Professional Documents
Culture Documents
Summary
Lancet Oncol 2017; 18: 136072 Background The oral AKT inhibitor ipatasertib is being investigated in cancers with a high prevalence of PI3K/AKT
Published Online pathway activation, including triple-negative breast cancer. The LOTUS trial investigated the addition of ipatasertib to
August 8, 2017 paclitaxel as first-line therapy for triple-negative breast cancer.
http://dx.doi.org/10.1016/
S1470-2045(17)30450-3
Methods In this randomised, placebo-controlled, double-blind, phase 2 trial, women aged 18 years or older with
See Comment page 1293
measurable, inoperable, locally advanced or metastatic triple-negative breast cancer previously untreated with
*Contributed equally
systemic therapy were recruited from 44 hospitals in South Korea, the USA, France, Spain, Taiwan, Singapore, Italy,
Listed in the appendix
and Belgium. Enrolled patients were randomly assigned (1:1) to receive intravenous paclitaxel 80 mg/m (days 1, 8,
Department of Oncology, Asan
15) with either ipatasertib 400 mg or placebo once per day (days 121) every 28 days until disease progression or
Medical Center, University of
Ulsan College of Medicine, Seoul, unacceptable toxicity. Randomisation was by stratified permuted blocks (block size of four) using an interactive
South Korea (Prof S-B Kim MD); web-response system with three stratification criteria: previous (neo)adjuvant therapy, chemotherapy-free interval,
Division of Medical Oncology, and tumour PTEN status. The co-primary endpoints were progression-free survival in the intention-to-treat population
National Cancer Centre,
and progression-free survival in the PTEN-low (by immunohistochemistry) population. This ongoing trial is registered
Singapore, Singapore
(R Dent MD); Department of with ClinicalTrials.gov (NCT02162719).
Internal Medicine, Seoul
National University Hospital, Findings Between Sept 2, 2014, and Feb 4, 2016, 166 patients were assessed for eligibility and 124 patients were
Cancer Research Institute, Seoul
National University College of
enrolled and randomly assigned to paclitaxel plus ipatasertib (n=62) or paclitaxel plus placebo (n=62). Median
Medicine, Seoul, South Korea follow-up was 104 months (IQR 65141) in the ipatasertib group and 102 months (60136) in the placebo
(S-A Im MD); Breast Disease group. Median progression-free survival in the intention-to-treat population was 62 months (95% CI 3890) with
Center, Hospital Saint Louis, ipatasertib versus 49 months (3654) with placebo (stratified hazard ratio [HR] 060, 95% CI 037098; p=0037)
Paris, France (M Espi MD);
Northwest Medical Specialties
and in the 48 patients with PTEN-low tumours, median progression-free survival was 62 months (95% CI 3691)
and Division of Oncology, with ipatasertib versus 37 months (1973) with placebo (stratified HR 059, 95% CI 026132, p=018). The most
University of Washington, common grade 3 or worse adverse events were diarrhoea (14 [23%] of 61 ipatasertib-treated patients vs none of
Washington, WA, USA 62 placebo-treated patients), neutrophil count decreased (five [8%] vs four [6%]), and neutropenia (six [10%] vs
(S Blau MD); Levine Cancer
Institute, Carolinas HealthCare
one [2%]). No colitis, grade 4 diarrhoea, or treatment-related deaths were reported with ipatasertib. One treatment-
System, Charlotte, NC, USA related death occurred in the placebo group. Serious adverse events were reported in 17 (28%) of 61 patients in the
(A R Tan MD); Massachusetts ipatasertib group and nine (15%) of 62 patients in the placebo group.
General Hospital, Boston, MA,
USA (S J Isakoff MD); Medical
Oncology Department, Vall
Interpretation Progression-free survival was longer in patients who received ipatasertib than in those who received
dHebron University Hospital, placebo. To our knowledge, these are the first results supporting AKT-targeted therapy for triple-negative breast
Vall dHebron Institute of cancer. Ipatasertib warrants further investigation for the treatment of triple-negative breast cancer.
Oncology, Barcelona, Spain
(M Oliveira MD, C Saura MD);
Genentech Inc, South
Funding F Hoffmann-La Roche.
