Safety and Efficacy of the mTOR Inhibitor, Vistusertib, Combined With Anastrozole in Patients With Hormone Receptor−Positive Recurrent or Metastatic Endometrial Cancer

Abstract

IMPORTANCEEndometrial cancer is often hormone-dependent and treated with aromatase inhibitors. The PI3K-AKT-mTOR pathway deregulation observed in endometrial cancer drives hormonal resistance, thus supporting the rationale of combining mTOR inhibitor with endocrine therapy. OBJECTIVE To evaluate the safety and efficacy of vistusertib in combination with anastrozole in the treatment of women with hormone receptor−positive recurrent or metastatic endometrial cancer. DESIGN, SETTINGS, AND PARTICIPANTSThe VICTORIA study was a multicenter, open-label, randomized clinical trial that accrued 75 patients with hormone receptor−positive recurrent or metastatic endometrial cancer from 12 cancer centers in France in April 2016 to October 2019. After a safety run-in period, a Simon 2-stage design was used. Data analyses were performed from December 11, 2020, to March 11, 2021.INTERVENTIONS Patients were randomized in a 2:1 ratio to oral vistusertib (125 mg twice daily 2 days per week) and oral anastrozole (1 mg daily) in the combination vistusertib with anastrozole arm (V+A arm) or oral anastrozole alone (A arm). MAIN OUTCOMES AND MEASURESThe primary end point was serious adverse events for the safety run-in period and progression-free rate at 8 weeks (8wk-PFR)-assessed with a blinded independent central review in phase 2. The secondary end points were objective response rate, duration of response, progression-free survival (PFS), overall survival, and incidence of adverse events. RESULTSOf the 75 patients who were randomized, 73 (median [range] age, 69.5 [37-88] y; all female) were treated: V+A arm, 49 patients; A arm, 24 patients. In the V+A arm, the 8wk-PFR was 67.3% (unilateral 95% CI, 54.7%) and in the A arm, 39.1% (unilateral 95% CI, 22.2%). No significant serious adverse events were reported during the safety run-in period (n = 6 in V+A arm). The overall response rate was 24.5% (95% CI, 13.3%-38.9%) in the V+A arm vs 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. Fatigue, lymphopenia, hyperglycemia, and diarrhea were the most common (grade Ն2) adverse events associated with vistusertib. CONCLUSIONS AND RELEVANCEThis multicenter, open-label, phase 1/2 randomized clinical trial demonstrated that adding vistusertib to anastrozole improved 8wk-PFR, overall response rate, and PFS for patients with endometrial cancer and had manageable adverse events. Identification of molecular subgroups would allow for more precise selection of patients who may be most likely to experience favorable outcomes.

Thyroid Hormone Receptor β Knockdown Reduces Suppression of Progestins by Activating the mTOR Pathway in Endometrial Cancer Cells

“…Akt inhibitor has been used in treating ER/PR-positive breast cancer to disrupt the function of the PI3K/Akt/mTOR pathway and alleviate endocrine resistance [ 16 , 32 ]. The mTOR inhibitor has also been tested as an EC therapy in phase II clinical trials [ 33 , 34 ]. We previously found that activating the mTOR-4EBP1/eIF4G pathway could promote proliferation and inhibit apoptosis in RL95-2 and HEC-1A EC cells [ 30 ].…”

Small molecule inhibitors targeting the cancers

“… 328 Currently, no mTOR kinase inhibitors are approved, but some are under evaluation, such as AZD2014, sapanisertib, and vistusertib. 367 , 368 , 369 Notably, vistusertib plus anastrozole improved was superior to anastrozole alone in HR‐positive, recurrent or metastatic endometrial cancer in the form of PFS and ORR with manageable adverse events. 369 Dual inhibition of PI3K and mTOR is a direction, and many dual PI3K/mTOR inhibitors are in their early‐stage trials, such as gedatolisib, paxalisib, samotolisib, voxtalisib, and apitolisib.…”

“… 367 , 368 , 369 Notably, vistusertib plus anastrozole improved was superior to anastrozole alone in HR‐positive, recurrent or metastatic endometrial cancer in the form of PFS and ORR with manageable adverse events. 369 Dual inhibition of PI3K and mTOR is a direction, and many dual PI3K/mTOR inhibitors are in their early‐stage trials, such as gedatolisib, paxalisib, samotolisib, voxtalisib, and apitolisib. 370 For example, samotolisib is a promising dual PI3K/mTOR inhibitor and had a clinical benefit on PFS in metastatic castration‐resistant prostate cancer with tolerable side effects when combined with enzalutamide.…”

“…mTOR kinase inhibitors can inhibit TORC1 and TORC2 and are supposed to avoid resistance caused by AKT phosphorylation 328 . Currently, no mTOR kinase inhibitors are approved, but some are under evaluation, such as AZD2014, sapanisertib, and vistusertib 367–369 . Notably, vistusertib plus anastrozole improved was superior to anastrozole alone in HR‐positive, recurrent or metastatic endometrial cancer in the form of PFS and ORR with manageable adverse events 369 .…”

Ribosome biogenesis‐based predictive biomarkers in endocrine therapy (Anastrozole) combined with mTOR inhibitor (Vistusertib) in endometrial cancer: translational study from the VICTORIA trial in collaboration with the GINECO group

“…In HR+ metastatic endometrial patients, although endocrine therapy allows response in 15–30% of cases, it is only of short duration. In order to avoid resistance to endocrine therapy, we recently evaluated safety and efficacy of combining the aromatase inhibitor Anastrozole with the mTOR inhibitor Vistusertib, in 73 patients with advanced or relapsed HR+ endometrial cancer maximally treated with one line of chemotherapy [ 4 ]. This multicentric, randomized open‐label phase I/II VICTORIA trial (NCT02730923) showed that Vistusertib and Anastrozole combination treatment (V + A, n = 49) improve neoplastic control compared to Anastrozole alone (A, n = 24), with a progression‐free rate at 8 weeks of 67% in the V + A arm and of 39% in the A arm.…”