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
| Autor: | Sung-Bae Kim, Rebecca Dent, Seock-Ah Im, Marc Espié, Sibel Blau, Antoinette R Tan, Steven J Isakoff, Mafalda Oliveira, Cristina Saura, Matthew J Wongchenko, Amy V Kapp, Wai Y Chan, Stina M Singel, Daniel J Maslyar, José Baselga, Keun Seok Lee, Hwei-Chung Wang, Antoinette Tan, Joo Hyuk Sohn, Michelino De Laurentiis, Laura Garcia Estevez, Chiun-Sheng Huang, Gilles Romieu, Michel Velez, Rafael Villanueva, Pier Franco Conte, Shaker Dakhil, Marc Debled, Antonio Gonzalez Martin, Sara Hurvitz, Jee Hyun Kim, Christelle Levy, Pedro Sanchez Rovira, Jae Hong Seo, Vicente Valero, Gregory Vidal, Andrea Wong, Mary Ann K Allison, Robert Figlin, David Chan, Shin-Cheh Chen, Yen-Hsun Chen, Melody Cobleigh, Filippo De Braud, Luc Dirix, Vincent Hansen, Anne Hardy Bessard, Nicholas Iannotti, Steven Isakoff, William Lawler, Alvaro Montaño, Mohamad Salkini, Leonard Seigel |
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| Přispěvatelé: | Kim, Sung-bae, Dent, Rebecca, Im, Seock-ah, Espié, Marc, Blau, Sibel, Tan, Antoinette R, Isakoff, Steven J, Oliveira, Mafalda, Saura, Cristina, Wongchenko, Matthew J, Kapp, Amy V, Chan, Wai Y, Singel, Stina M, Maslyar, Daniel J, Baselga, José, De Laurentiis, Michelino |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Administration Oral Triple Negative Breast Neoplasms LOTUS investigators law.invention Placebos 0302 clinical medicine Randomized controlled trial law Antineoplastic Combined Chemotherapy Protocols Cancer education.field_of_study Hazard ratio Middle Aged Prognosis Treatment Outcome Oncology 030220 oncology & carcinogenesis 6.1 Pharmaceuticals Administration Female Survival Analysi Drug Human Oral Adult medicine.medical_specialty Paclitaxel Maximum Tolerated Dose Prognosi Population Clinical Trials and Supportive Activities Oncology and Carcinogenesis Placebo Risk Assessment Disease-Free Survival Drug Administration Schedule Dose-Response Relationship 03 medical and health sciences Breast cancer Double-Blind Method Clinical Research Internal medicine Breast Cancer medicine Adjuvant therapy Confidence Intervals Humans Neoplasm Invasiveness Oncology & Carcinogenesis education Survival analysis Neoplasm Staging Proportional Hazards Models Aged Neoplasm Invasivene Antineoplastic Combined Chemotherapy Protocol Dose-Response Relationship Drug business.industry Patient Selection Evaluation of treatments and therapeutic interventions medicine.disease Survival Analysis Surgery Clinical trial 030104 developmental biology Proportional Hazards Model business Confidence Interval Proto-Oncogene Proteins c-akt |
| Zdroj: | The Lancet. Oncology, vol 18, iss 10 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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