San Francisco, CA, USA
(M J Wongchenko BS, Introduction The PI3K/AKT signalling pathway is often activated in
A V Kapp PhD, W Y Chan PhD,
The PI3K/AKT signalling pathway plays a crucial part in breast cancer, and has attracted interest as a target in triple-
S M Singel MD, D J Maslyar MD);
and Memorial Sloan Kettering carcinogenesis, promoting cell survival and growth.1,2 negative breast cancer.5,6 Large-scale comp rehensive
Cancer Center, New York, NY, AKT is the central node of the PI3K/AKT pathway.3 genomic analyses have characterised the heterogeneous
USA (J Baselga MD) Phosphatidylinositol (3,4,5)-triphosphate, a direct nature of triple-negative breast cancer, including a
Correspondence to: product of PI3K activity, promotes AKT trafficking to the subgroup with genetic activation of the PI3K/AKT pathway
Prof Sung-Bae Kim, Department cell membrane and association with other cell- signalling through activating mutations in PIK3CA or AKT1, and
of Oncology, Asan Medical
Center, University of Ulsan
proteins.4 Full activation of AKT occurs via alterations in PTEN.79 Additionally, approximately half of
College of Medicine, Songpa-gu, phosphorylation at two threonine and serine residues, triple-negative breast cancers have deficient expression of
Seoul 05505, South Korea leading to phosphorylation and regulation of numerous the tumour suppressor PTEN, which is associated with a
sbkim3@amc.seoul.kr
cellular proteins, including mTORC1 and S6 kinase. higher degree of AKT pathway activation.2,10
institutional review boards at all participating centres managed with loperamide or according to institutional
approved the protocol and all study-related documents. guidelines and standard of care, including but not limited
The protocol is available in the appendix. to therapy with diphenoxylate and atropine, codeine,
or octreotide. If symptoms persisted despite adequate
Randomisation and masking (combination) antidiarrhoeal medications and dose
Eligible patients were randomly assigned (1:1) to either interruptions, dose reductions were implemented.
ipatasertib plus paclitaxel or placebo plus paclitaxel by Ipatasertib (or placebo) was initially reduced to
investigators using an interactive web-response system 300 mg/day, then to 200 mg/day, and was discontinued
with an allocation sequence generated by Bracket Global permanently at the third appearance of an adverse event
LCC (Reading, UK). Randomisation was by stratified requiring dose reduction. Paclitaxel dose modifications
permuted blocks (block size of four). Randomisation was were implemented according to standard practice or
stratified by three criteria: previous (neo)adjuvant institutional guidelines. The protocol suggested a
chemotherapy (yes vs no), chemotherapy-free interval reduction to 65 mg/m at the first reduction and then
(12 vs >12 months vs no previous chemotherapy), and permanent discontinuation if toxicity recurred. All
central tumour PTEN status as assessed by patients who discontinued study therapy were allowed to
immunohistochemistry (H score 0 vs 1150 vs >150). In receive subsequent anticancer therapy outside the study
some cases, patients were randomly assigned before protocol. Disease progression that occurred after initiation
PTEN status was available; for stratification, these of a new anticancer therapy was not collected per protocol;
patients were assigned to the stratum with an H score in such patients, progression-free survival was censored at
more than 150. This approach was adopted because if the time of the last tumour assessment.
patients were otherwise eligible and able to enrol on the Tumours were assessed every 8 weeks by the
study, we did not consider it ethically acceptable to delay investigators according to RECIST (version 1.1). After
their first-line treatment while waiting for centrally discontinuation of treatment, patients were followed up
assessed PTEN status or if tissue samples were inadequate every 3 months for survival and subsequent anticancer
for central PTEN analysis. However, for stratified efficacy therapies. Safety was assessed and graded according to
analyses, the actual PTEN status (if known) was used. National Cancer Institute Common Terminology Criteria
The stratification factors of previous (neo)adjuvant for Adverse Events (version 4.0) on an ongoing basis until
chemotherapy and chemotherapy-free interval partly the study drug discontinuation visit (or resolution or
overlap. However, our intention was to try to balance the stabilisation of ongoing related adverse events).
