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.
Summary (2 min read)
Introduction
- The PI3K/AKT signalling pathway plays a crucial part in carcinogenesis, promoting cell survival and growth.
- 1,2 AKT is the central node of the PI3K/AKT pathway.
- 14 Based on these findings and its mechanism of action, ipatasertib is under clinical assessment in cancers with a high prevalence of PI3K/AKT pathway activation.
- A phase 1 study15 of single-agent ipatasertib in 52 pretreated patients with various tumour types, including breast cancer, showed an acceptable safety profile (characterised by gastrointestinal effects, asthenia or fatigue, and rash) and preliminary antitumour activity.
Study design and participants
- Patients were enrolled at 44 hospitals in South Korea, the USA, France, Spain, Taiwan, Singapore, Italy, and Belgium .
- Patients had to have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) and adequate haema tological, renal, hepatic, and cardiac functions.
- All patients provided written informed consent before undergoing any study-specific procedures.
- The authors did not use any language restrictions in their search.
- No previous randomised trials have investigated the targeting of AKT or PI3K specifically in triple-negative breast cancer.
Randomisation and masking
- Eligible patients were randomly assigned (1:1) to either ipatasertib plus paclitaxel or placebo plus paclitaxel by investigators using an interactive web-response system with an allocation sequence generated by Bracket Global LCC (Reading, UK).
- Randomisation was by stratified permuted blocks (block size of four).
- Randomisation was stratified by three criteria: previous (neo)adjuvant chemotherapy (yes vs no), chemotherapy-free interval (≤12 vs >12 months vs no previous chemotherapy), and central tumour PTEN status as assessed by immunohistochemistry (H score 0 vs 1–150 vs >150).
- In some cases, patients were randomly assigned before PTEN status was available; for stratification, these patients were assigned to the stratum with an H score more than 150.
- Placebo tablets were identical in shape and colour to the ipatasertib tablets.
Procedures
- Patients received intravenous paclitaxel 80 mg/m² on days 1, 8, and 15 of each 28-day cycle in combination with either oral ipatasertib 400 mg/day or placebo, administered on days 1–21 of each 28-day cycle.
- This schedule has been used in previous clinical studies16,17 and maintains the cumulative dose intensity achieved with 175 mg/m² every 3 weeks (as recommended in the prescribing information).
- If symptoms persisted despite adequate antidiarrhoeal medications and dose interruptions, dose reductions were implemented.
- After discontinuation of treatment, patients were followed up every 3 months for survival and subsequent anticancer therapies.
- Before the primary analysis, tumour tissue samples were assessed centrally by additional molecular assays to define the patient population with PTEN-low tumours (by immuno histochemistry; co-primary endpoint) and the patient population with PI3K/AKT pathway-activated tumours (secondary endpoint).
Outcomes
- The co-primary endpoints were investigator-assessed progression-free survival in the intention-to-treat population and progression-free survival in the subgroup of patients with PTEN-low tumours.
- Progression-free survival was defined as the interval between randomisation and the first occurrence of disease progression or death from any cause within 30 days of the last dose of study treatment (death on study).
- As specified in the protocol, patients who discontinued study treatment without documented disease progression were censored at the date of last tumour assessment before initiation of new anticancer therapy.
- Additional objectives included assessment of pharmacokinetics; PROs for diseaserelated and treatment-related symptoms, patient functioning, and health-related quality of life; and further exploratory translational research.
Statistical analysis
- The planned sample size was 60 patients per group for a total of 120 patients overall to ensure 83 progression-free survival events for the primary analysis.
- As this hypothesis-generating trial was designed to assess safety and provide preliminary evidence of activity, it was not powered to detect minimal clinically meaningful differences between treatment groups at a significant α level of 5%.
- Instead, 90% CIs for the hazard ratio (HR) were calculated, anticipating that for clinically 1364 www.thelancet.com/oncology.
- The primary analysis was intended to include 50 progression-free survival events in patients with PTEN-low tumours.
- Analyses for the co-primary endpoints were stratified; the Cox proportional hazard model included the treatment group and three stratification factors as covariates.
Results
- Between Sept 2, 2014, and Feb 4, 2016, 166 patients were assessed for eligibility and 124 patients were randomly assigned to treatment with ipatasertib (62 patients) or placebo .
- Of the 15 patients with PTEN genetic alterations by next-generation sequencing, and samples assessed for immunohistochemistry, 14 (93%) had loss of PTEN protein expression .
- Secondary endpoints of objective response and duration of response, and the post-hoc assessment of clinical benefit are shown in table 3.
- Serious adverse events were more common in the ipatasertib group (17 [28%] of 61 patients, predominantly infections and gastrointestinal effects) than in the placebo group (nine [15%] of 62 patients, predominantly infections).
Discussion
- Results of the randomised, double-blind, placebocontrolled, phase 2 LOTUS trial show that adding ipatasertib to paclitaxel as first-line therapy for triplenegative breast cancer increased progression-free survival compared with that for placebo plus paclitaxel.
- Additional research in triple-negative breast cancer includes the randomised phase 2 FAIRLANE trial (NCT02301988), which is assessing the addition of ipatasertib to paclitaxel in the neoadjuvant setting.30 Results from FAIRLANE might provide further information on patient selection, although, as in LOTUS, patients were not stratified by PIK3CA/AKT1/PTEN-altered tumours.
- The authors thank the members of the internal monitoring committee, the study clinical operations team, the biostatisticians, Premal Patel (trial design and initiation), and Agnes Hong (PRO interpretation).
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Frequently Asked Questions (7)
Q2. What were the common adverse events in the LOTUS trial?
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%]).
Q3. What was the primary endpoint of the LOTUS trial?
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.
Q4. What is the main purpose of the study?
The oral AKT inhibitor ipatasertib is being investigated in cancers with a high prevalence of PI3K/AKT pathway activation, including triple-negative breast cancer.
Q5. How many patients were enrolled in the LOTUS trial?
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.
Q6. How many patients were randomly assigned to ipatasertib?
Enrolled patients were randomly assigned (1:1) to receive intravenous paclitaxel 80 mg/m² (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.
Q7. How long did the LOTUS trial last?
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).