10.1016/S1470-2045(17)30450-3 [doi]
AB  - BACKGROUND: The oral AKT inhibitor ipatasertib is being investigated in cancers
      with a high prevalence of PI3K/AKT pathway activation, including triple-negative 
      breast cancer. The LOTUS trial investigated the addition of ipatasertib to
      paclitaxel as first-line therapy for triple-negative breast cancer. METHODS: In
      this randomised, placebo-controlled, double-blind, phase 2 trial, women aged 18
      years or older with measurable, inoperable, locally advanced or metastatic
      triple-negative breast cancer previously untreated with systemic therapy were
      recruited from 44 hospitals in South Korea, the USA, France, Spain, Taiwan,
      Singapore, Italy, and Belgium. Enrolled patients were randomly assigned (1:1) to 
      receive intravenous paclitaxel 80 mg/m(2) (days 1, 8, 15) with either ipatasertib
      400 mg or placebo once per day (days 1-21) every 28 days until disease
      progression or unacceptable toxicity. Randomisation was by stratified permuted
      blocks (block size of four) using an interactive web-response system with three
      stratification criteria: previous (neo)adjuvant therapy, chemotherapy-free
      interval, and tumour PTEN status. The co-primary endpoints were progression-free 
      survival in the intention-to-treat population and progression-free survival in
      the PTEN-low (by immunohistochemistry) population. This ongoing trial is
      registered with ClinicalTrials.gov (NCT02162719). FINDINGS: Between Sept 2, 2014,
      and Feb 4, 2016, 166 patients were assessed for eligibility and 124 patients were
      enrolled and randomly assigned to paclitaxel plus ipatasertib (n=62) or
      paclitaxel plus placebo (n=62). Median follow-up was 10.4 months (IQR 6.5-14.1)
      in the ipatasertib group and 10.2 months (6.0-13.6) in the placebo group. Median 
      progression-free survival in the intention-to-treat population was 6.2 months
      (95% CI 3.8-9.0) with ipatasertib versus 4.9 months (3.6-5.4) with placebo
      (stratified hazard ratio [HR] 0.60, 95% CI 0.37-0.98; p=0.037) and in the 48
      patients with PTEN-low tumours, median progression-free survival was 6.2 months
      (95% CI 3.6-9.1) with ipatasertib versus 3.7 months (1.9-7.3) with placebo
      (stratified HR 0.59, 95% CI 0.26-1.32, p=0.18). The most common grade 3 or worse 
      adverse events were diarrhoea (14 [23%] of 61 ipatasertib-treated patients vs
      none of 62 placebo-treated patients), neutrophil count decreased (five [8%] vs
      four [6%]), and neutropenia (six [10%] vs one [2%]). No colitis, grade 4
      diarrhoea, or treatment-related deaths were reported with ipatasertib. One
      treatment-related death occurred in the placebo group. Serious adverse events
      were reported in 17 (28%) of 61 patients in the ipatasertib group and nine (15%) 
      of 62 patients in the placebo group. INTERPRETATION: Progression-free survival
      was longer in patients who received ipatasertib than in those who received
      placebo. To our knowledge, these are the first results supporting AKT-targeted
      therapy for triple-negative breast cancer. Ipatasertib warrants further
      investigation for the treatment of triple-negative breast cancer. FUNDING: F
      Hoffmann-La Roche.
CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
FAU - Kim, Sung-Bae
AU  - Kim SB
AD  - Department of Oncology, Asan Medical Center, University of Ulsan College of
      Medicine, Seoul, South Korea. Electronic address: sbkim3@amc.seoul.kr.
FAU - Dent, Rebecca
AU  - Dent R
AD  - Division of Medical Oncology, National Cancer Centre, Singapore, Singapore.
FAU - Im, Seock-Ah
AU  - Im SA
AD  - Department of Internal Medicine, Seoul National University Hospital, Cancer
      Research Institute, Seoul National University College of Medicine, Seoul, South
      Korea.
FAU - Espie, Marc
AU  - Espie M
AD  - Breast Disease Center, Hospital Saint Louis, Paris, France.
FAU - Blau, Sibel
AU  - Blau S
AD  - Northwest Medical Specialties and Division of Oncology, University of Washington,
      Washington, WA, USA.
FAU - Tan, Antoinette R
AU  - Tan AR
AD  - Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA.
FAU - Isakoff, Steven J
AU  - Isakoff SJ
AD  - Massachusetts General Hospital, Boston, MA, USA.
FAU - Oliveira, Mafalda
AU  - Oliveira M
AD  - Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron
      Institute of Oncology, Barcelona, Spain.
FAU - Saura, Cristina
AU  - Saura C
AD  - Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron
      Institute of Oncology, Barcelona, Spain.
FAU - Wongchenko, Matthew J
AU  - Wongchenko MJ
AD  - Genentech Inc, South San Francisco, CA, USA.
FAU - Kapp, Amy V
AU  - Kapp AV
AD  - Genentech Inc, South San Francisco, CA, USA.
FAU - Chan, Wai Y
AU  - Chan WY
AD  - Genentech Inc, South San Francisco, CA, USA.
FAU - Singel, Stina M
AU  - Singel SM
AD  - Genentech Inc, South San Francisco, CA, USA.
