Study Suggests Benefit for mTor Inhibitor plus Aromatase Inhibitor for Advanced Endometrial Cancer

Combining a once-promising novel mTOR inhibitor, vistusertib, with the aromatase inhibitor anastrozole increased progression-free survival (PFS) compared to anastrozole monotherapy in women with hormone-receptor positive recurrent or metastatic endometrial cancer, investigators with the VICTORIA trial reported in JAMA Oncology.

The trial recruited patients over roughly 30 months beginning in 2016 and ending in 2019, but a little over midway through that process, the developer of vistusertib halted its development based on negative-to-middling results from other studies.

The primary end point "was serious adverse events for the safety run-in period and progression-free rate at 8 weeks." Assessing that primary end point, Pierre Heudel, MD, MSc, LLM, of the Medical Oncology Department, Centre Léon Bérard in Lyon, France, and colleagues wrote that at 8 weeks, the progression-free response rate was 67.3% among women treated with the vistusertib/anastrozole combination (V+A arm) versus 39.1% among women assigned to anastrozole monotherapy (A arm).

Turning to secondary endpoints—objective response rate, progression free survival (PFS), and duration of response—they wrote: "The overall response rate was 24.5% (95% CI, 13.3%-38.9%) in the V+A arm versus 17.4% (95% CI, 5.0%-38.8%) in the A arm. With a median follow-up of 27.7 months, median PFS was 5.2 (95% CI, 3.4-8.9) in the V+A arm and 1.9 (95% CI, 1.6-8.9) months in the A arm."

Moreover, the "median (range) treatment duration was 3.4 (0.5-41) months in the combination V+A arm versus 2.9 (0.2-29) months in the A arm… At the time of the data cutoff (Nov. 9, 2020; median follow-up, 27.7 months), 7 patients were still receiving the study treatment in the V+A combination arm and 3 patients were still receiving treatment in the anastrozole arm."

And in a subset of 16 patients, identified as long-response patients, researchers observed a median duration of response of 29.6 months in the combination therapy arm versus 7.5 months in the monotherapy arm.

As anticipated, the overall survival rate varied by time point, and overall, favored anastrozole monotherapy:

• 12 months—71.3% in the combination arm versus 70.8% in monotherapy arm;
• 24 months—38.1% versus 53%, respectively.

The trial was a combined safety/efficacy study, and among the 73 patients randomized, almost a third experienced one or more serious adverse events—with more patients in the vistusertib-anastrozole arm reporting adverse events, most of which were grade 1 or 2.

"In the V+A arm, the most common nonhematologic adverse events were fatigue (n=34; 69%), nausea (n=25; 51%), and diarrhea (n=20; 41%), and in the A arm, fatigue (n=7; 29%) and arthralgia (n=7; 29%). The most common grade 3 and 4 adverse events in the V+A arm were lower lymphocyte count (20%), hyperglycemia (12%), and fatigue (8%); treatment was discontinued by 11 patients (22%), 4 of whom permanently discontinued vistusertib."

The authors pointed out that histologic factors "associated with response to endocrine therapy include low grade, endometrioid histologic subtype, and positive ER or PR status. However, with an overall response rate of only 17.4% and a PFS of less than 2 months in the anastrozole alone arm, it is clear that these criteria are not sufficient. Improved selection of patients who may better respond to endocrine therapy is still required, although tumor responses have been reported in patients with HR-negative endometrial cancer. In that respect, the choice of treatment according to the histologic characteristics is not sufficient, and highly selected molecular criteria are necessary."

Heudel et al said the study was limited by its small sample size, as well as "the absence of data on the level of expression of hormone receptors, and the predefined absence of statistical comparison between the 2 treatment arms…"

Although they acknowledged that the drug’s development had been halted, Heudel et al argued that the VICTORIA results "show that there is need for further research…"

Noting what they termed "a major evolution in metastatic endometrial cancer treatments" in recent years, the researchers said "the challenge now is to identify this patient population, to evaluate new therapeutic combinations, and to propose benefits from these therapeutic innovations for the greatest number of patients. Thus, among the HR+ endometrial cancer population, even though histologically driven treatment may not be sufficient, molecular characteristics cannot guide treatment yet. The arrival of immune checkpoint inhibitors and the possibility of selecting patients based on molecular characteristics gives us hope for the future."

This study was funded by a grant from the National Cancer Institute of France.

Heudel reported personal fees from Seagen, Novartis, and AstraZeneca, and nonfinancial support from Lilly, Pfizer, and Roche outside the submitted work.

Heudel, P et al "Safety and efficacy of the mTOR inhibitor, vistusertib, combined with anastrozole in patients with hormone receptor−positive recurrent or metastatic endometrial cancer: The VICTORIA multicenter, open-label, phase 1/2 randomized clinical trial" JAMA Oncol 2022; DOI: 10.1001/jamaoncol.2022.1047.