treatment groups in this heterogeneous treatment setting Laboratory assessments (including haematology, fasting
not only by sensitivity to previous (neo)adjuvant serum chemistry, coagulation, fasting lipid profile, and
chemotherapy, but also according to tumour biology urinalysis) were done within 48 h before each study drug
(depending on priming of the PI3K/AKT signalling administration. Patient-reported outcomes (PROs) were
pathway by previous chemotherapy) or clinical features of assessed using the European Organisation for Research
recurrence or de-novo stage IV disease that could be and Treatment of Cancer Core Quality of Life
differentiated by previous (neo)adjuvant chemotherapy. Questionnaire C30 (EORTC QLQ-C30), which includes
Placebo tablets were identical in shape and colour to 30 questions assessing five functional scales, three
the ipatasertib tablets. Investigators, patients, and the symptom scales, and six single items. Questionnaires
sponsor were masked to treatment assignment. were distributed by staff at the site and completed by the
patient before study assessments or drug administration
Procedures on day 1 of every cycle, at treatment discontinuation, and
Patients received intravenous paclitaxel 80 mg/m on at tumour follow-up. Pharmacokinetic parameters of
days 1, 8, and 15 of each 28-day cycle in combination ipatasertib were assessed in all patients by sparse plasma
with either oral ipatasertib 400 mg/day or placebo, sampling on day 1 of cycle 1 (052 h and 46 h after study
administered on days 121 of each 28-day cycle. There is drug administration) and on day 8 of cycle 1 (02 h and
no standard paclitaxel schedule in metastatic breast 25 h after study drug administration).
cancer. Investigators indicated a strong preference for the At screening, PTEN status was centrally assessed using
3 weeks on/1 week off schedule of paclitaxel 80 mg/m per antibody clone 138G6 (cat #9559, Cell Signaling
week when the LOTUS trial was designed. This schedule Technology, Leiden, Netherlands; Targos Molecular
has been used in previous clinical studies16,17 and maintains Pathology GmbH, Kassel, Germany). Before the primary
the cumulative dose intensity achieved with 175 mg/m analysis, tumour tissue samples were assessed centrally
every 3 weeks (as recommended in the prescribing by additional molecular assays to define the patient
information). Treatment was continued until disease population with PTEN-low tumours (by immuno histo
progression, intolerable toxicity, or withdrawal of consent. chemistry; co-primary endpoint) and the patient
Ipatasertib or placebo could be temporarily interrupted for population with PI3K/AKT pathway-activated tumours
up to 4 consecutive weeks if patients had toxicity (secondary endpoint). For the co-primary endpoint,
considered related to the study drug. Diarrhoea was PTEN-low tumours were defined as those having
Data are n (%) or median (IQR). ECOG=Eastern Cooperative Oncology Group. IXRS=interactive web-response system. *Stratification factor, reported per IXRS. Data not from
IXRS. More than one answer possible.
meaningful outcomes, the upper limit of the 90% CI Efficacy analyses were based on all randomly assigned
would be less than 1. We report 95% CIs to be consistent patients (intention-to-treat population). Analyses for
with published literature. The primary analysis was the co-primary endpoints were stratified; the Cox
intended to include 50 progression-free survival events proportional hazard model included the treatment group
in patients with PTEN-low tumours. Assuming and three stratification factors as covariates. In this proof-
60% prevalence of PTEN-low tumours, we anticipated of-concept study, the definition of progression-free
83 progression-free survival events in the intention-to- survival for the primary endpoint was chosen with the
treat population. aim of identifying antitumour activity closely related to
Diagnostic
prevalence (%)*
80
60 Results
Between Sept 2, 2014, and Feb 4, 2016, 166 patients were
40
assessed for eligibility and 124 patients were randomly
20
assigned to treatment with ipatasertib (62 patients) or
Stratified HR 060 (95% CI 037098) placebo (62 patients; figure 1). One randomly assigned
Log-rank p=0037
0 patient who received no study treatment was excluded
0 2 4 6 8 10 12 14 16 18 from the safety analysis population. Baseline character
Number at risk
(number censored)
istics were generally balanced between treatment groups
Ipatasertib plus paclitaxel 62 50 (4) 31 (9) 22 (13) 14 (15) 11 (15) 6 (19) 2 (21) 1 (22) 0 (23) (table 1). Biomarker-assessable populations for both
Placebo plus paclitaxel 62 43 (3) 23 (12) 13 (12) 10 (12) 6 (13) 3 (14) 0 (17) PTEN status and PIK3CA/AKT1/PTEN alterations
B showed similar baseline characteristics to the intention-
100 Ipatasertib plus paclitaxel (n=25) to-treat population. In 11 patients (four randomly assigned
Placebo plus paclitaxel (n=23) to placebo and seven randomly assigned to ipatasertib),
the PTEN status used for stratification differed from that
Progression-free survival (%)
80
used for analysis. Of these, five (two placebo, three
60 ipatasertib) were classified as having a PTEN status of
more than 150 at randomisation but their PTEN status in
40
analyses was unknown, four (one placebo, three
20 ipatasertib) were classified as having a PTEN status of
Stratified HR 059 (95% CI 026132)
Log-rank p=018
more than 150 at randomisation but in the analyses, their
0 PTEN H score was 1150, and one (placebo) was classified
0 2 4 6 8 10 12 14 16 18
with a PTEN status of 0 at randomisation but was
Number at risk
(number censored) classified with a PTEN H score of 1150 in the analyses.
