mTOR Inhibitor Activity Suggested In Recurrent Low-Grade Gliomas

Disease stability reported for patients with recurrent low-grade gliomas treated with everolimus

medwireNews: Findings from a phase II study of patients with recurrent low-grade gliomas (LGGs) suggests that the mammalian target of rapamycin (mTOR) inhibitor everolimus may be active in this tumour type.

Although none of the patients achieved a complete or partial radiographical tumour response, the investigators report a “high rate of disease stability” with everolimus 10 mg/day.

The progression-free survival rate at 6 months (PFS-6) was 84% for the 47 patients with WHO grade II disease, which met the trial's primary endpoint of a significant improvement compared with a historical cohort that achieved a PFS-6 of just 17%, say Susan Chang, from the University of California San Francisco in the USA, and co-workers.

The PFS-6 rate was 55% for the 11 patients with WHO grade III/IV disease at enrolment.

After a median of 11 months of treatment and a median of 3.5 years of follow-up, PFS for the WHO grade II and grade III/IV groups was a median of 1.4 and 0.6 years, respectively, while median overall survival was unreached in the WHO grade II patients and 2.9 years in the WHO grade III/IV patients.

Assessing the phosphatidylinositol 3-kinase/mTOR pathway in the patients revealed a significant relationship between positivity for the serine 240/244 epitope of the phosphorylated ribosomal S6 (p-S6) protein and shorter PFS, with a hazard ratio (HR) of 3.0 for 19% or greater staining versus below 19% staining. Similarly, there was a HR of 12.7 for overall survival using this cutoff.

These findings therefore support “the use of p-S6 as a clinically meaningful prognostic marker in recurrent LGGs”, the authors write in Cancer.

The team also reports results for multiparametric magnetic resonance imaging performed at baseline and again at 2-month intervals during everolimus therapy for 38 patients, 32 of whom had grade II tumours.

This demonstrated a significant decrease in the median capillary density after the first 6 months of therapy, as well as a trend towards decreased vascular permeability, changes that are “consistent with the antiangiogenic properties of mTOR inhibitors”, the researchers believe.

Moreover, decreases in both measures after 6 months were associated with better PFS, with a HR of 0.71 and 0.82 for each 10% decrease in capillary density and permeability, respectively.

While acknowledging that the study is limited by a lack of control arm, the investigators conclude: “Our results support further investigation of the utility of everolimus in this population; a study for patients with newly diagnosed LGGs is underway at our institution.” 

Reference

Wahl M, Chang SM, Phillips JJ, et al. Probing the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in gliomas: A phase 2 study of everolimus for recurrent adult low-grade gliomas. Cancer; Advance online publication 31 July 2017. DOI: 10.1002/cncr.30909  

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