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Ipatasertib shows promise for triple-negative breast cancer
The addition of ipatasertib to paclitaxel improved PFS among women with triple-negative breast cancer, according to results from the LOTUS trial published in Lancet Oncology.
Ipatasertib (GDC-0068; Genentech/Roche) is a highly selective oral adenosine triphosphate -competitive small-molecule AKT inhibitor.
“The PI3K/AKT signaling pathway is often activated in breast cancer, and has attracted interest as a target in triple-negative breast cancer,” Sung-Bae Kim, MD, PhD, from the department of oncology at Asan Medical Center at University of Ulsan in Seoul, and colleagues wrote.
“Additionally, approximately half of triple-negative breast cancer have deficient expression of the tumor suppressor PTEN, which is associated with a higher degree of AKT pathway activation,” they added.
In a phase 1 study of multiple malignancies, combination use of ipatasertib with paclitaxel induced responses among patients with breast cancer.
Kim and colleagues conducted the multicenter, randomized, double-blind, placebo-controlled, phase 2 LOTUS trial to evaluate the addition of ipatasertib to paclitaxel as first-line therapy for the treatment of metastatic triple-negative breast cancer.
The researchers recruited women aged 18 years or older with measurable, inoperable, locally advanced or metastatic triple-negative breast cancer previously untreated with systemic therapy from 44 hospitals in South Korea, United States, France, Spain, Taiwan, Singapore, Italy and Belgium.
The researchers randomly assigned 124 patients 1:1 to receive 80 mg/m² paclitaxel IV on days 1, 8 and 15 of each 28-day cycle in combination with 400 mg ipatasertib or placebo, administered once daily on days 1 through 21 of each cycle until disease progression or unacceptable toxicity.
PFS in the intent-to-treat population and the subgroup of patients with PTEN-low tumors served as the co-primary endpoints.
Secondary endpoints included objective response rate, duration of confirmed ORR, OS in the intent-to-treat population and the PTEN-low subgroup, efficacy in patients with PI3K/AKT pathway-activated tumors and safety.
Forty-eight of 101 patients assessed for PTEN status had PTEN-low tumors. Of 103 patient samples assessed by next-generation sequencing, 42 had PIK3CA/AKT1/PTEN-altered tumors.
Median follow-up was 10.4 months in the ipatasertib group and 10.2 months in the placebo group.
Median PFS was 6.2 months (95% CI, 3.8–9) in the ipatasertib arm compared with 4.9 months (95% CI, 3.6–5.4) in the placebo arm (HR = 0.6, 95% CI, 0.37-0.98).
At data cutoff, PFS events occurred in 34 (71%) patients classified as PTEN low. Among this subgroup, median PFS was 6.2 months among those treated with ipatasertib and 3.7 months in the placebo arm (HR = 0.59; 95% CI, 0.26-1.32).
PFS events occurred in 25 patients with PIK3CA/AKT1/PTEN-altered tumors. Among this subgroup, patients treated with ipatasertib showed longer median PFS (9 months vs. 4.9 months; HR = 0.44; 95% CI, 0.2-0.99).
The researchers noted OS data were immature, with nine deaths in the ipatasertib group and 17 in the placebo group. Twenty-two of these deaths resulted from disease progression.
Median duration of response appeared similar between groups; however, patients treated with ipatasertib among the PIK3CA/AKT1/PTEN-altered subgroup demonstrated longer responses.
The most common adverse events included gastrointestinal effects, alopecia, neuropathy, fatigue and rash.
Common grade 3 or worse adverse events that occurred more frequently in the ipatasertib group included diarrhea (23% vs. 0%), neutropenia (18% vs. 8%), peripheral neuropathy (7% vs. 5%), and pneumonia or lower respiratory tract infection (5% vs. 0%). No cases of colitis or grade 4 diarrhea occurred.
Serious adverse events occurred in more patients treated with ipatasertib (n = 17, predominantly infections and gastrointestinal effects) than the placebo group (n = 9, predominantly infections).
No treatment-related deaths occurred in the ipatasertib group, and one treatment-related death occurred in the placebo group.
The researchers acknowledged the study was limited by its small sample size and randomization stratification.
With a phase 3 trial underway, Kim and colleagues support future assessment of ipatasertib in combination with paclitaxel in malignancies with PI3K/AKT pathway activation, particularly in patients with PIK3CA/AKT1/PTEN-altered tumors.
“If emerging agents fulfil their potential, treatment decision making and sequencing could become increasingly complex, and biomarker selection is expected to play an important part in individualized therapy for the heterogeneous collection of diseases traditionally described as triple-negative breast cancer,” they added.
Although these data show promise, the ways in which oncologists identify relevant targets in the clinic remain questionable, Suzette Delaloge, MD, MSc, head of the breast cancer department, and Louise DeForceville, from the department of medical oncology at Gustave Roussy Institute in France, wrote in an accompanying editorial.
“The unstable genomic background of triple-negative breast cancer makes it a difficult context for identification of therapeutic targets,” they added. “The reliability of any tumor biopsy is questionable given the major spatial and temporal tumor heterogeneity of this disease.”
However, the LOTUS trial may help to better define therapeutic targets and conditions of activity of other drugs targeting the PI3K pathway.
“If, as suggested by the results of LOTUS, genomic alterations are the preferred biomarker, testing of circulating tumor DNA might also be useful to allow better therapeutic targeting,” Delalogue and DeForceville wrote. “Ongoing randomized studies testing precision medicine as a way to determine treatment rather than stratified approaches ... might also help us pick the best strategies and best drug combinations.” – by Kristie L. Kahl
Disclosures: Roche funded this study. Kim reports he receives research funding from Aventis, Dongkook Pharma, Kyowa Kirin, Novartis and Sanofi. Please see the full study for a list of all other researchers’ relevant financial disclosures. Delaloge and DeForceville report they have no relevant financial disclosures.