Ipatasertib plus paclitaxel 25 21 (0) 12 (4) 9 (5) 5 (6) 4 (6) 0 (9) The remaining patient (ipatasertib) was classified as
Placebo plus paclitaxel 23 15 (1) 8 (3) 6 (3) 5 (3) 3 (3) 2 (3) 0 (5)
having a PTEN status of more than 150 at randomisation
C but in the analyses her PTEN H score was 0.
100 Ipatasertib plus paclitaxel (n=26) Samples were centrally assessable for PTEN in
Placebo plus paclitaxel (n=16) 101 (81%) of 124 patients; in the remaining 23 (19%)
Progression-free survival (%)
Age (years)
<50 16/22 17/24 62 (3691) 29 (1854) 062 (031124)
50 23/40 28/38 57 (37129) 51 (3763) 062 (035109)
DFI since last chemotherapy (months)
12 8/11 12/14 44 (1973) 35 (1639) 046 (016136)
>12 16/31 20/28 91 (67NA) 54 (3673) 049 (025095)
No prior chemotherapy 15/20 13/20 37 (3690) 54 (2891) 100 (046217)
(Neo)adjuvant chemotherapy
Yes 24/42 31/41 72 (5593) 37 (2951) 048 (028081)
No 15/20 14/21 37 (3690) 54 (2891) 103 (048220)
Targos IHC PTEN status (H-score)
0 5/11 7/10 72 (55NA) 18 (18109) 021 (006075)
1150 23/30 22/29 37 (3357) 51 (3673) 101 (056183)
>150 9/18 15/21 90 (55NA) 37 (1963) 036 (015086)
Unknown 2/3 1/2 72 (1672) 54 (NA) 082 (0051324)
Ventana IHC PTEN status (staining intensity)
PTEN low 16/25 18/23 62 (3691) 36 (1973) 068 (035135)
PTEN non-low 17/29 19/24 67 (37129) 50 (2955) 054 (027107)
Unknown 6/8 8/15 57 (3393) 51 (2954) 051 (016163)
NGS PIK3CA/AKT1/PTEN
Altered 12/26 13/16 90 (46NA) 49 (3663) 044 (020099)
Non-altered 21/28 23/33 53 (3673) 36 (2955) 076 (041140)
Unknown 6/8 9/13 57 (3273) 51 (17110) 083 (029242)
All 39/62 45/62 62 (3890) 49 (3654) 062 (040095)
02 05 1 2 4
follow-up was 104 months (IQR 65141) in the p=0081); median progression-free survival
ipatasertib group and 102 months (60136) in the was 59 months (95% CI 3873) with ipatasertib versus
placebo group. Among patients who discontinued study 50 months (3654) with placebo.
treatment before disease progression, the proportions At the time of data cutoff, progression-free survival
subsequently receiving non-study systemic anticancer events had been documented in 34 (71%) of 48 patients in
therapy were similar in the two treatment groups (five [8%] the PTEN-low population (16 [64%] of 25 in the ipatasertib
of 62 patients in the ipatasertib group and six [10%] of group and 18 [78%] of 23 in the placebo group). In this
62 patients in the placebo group). These patients were population, median progression-free survival was
censored at the date of last tumour assessment before 62 months (95% CI 3691) with ipatasertib versus
initiation of new anticancer therapy except for two patients 37 months (1973) with placebo (stratified HR 059,
(both with a progression-free survival event; appendix p 5). 95% CI 026132, log-rank p=018; figure 3B).
