Adding vistusertib, a dual inhibitor of mammalian target of rapamycin complex 1 (mTORC1) and 2 (mTORC2), to fulvestrant failed to demonstrate benefit in patients with estrogen receptor (ER)-positive advanced or metastatic breast cancer, according to a new study. The combination of everolimus and fulvestrant offered significantly longer progression-free survival (PFS) compared with vistusertib and fulvestrant, as well as fulvestrant alone.
Previous research has shown substantial benefit when everolimus is added to endocrine therapy, said Peter Schmid, MD, PhD, of Queen Mary University of London in the United Kingdom. Inhibition of mTORC1 alone, as everolimus achieves, can lead to resistance; vistusertib has shown superior activity to everolimus in preclinical models.
Schmid presented results of the phase II MANTA trial, testing the new agent, at the 2017 San Antonio Breast Cancer Symposium, held December 5–9. The trial included 333 patients in 9 countries, randomized to receive either fulvestrant alone (66 patients), fulvestrant plus everolimus (64 patients), fulvestrant plus daily vistusertib (101 patients), or fulvestrant plus intermittent vistusertib (95 patients; 2 days on, 5 days off schedule).
Patient characteristics were well balanced between the groups, with a median age of approximately 63 years, and most patients had visceral metastases only.
“Fulvestrant plus everolimus clearly outperforms all three other arms in this trial,” Schmid said. The median PFS in the fulvestrant plus daily vistusertib group was 7.6 months; 8.0 months in the fulvestrant plus intermittent vistusertib group; 12.3 months in the fulvestrant plus everolimus group; and 5.4 months in the fulvestrant-alone group.
A comparison of the daily vistusertib patients and the fulvestrant-alone patients yielded a hazard ratio (HR) of 0.88 (95% CI, 0.63–1.24; P = .42). Comparing the same vistusertib patients with the everolimus group favored the latter treatment, with an HR of 0.63 (95% CI, 0.45–0.90; P = .01); the everolimus group was also significantly better than the fulvestrant-alone group, with an HR of 0.63 (95% CI, 0.42–0.92; P = .01). There was no difference when the two vistusertib groups were compared with each other.
Objective response rates were also better with everolimus, at 41.2%, compared with 30.4% in the daily vistusertib group, 28.6% in the intermittent vistusertib group, and 25.0% with fulvestrant alone. The intermittent scheduling of the study drug was associated with a lower rate of rash and stomatitis, but with a higher rate of nausea/vomiting.
“The combination of everolimus and fulvestrant demonstrated improved PFS compared to vistusertib and fulvestrant, and to fulvestrant [alone],” Schmid concluded.