Novel dual mTOR inhibitor fails to extend PFS for ER-positive breast cancer

Issue: January 25, 2018

SAN ANTONIO — Vistusertib, a dual mTOR inhibitor, did not extend PFS when combined with fulvestrant among postmenopausal women with advanced or metastatic ER-positive breast cancer, according to results of the ongoing, randomized, open-label, phase 2 MANTA trial presented at the San Antonio Breast Cancer Symposium.

Thus, the trial failed to meet its primary efficacy endpoint of PFS — defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause, whichever occurred first.

“The addition of vistusertib [AZD2014, AstraZeneca] to fulvestrant [Faslodex, AstraZeneca] failed to demonstrate a significant improvement in PFS in the intention-to-treat population and continuous daily and intermittent high-dose scheduling of vistusertib resulted in similar antitumor activity,” Peter Schmid, MD, of Queen Mary's University of London, said during his presentation.

Previous data have shown that aberrant PI3K/mTOR pathway activation is one of the main drivers of resistance to endocrine therapy in this patient population. However, randomized clinical trials have demonstrated a significant benefit with the addition of everolimus — which inhibits mTORC1 — to endocrine therapy. Vistusertib — a dual inhibitor of mTORC1 and mTORC2 — has shown a broader range of activity in preclinical ER-positive breast cancer models.

For this reason, Schmid and colleagues assessed the safety and efficacy of continuous and intermittent high-dose vistusertib among 333 women with postmenopausal ER-positive breast cancer. Patients recurred on treatment or within 1 year of stopping treatment with an aromatase inhibitor, or progressed while undergoing treatment or at 1-month posttreatment with an aromatase inhibitor for locally advanced or metastatic disease.

Between April 2014 and October 2016, researchers randomly assigned patients in a 2:3:3:2 fashion to one of four arms:

500 mg fulvestrant on days 1, 15 and 29, followed by 500 mg fulvestrant every 28 days (n = 66);
fulvestrant plus 50 mg continuous daily vistusertib (n = 101);
500 mg fulvestrant plus intermittent 125 mg vistusertib for 2 days on, 5 days off (n = 95); or
500 mg fulvestrant plus once-daily 10 mg everolimus (n = 64).

PFS served as the study’s primary outcome; secondary outcomes included ORR, OS, clinical benefit and change in tumor size.

Median follow-up was 17.1 months.

Median PFS was 7.6 months in the fulvestrant plus continuous vistusertib arm compared with 5.4 months in the fulvestrant-alone arm, which did not represent a significant difference (HR = 0.88; 95% CI, 0.63-1.24). The continuous-dosing arm also had significantly shorter survival than the fulvestrant and everolimus arm (12.3 months; HR = 0.63; 95% CI, 0.45-0.9).

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Patients assigned fulvestrant plus everolimus demonstrated significantly longer PFS than those assigned fulvestrant alone (HR = 0.63; 95% CI, 0.42-0.92).

Median PFS appeared similar in the vistusertib continuous and intermittent arms (7.6 months vs. 8 months; HR = 1.11; 95% CI, 0.81-1.52).

Objective response rate was 41.2% in the fulvestrant-everolimus arm, compared with 30.4% in the fulvestrant and continuous vistusertib arm, 28.6% in the fulvestrant and intermittent vistusertib arm, and 25% in the fulvestrant-alone arm.

Intermittent dosing of vistusertib led to lower rates of rash (22.8% vs. 54.3%) and stomatitis (29.3% vs. 40.2%) but higher rates of nausea (68.5% vs. 31.5%) and vomiting (40.2% vs. 12%). In the fulvestrant plus everolimus arm, 50% of patients experienced rash and 60% experienced stomatitis. – by Jen Southall

Reference:

Schmid P, et al. Abstract GS2-07. Presented at: San Antonio Breast Cancer Symposium; Dec. 5-9, 2017; San Antonio.

Disclosures: Schmid reports consultant fees from AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Pfizer and Puma. Please see the abstract for all other authors’ relevant financial disclosures.