The primary progression-free survival analysis was Prespecified analyses in the subgroup of 42 patients
triggered by reaching approximately 83 progression-free with PIK3CA/AKT1/PTEN-altered tumours, after
survival events in the intention-to-treat population: progression-free survival events in 12 (46%) of 26 patients
39 events in the ipatasertib group and 45 in the placebo in the ipatasertib group and 13 (81%) of 16 patients in the
group. One patient in each group died without evidence placebo group, showed median progression-free survival
of progression; the remaining events were disease of 90 months (95% CI 46not assessable) with
progression. Median progression-free survival was ipatasertib versus 49 months (3663) with placebo
62 months (95% CI 3890) with ipatasertib versus (non-stratified HR 044, 95% CI 020099, log-rank
49 months (3654) with placebo (stratified HR 060, p=0041; figure 3C). In patients with PIK3CA/AKT1/
95% CI 037098; log-rank p=0037; figure 3A). In the PTEN-non-altered tumours, with progression-free
sensitivity analysis, including all deaths from any cause, survival events in 21 (75%) of 28 patients in the ipatasertib
the stratified HR was 066 (95% CI 041106; log-rank group and 23 (70%) of 33 patients in the placebo group,
Data are n (%) or median (95% CI). Objective response is per Response Evaluation Criteria in Solid Tumors version 1.1. Clinical benefit is defined as either an objective
response, or a best overall response of complete or partial response or stable disease together with a progression-free survival of 24 weeks. NA=not assessable.
the median progression-free survival was 53 months respiratory tract infection (three [5%] vs none). Of note,
(95% CI 3673) in the ipatasertib group versus there were no episodes of grade 4 diarrhoea and no
37 months (2955) in the placebo group (non-stratified reported cases of colitis. Serious adverse events were
HR 076, 95% CI 041140, p=036). Progression-free more common in the ipatasertib group (17 [28%] of
survival in selected subgroups, including the 61 patients, predominantly infections and gastro
randomisation stratification factors, is shown in figure 4. intestinal effects) than in the placebo group (nine [15%]
Further anticancer therapy was administered after of 62 patients, predominantly infections). Four patients
disease progression to 30 (77%) of 39 patients in the had adverse events resulting in death: one patient with
ipatasertib group and 38 (84%) of 45 patients in the pneumonia in the ipatasertib group (not considered
placebo group whose disease had progressed by the time related to study treatment) and three in the placebo
of data cutoff. Overall survival results are immature, with group (one case each of cholestasis together with cell
deaths in nine (15%) of 62 patients in the ipatasertib death [reported by the investigator as cytolysis (liver),
group and 17 (27%) of 62 patients in the placebo group. both events assessed as related to placebo and
The primary cause of death was disease progression in paclitaxel]; metastatic breast cancer; and death from
22 (85%) of 26 patients. Secondary endpoints of objective unknown cause 287 days after the last dose of the study
response and duration of response, and the post-hoc drug).
assessment of clinical benefit are shown in table 3. Diarrhoea typically occurred during the first cycle of
Median duration of response was similar in the two ipatasertib (median time to onset 5 days) but some
treatment groups for the intention-to-treat and PTEN- cases were observed in later cycles. Diarrhoea led to
low populations, but was longer in ipatasertib-treated discontinuation of ipatasertib in two (3%) of 61 patients,
patients compared with placebo in the PIK3CA/AKT1/ dose reduction of ipatasertib in eight (13%), and
PTEN-altered subgroup. temporary interruption of ipatasertib in four (7%). Anti-
The most common adverse events of any grade in the diarrhoeal drugs (predominantly loperamide) were
ipatasertib group were gastrointestinal effects administered in 39 (64%) of 61 patients in the ipatasertib
(diarrhoea, nausea, and vomiting), alopecia, neuropathy, group and six (10%) of 62 patients in the placebo group.
fatigue, and rash (table 4). These were typically grade 1 At data cutoff, almost all episodes of diarrhoea had
or 2 in severity. Grade 3 or worse adverse events resolved.
occurred in 33 (54%) of 61 patients in the ipatasertib There was high compliance with PRO assessment
group and 26 (42%) of 62 patients in the placebo group questionnaires: more than 90% of patients in each
(table 4). The most common individual grade 3 or worse treatment group completed at least one item of the
adverse events in the ipatasertib group were diarrhoea, EORTC QLQ-C30 at each cycle (appendix p 7). In both
neutrophil count decreased, and neutropenia). The treatment groups, mean change from baseline scores for
most common grade 3 or worse adverse events by most functional scales (cognitive, physical, and social)
grouped term (appendix p 6) were diarrhoea (14 [23%] and the global health status/quality-of-life domain were
of 61 ipatasertib-treated patients vs none of 62 placebo- not clinically meaningful according to the predefined
treated patients), neutropenia (comprising neutropenia, threshold of a 10-point change from baseline (appendix
neutrophil count decreased, and febrile neutropenia; pp 89). Similarly, no clinically meaningful changes were
11 [18%] vs five [8%]), peripheral neuropathy (comprising observed for most of the disease-related and treatment-
peripheral sensory neuropathy, neuropathy peripheral, related symptom scales (appetite loss, constipation,
paraesthesia, hypo aesthesia, dysaesthesia, muscular dyspnoea, nausea and vomiting, insomnia, pain, and
weakness, neuro toxicity, and peripheral motor financial difficulties) up to and including cycle 5.
