Ipatasertib improves PFS in triple-negative breast cancer
medwireNews: Adding the oral AKT inhibitor ipatasertib to paclitaxel significantly prolongs progression-free survival (PFS), compared with placebo plus paclitaxel, when used as first-line therapy for triple-negative breast cancer, phase II study data show.
“The increase in median progression-free survival was quite modest in the intention-to-treat population and PTEN-low subgroup but more pronounced in predefined analyses of the patient population with PIK3CA/AKT1/PTEN-altered tumours,” Sung-Bae Kim (University of Ulsan College of Medicine, Seoul, South Korea) and colleagues remark.
The multicenter LOTUS trial randomly assigned women with inoperable, locally advanced or metastatic triple-negative breast cancer, naïve to systemic therapy, to receive intravenous paclitaxel 80 mg/m2 (days 1, 8, 15 of a 28-day cycle) with either ipatasertib 400 mg (n=62) or placebo (n=62) once per day (days 1–21) until disease progression or unacceptable toxicity.
As reported in The Lancet Oncology, median PFS was significantly longer with ipatasertib than with placebo, at 6.2 versus 4.9 months, meaning that patients in the ipatasertib group had a significant 40% lower risk for disease progression than those in the placebo group during the 10.4- and 10.2-month respective follow-up periods.
The researchers also looked at a subgroup of 48 patients with PTEN-low (by immunohistochemistry) tumours, which are associated with a higher degree of AKT pathway activation. In these patients, median PFS was longer with ipatasertib, at 6.2 months, than with placebo, at 3.7 months, but not significantly so.
However, Kim and team observed that “a substantial proportion of patients with PTEN-low tumours by immunohistochemistry did not have a genetic alteration.”
And analyses of 42 patients with PIK3CA/AKT1/PTEN-altered tumours, defined by next-generation sequencing, showed that median PFS was significantly longer with ipatasertib versus placebo in these patients, at 9.0 versus 4.9 months.
“This difference in efficacy based on absence of expression of PTEN through non-genetic mechanisms compared with loss of PTEN function through mutations and copy-number loss could be a key difference in how PTEN loss might drive tumours and be PI3K/AKT-addicted in prostate versus breast cancers,” say the researchers.
There were no unexpected adverse events; 23% of patients receiving ipatasertib experienced grade 3 diarrhea, which was “manageable and reversible,” and led to treatment discontinuation in just two cases.
Kim et al conclude that their findings “support future investigation of ipatasertib plus paclitaxel in diseases with high prevalence of PI3K/AKT pathway activation, particularly in patients with PIK3CA/AKT1/PTEN-altered tumours.”
Commenting on the findings, Suzette Delaloge and Louise DeForceville, both from Gustave Roussy in Villejuif, France say the trial “brings hope to a field where medical need is great.”
However, they add that “the ways we identify relevant targets in the clinic remain questionable: not only were PTEN-low tumours observed much less frequently than expected, but genomic approaches seemed potentially more relevant than the initially planned and poorly feasible immunohistochemistry analyses in LOTUS.”
They continue: “The most recent tumour sample available was used for immunohistochemistry and genomic studies; however, the unstable genomic background of triple-negative breast cancer makes it a difficult context for identification of therapeutic targets.
“The reliability of any tumour biopsy is questionable given the major spatial and temporal tumour heterogeneity of this disease,” Delaloge and DeForceville caution.
By Laura Cowen
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