Despite promising preclinical study results, the combination of the mTOR inhibitor vistusertib plus fulvestrant was inferior to everolimus plus fulvestrant in a randomized clinical trial including women with advanced breast cancer, investigators have reported. Vistusertib, which inhibits signaling of both mTOR complexes (mTORC1 and mTORC2), demonstrated superior activity in preclinical studies compared to everolimus, which inhibits MTORC1, according to the investigators. However, vistusertib plus fulvestrant had significantly shorter progression-free survival (PFS) versus the combination of the mTOR inhibitor everolimus and fulvestrant in the phase 2 MANTA study, which recruited postmenopausal women with estrogen receptor (ER)-positive advanced or metastatic breast cancer that had progressed following treatment with an aromatase inhibitor (AI).

However, vistusertib plus fulvestrant had significantly shorter progression-free survival (PFS) versus the combination of the mTOR inhibitor everolimus and fulvestrant in the phase 2 MANTA study.

Moreover, vistusertib plus fulvestrant did not significantly improve PFS versus fulvestrant alone; by contrast, everolimus plus fulvestrant offered significantly longer PFS versus both vistusertib plus fulvestrant and fulvestrant alone, according to investigators led by Peter Schmid, FRCP, PhD, of Barts Cancer Institute, London. While these results do not support further study of vistusertib in ER-positive metastatic breast cancer, MANTA does “raise important questions around the future of this class of drugs,” noted Dr. Schmid and colleagues. Their report is in JAMA Oncology. Of note, an intermittent vistusertib dosing strategy—also evaluated as part of MANTA—was associated with improved safety, so that type of dosing strategy might be warranted in the future with other agents, they said. William J. Gradishar, MD, professor of medicine at the Northwestern University, Chicago, said that while vistusertib did not improve on everolimus in MANTA, the study at least provides additional support for the use of everolimus in combination with fulvestrant. “For an individual who is a candidate for antihormone therapy, this data would suggest that the consideration might be to add everolimus to fulvestrant, and that may enhance the benefit over fulvestrant alone,” Dr. Gradishar said in an interview. That said, the MANTA findings may not be directly reflective of current clinical practice, he added. That’s because the women in the study had all progressed on aromatase inhibitor therapy, whereas today, postmenopausal women with ER-positive advanced breast cancer may receive a CDK4/6 inhibitor as part of first-line therapy.

Dr. Peter Schmid Dr. William J. Gradishar

“For an individual who is a candidate for antihormone therapy, this data would suggest that the consideration might be to add everolimus to fulvestrant, and that may enhance the benefit over fulvestrant alone,” Dr. Gradishar said in an interview.

Nevertheless, MANTA corroborates studies demonstrating the benefit of everolimus after initial treatment, according to authors of a related editorial. Those studies include the randomized phase 3 BOLERO trial, in which everolimus and exemestane improved PFS versus exemestane alone in women with hormone receptor–positive advanced breast cancer who had previously received a nonsteroidal AI; and the more recent randomized PrE0102 phase 2 study showing that everolimus enhanced the efficacy of fulvestrant in women with ER-positive metastatic breast cancer that was AI resistant. In theory, specifically inhibiting mTORC1 and mTORC2 using vistusertib should have been superior to inhibition of mTORC1 with everolimus, or at least equivalent in effect, according to Nisha Unni, MD, and Carlos L. Arteaga, MD, authors of the related editorial. Specifically, blocking mTORC1 results in a negative feedback loop that ultimately results in activation of mTORC2. “Combined inhibition of TORC1 andTORC2 has been suggested as an approach to block the feedback compensation that follows therapeutic blockade of mTORC1,” wrote Dr. Unni and Dr. Arteaga, of UT Southwestern Medical Center, Dallas.

Dr. Carlos L. Arteaga

MANTA was an investigator-led, open-label trial including 333 women with ER-positive locally advanced or metastatic breast cancer that progressed after AI therapy. The women were recruited at 88 centers outside the United States between April 2014 and October 2016 and randomly assigned to receive fulvestrant alone (67 patients) or with daily vistusertib (103 patients), intermittent vistusertib, given on days 1-2 of each week (98 patients), or everolimus (65 patients). With a median follow-up of 17.1 months, median PFS was 5.6 months for fulvestrant alone, and 7.6 months for fulvestrant plus daily vistusertib, 8.0 months for fulvestrant plus intermittent vistusertib, and 12.3 months for fulvestrant plus exemestane. There was not a significant different in PFS between either fulvestrant-plus-vistusertib arm and fulvestrant alone, with hazard ratios of 0.88 and 0.79, respectively, Dr. Schmid and colleagues reported. By contrast, PFS was significantly longer for fulvestrant plus everolimus compared with fulvestrant plus daily vistusertib (hazard ratio, 0.63; 95% confidence interval, 0.45-0.90; P = .01), they said in the report. Likewise, fulvestrant plus everolimus resulted in significantly higher PFS compared with fulvestrant alone (hazard ratio, 0.63; 95% CI, 0.42-0.92; P = .01). Intermittent dosing of vistusertib was associated with lower rates of rash and stomatitis, but also with higher rates of short-term nausea and vomiting, according to the investigators. While vistusertib may not have a role in metastatic breast cancer based on MANTA, the study does suggest fulvestrant plus everolimus for selected patients, according to Dr. Gradishar. “I think it’s informing, and I think people who choose to consider it, have data to support it,” he said. “The PFS was improved, and that’s what we try to provide our patients – delays until something changes with their disease.”

Funding for the study came in part from AstraZeneca, which also supplied medication. Dr. Schmid reported disclosures related to Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Medivation, Merck, Novartis, Oncogenex, Pfizer, Puma, Roche, and Roche/Genentech.