neuropathy; four [7%] vs three [5%]), fatigue or asthenia However, in the ipatasertib group, a clinically meaningful
(three [5%] vs four [6%]), and pneumonia or lower improvement in emotional functioning was observed at
All grades Grade 3 Grade 3* Grade 4* All grades Grade 3 Grade 3* Grade 4*
Adverse events in 10% or more of patients (any grade), all grade 3 or worse in more than one patient in either treatment group, or any grade 4 or 5. *Worst grade
reported (eg, a patient who has an event at both grade 3 and grade 4 appears only in the grade 4 column). Grade 5 in one patient (2%). Unmapped (verbatim term
shown).
cycle 2, whereas a clinically meaningful worsening was after cycle 5 are not described due to sample size attrition
observed for diarrhoea (cycles 25), fatigue (cycle 5), and (in both groups, fewer than 50% of patients remained on
role functioning (cycles 35). Scores from timepoints treatment beyond cycle 5).
The plasma concentrations of ipatasertib obtained by PTEN-low tumours by immunohistochemistry did not
sparse sampling in this study were consistent with known have a genetic alteration. This is consistent with previous
pharmacokinetic profiles and overall characteristics of reports of non-genetic loss of PTEN in triple-negative
ipatasertib and its metabolite G-037720. Exploratory breast cancer.26 In the LOTUS trial, the effect of ipatasertib
analyses showed no relationship between ipatasertib in the subgroup of patients with PTEN-low tumours by
exposure and incidence of diarrhoea, neutropenia, and immunohistochemistry was no greater than in those with
neuropathy (data not shown). PTEN-non-low tumours or in the intention-to-treat
population. However, efficacy analysis in the population
Discussion with PIK3CA/AKT1/PTEN-altered tumours supporting
Results of the randomised, double-blind, placebo- the studys secondary objectives showed an encouraging
controlled, phase 2 LOTUS trial show that adding progression-free survival HR of 044 and an increase of
ipatasertib to paclitaxel as first-line therapy for triple- 41 months in the median progression-free survival
negative breast cancer increased progression-free survival (median 90 months in the ipatasertib group vs 49 months
compared with that for placebo plus paclitaxel. The in the placebo group). Duration of response results
increase in median progression-free survival was quite supported these findings. This difference in efficacy based
modest in the intention-to-treat population and PTEN- on absence of expression of PTEN through non-genetic
low sub group but more pronounced in predefined mechanisms compared with loss of PTEN function
analyses of the patient population with through mutations and copy-number loss could be a key
PIK3CA/AKT1/PTEN-altered tumours characterised by difference in how PTEN loss might drive tumours and be
next-generation sequencing. Overall, adverse events were PI3K/AKT-addicted in prostate versus breast cancers.
consistent with previous experience, manageable, and The most common adverse events were gastrointestinal,
reversible. in particular diarrhoea. Most cases of diarrhoea were
The 49-month median progression-free survival in grade 1 or 2; grade 3 diarrhoea occurred in 23% of patients
the control group of the intention-to-treat population and there were no grade 4 cases. Diarrhoea was manageable
was within the range reported in subgroup analyses and reversible, and only two patients discontinued
of patients with triple-negative breast cancer in previous ipatasertib because of diarrhoea. Of note, primary
randomised trials (46 months in the E2100 trial,20 prophylactic antidiarrhoeal drugs were not specified as
55 months in the NU07B1 trial,21 and 63 months in the part of safety management guidelines in the protocol.