FAU - Maslyar, Daniel J
AU  - Maslyar DJ
AD  - Department of Oncology, Asan Medical Center, University of Ulsan College of
      Medicine, Seoul, South Korea.
FAU - Baselga, Jose
AU  - Baselga J
AD  - Memorial Sloan Kettering Cancer Center, New York, NY, USA.
CN  - LOTUS investigators
LA  - eng
SI  - ClinicalTrials.gov/NCT02162719
GR  - P30 CA008748/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase II
PT  - Comparative Study
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20170808
PL  - England
TA  - Lancet Oncol
JT  - The Lancet. Oncology
JID - 100957246
RN  - 0 (Placebos)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - P88XT4IS4D (Paclitaxel)
SB  - IM
CIN - Lancet Oncol. 2017 Oct;18(10):1293-1294. PMID: 28800863
MH  - Administration, Oral
MH  - Adult
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse
      effects
MH  - Confidence Intervals
MH  - Disease-Free Survival
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Drug Administration Schedule
MH  - Female
MH  - Humans
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Neoplasm Invasiveness/pathology
MH  - Neoplasm Staging
MH  - Paclitaxel/*administration & dosage/adverse effects
MH  - Patient Selection
MH  - Placebos/administration & dosage
MH  - Prognosis
MH  - Proportional Hazards Models
MH  - Proto-Oncogene Proteins c-akt/administration & dosage/*antagonists & inhibitors
MH  - Risk Assessment
MH  - Survival Analysis
MH  - Treatment Outcome
MH  - Triple Negative Breast Neoplasms/*drug therapy/*mortality/pathology
PMC - PMC5626630
MID - NIHMS899700
IR  - Kim SB
FIR - Kim, Sung-Bae
IR  - Lee KS
FIR - Lee, Keun Seok
IR  - Im SA
FIR - Im, Seock-Ah
IR  - Espie M
FIR - Espie, Marc
IR  - Wang HC
FIR - Wang, Hwei-Chung
IR  - Blau S
FIR - Blau, Sibel
IR  - Dent R
FIR - Dent, Rebecca
IR  - Tan A
FIR - Tan, Antoinette
IR  - Sohn JH
FIR - Sohn, Joo Hyuk
IR  - De Laurentiis M
FIR - De Laurentiis, Michelino
IR  - Estevez LG
FIR - Estevez, Laura Garcia
IR  - Huang CS
FIR - Huang, Chiun-Sheng
IR  - Romieu G
FIR - Romieu, Gilles
IR  - Velez M
FIR - Velez, Michel
IR  - Villanueva R
FIR - Villanueva, Rafael
IR  - Conte PF
FIR - Conte, Pier Franco
IR  - Dakhil S
FIR - Dakhil, Shaker
IR  - Debled M
FIR - Debled, Marc
IR  - Martin AG
FIR - Martin, Antonio Gonzalez
IR  - Hurvitz S
FIR - Hurvitz, Sara
IR  - Kim JH
FIR - Kim, Jee Hyun
IR  - Levy C
FIR - Levy, Christelle
IR  - Oliveira M
FIR - Oliveira, Mafalda
IR  - Rovira PS
FIR - Rovira, Pedro Sanchez
IR  - Seo JH
FIR - Seo, Jae Hong
IR  - Valero V
FIR - Valero, Vicente
IR  - Vidal G
FIR - Vidal, Gregory
IR  - Wong A
FIR - Wong, Andrea
IR  - Allison MAK
FIR - Allison, Mary Ann K
IR  - Figlin R
FIR - Figlin, Robert
IR  - Chan D
FIR - Chan, David
IR  - Chen SC
FIR - Chen, Shin-Cheh
IR  - Chen YH
FIR - Chen, Yen-Hsun
IR  - Cobleigh M
FIR - Cobleigh, Melody
IR  - De Braud F
FIR - De Braud, Filippo
IR  - Dirix L
FIR - Dirix, Luc
IR  - Hansen V
FIR - Hansen, Vincent
IR  - Bessard AH
FIR - Bessard, Anne Hardy
IR  - Iannotti N
FIR - Iannotti, Nicholas
IR  - Isakoff S
FIR - Isakoff, Steven
IR  - Lawler W
FIR - Lawler, William
IR  - Montano A
FIR - Montano, Alvaro
IR  - Salkini M
FIR - Salkini, Mohamad
IR  - Seigel L
FIR - Seigel, Leonard
EDAT- 2017/08/13 06:00
MHDA- 2017/10/13 06:00
CRDT- 2017/08/13 06:00
PHST- 2017/05/04 00:00 [received]
PHST- 2017/05/30 00:00 [revised]
PHST- 2017/05/31 00:00 [accepted]
PHST- 2017/08/13 06:00 [pubmed]
PHST- 2017/10/13 06:00 [medline]
PHST- 2017/08/13 06:00 [entrez]
AID - S1470-2045(17)30450-3 [pii]
AID - 10.1016/S1470-2045(17)30450-3 [doi]
PST - ppublish
SO  - Lancet Oncol. 2017 Oct;18(10):1360-1372. doi: 10.1016/S1470-2045(17)30450-3. Epub
      2017 Aug 8.