MERiDiAN22 trial). Of note, among patients in LOTUS Although patients in the ipatasertib plus paclitaxel
who had previously received (neo)adjuvant chemotherapy, group had clinically meaningful worsening in patient-
approximately a third had disease recurrence within reported role function, diarrhoea, and fatigue, patients
12 months of chemotherapy (25 [30%] of the 84 patients overall global health status or quality of life was
who had received prior chemotherapy), whereas such maintained up to and including cycle 5. There was also
patients were excluded from the MERiDiAN trial.22 no clinically meaningful change in cognitive, physical, or
Similarly, the 32% of patients achieving response in the social function scales or other symptom scales. Together,
control group of LOTUS seems to be consistent with the our results indicate that the tolerability of the ipatasertib
available data reported in the literature (21% with a plus paclitaxel regimen might allow rational combination
higher starting dose of single-agent paclitaxel in a mixed with other carefully selected agents.
population of triple-negative breast cancer and non- The similar pharmacokinetic profiles in this study and
triple-negative breast cancer patients in the E2100 trial;20 previous experience suggest that there was no paclitaxel
28% with paclitaxel plus onartuzumab in a randomised ipatasertib drug interaction that affected metabolism or
phase 2 trial in triple-negative breast cancer clearance (as predicted from the phase 1b study and
predominantly in the first-line setting23). preliminary assessment by population pharmacokinetic
When the trial was designed, it was anticipated that methodology [Roche data on file]). Although exploratory
patients with PTEN-low tumours by immunohisto- analyses showed no clear relationship between ipatasertib
chemistry might derive increased benefit from ipatasertib. exposure and incidence of diarrhoea, neutropenia,
This was hypothesised because a randomised phase 2 trial and neuropathy, assessment of the exposureresponse
in metastatic castration-resistant prostate cancer showed relationship is difficult in a trial with only one dose level.
that the effect of ipatasertib was more pronounced in One of the main limitations of these results is the small
the subgroup of patients with PTEN loss identified by sample size. The biomarker-selected population showing
immunohistochemistry or next-generation sequencing.24 the most encouraging effect of ipatasertib includes only
However, PTEN loss is only one of several mechanisms 42 patients; despite ours being prespecified analyses, our
leading to activation of the PI3K/AKT pathway. In breast findings should be interpreted with caution and require
cancer, activating mutations in PIK3CA and AKT1 are prospective validation. Furthermore, although baseline
frequently observed, whereas in castration-resistant characteristics in this population were generally
prostate cancer, these mutations are rare.8,9,25 In our study balanced, randomisation was not stratified by next-
population, a substantial proportion of patients with generation sequencing results.
The prevalence of PIK3CA/AKT1/PTEN alterations interpreted the data, reviewed and revised the draft manuscripts, and
was 41%. We observed no clinically significant difference approved the final version for submission.
in the prevalence of PIK3CA/AKT1/PTEN alterations in Declaration of interests
primary versus metastatic samples. We also saw no S-BK reports research funding from Novartis, Sanofi Aventis, Kyowa Kirin
Inc, and Dongkook Pharma Co, Ltd. RD reports honoraria for consultancy,
difference in alteration frequency between samples that advisory boards, and speaker engagements from Pfizer, Roche, Eisai,
were collected before administration of (neo)adjuvant Merck, Novartis, and AstraZeneca and research funding from
chemotherapy and samples collected from chemotherapy- AstraZeneca. S-AI reports honoraria for advisory roles from Novartis,
naive patients. However, this analysis does not preclude Hanmi, and Spectrum and a research grant from AstraZeneca. ME reports
honoraria from Pfizer and Merck Sharp & Dohme, and research funding
the possibility that these alterations might be enriched in to his institution from Roche and Novartis. SB reports a contract (but no
patients with metastatic disease. The apparent absence of honoraria) for consulting and advisory roles for BMS and declares that her
treatment effect in the population of patients who had husband receives royalties associated with his position as a professor at the
received no previous chemotherapy (most of whom had University of Washington and is the owner of the company All4cure. ART
reports honoraria for an advisory board from AbbVie, and research
de-novo stage IV disease at study entry) should be funding (to institution) from Merck, Pfizer, and Genentech. SJI reports
interpreted with caution due to the small sample size. clinical research funding from Genentech. MO reports honoraria for
There have been few targeted therapy advances in consulting and advisory roles from Genentech/Roche. CS reports
the management of triple-negative breast cancer; honoraria for consulting and advisory roles from Puma Biotechnology,
Pfizer, and Roche and research funding (to her institution) from
chemotherapy (with or without the anti-angiogenic Genentech and AstraZeneca. MJW is an employee of Genentech, Inc, and
agent bevacizumab) remains the standard of care for holds shares in Roche and Ariad Pharmaceuticals. AVK, WYC, SMS, and
these patients, who typically have a poor prognosis and DJM are employees of Genentech, Inc, and hold stock in Roche. JB reports
no targeted treatment options. Randomised phase 3 no competing interests.
14 Yan Y, Serra V, Prudkin L, et al. Evaluation and clinical analyses of 23 Diras V, Campone M, Yardley DA, et al. Randomized, phase II,
downstream targets of the Akt inhibitor GDC-0068. Clin Cancer Res placebo-controlled trial of onartuzumab and/or bevacizumab in
2013; 19: 697686. combination with weekly paclitaxel in patients with metastatic
15 Saura C, Roda D, Rosell S, et al. A first-in-human phase I study of triple-negative breast cancer. Ann Oncol 2015; 26: 190410.
the ATP-competitive AKT inhibitor ipatasertib demonstrates robust 24 De Bono JS, De Giorgi U, Massard C, et al. PTEN loss as a
and safe targeting of AKT in patients with solid tumors. predictive biomarker for the AKT inhibitor ipatasertib combined
Cancer Discov 2017; 7: 10213. with abiraterone acetate in patients with metastatic castration-
16 Sato K, Inoue K, Saito T, et al. Multicenter phase II trial of weekly resistant prostate cancer (mCRPC). Ann Oncol 2016;
paclitaxel for advanced or metastatic breast cancer: the Saitama 27 (suppl 6): 718O.
Breast Cancer Clinical Study Group (SBCCSG-01). Jpn J Clin Oncol 25 Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical
2003; 33: 37176. genomics of advanced prostate cancer. Cell 2015; 161: 121528.
17 Miles D, Kim S-B, McNally VA, et al. COLET (NCT02322814): 26 Khan S, Kumagai T, Vora J, et al. PTEN promoter is methylated in a
A multistage, phase 2 study evaluating the safety and efficacy of proportion of invasive breast cancers. Int J Cancer 2004; 112: 40710.
cobimetinib (C) in combination with paclitaxel (P) as first-line 27 Tutt A, Ellis P, Kilburn L, et al. The TNT trial: a randomized
treatment for patients (pts) with metastatic triple-negative breast phase III trial of carboplatin (C) compared with docetaxel (D) for
cancer (TNBC). Proc AmSoc Clin Oncol 2016; patients with metastatic or recurrent locally advanced triple negative
34 (suppl): abstr TPS1100. or BRCA1/2 breast cancer (CRUK/07/012). Cancer Res 2015;
18 Frampton GM, Fichtenholtz A, Otto GA, et al. Development and 75 (suppl 9): abstr S3-01.
validation of a clinical cancer genomic profiling test based on 28 OShaughnessy J, Schwartzberg L, Danso MA, et al. Phase III study
massively parallel DNA sequencing. Nat Biotechnol 2013; of iniparib plus gemcitabine and carboplatin versus gemcitabine
31: 102331. and carboplatin in patients with metastatic triple-negative breast
19 Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the cancer. J Clin Oncol 2014; 32: 384047.
significance of changes in health-related quality of life scores. 29 Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L.
J Clin Oncol 1998; 16: 13944. Triple-negative breast cancer: challenges and opportunities of a
20 Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab heterogeneous disease. Nat Rev Clin Oncol 2016; 13: 67490.
versus paclitaxel alone for metastatic breast cancer. N Engl J Med 30 Isakoff SJ, Saura C, Calvo I, et al. FAIRLANE: a phase II
2007; 357: 266676. randomized, double-blind, study of the Akt inhibitor ipatasertib
21 Gradishar WJ, Kaklamani V, Sahoo TP, et al. A double-blind, (GDC-0068) in combination with paclitaxel as neoadjuvant
randomised, placebo-controlled, phase 2b study evaluating treatment for early stage triple-negative breast cancer.
sorafenib in combination with paclitaxel as a first-line therapy in Proc AmSoc Clin Oncol 2016; 34 (suppl): abstr TPS1105.
patients with HER2-negative advanced breast cancer. Eur J Cancer
2013; 49: 31222.
22 Miles D, Cameron D, Bondarenko I, et al. Bevacizumab plus
paclitaxel versus placebo plus paclitaxel as first-line therapy for
HER2-negative metastatic breast cancer (MERiDiAN):
a double-blind placebo-controlled randomised phase III trial with
prospective biomarker evaluation. Eur J Cancer 2017; 70: 14655.