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Clinical Trial
. 2022 Jul 1;8(7):1001-1009.
doi: 10.1001/jamaoncol.2022.1047.

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

Pierre Heudel  1   2   3 , Jean-Sébastien Frenel  3   4 , Cécile Dalban  5 , Fernando Bazan  3   6 , Florence Joly  3   7 , Antoine Arnaud  3   8 , Cyril Abdeddaim  3   9 , Annick Chevalier-Place  3   9 , Paule Augereau  3   10 , Patricia Pautier  3   11 , Camille Chakiba  3   12 , Benoit You  2   3   13   14 , Laurence Lancry-Lecomte  3   15 , Gwenaelle Garin  5 , Virginie Marcel  2   16   17 , Jean Jacques Diaz  2   16   17 , Isabelle Treilleux  3   18 , David Pérol  5 , Michel Fabbro  19 , Isabelle Ray-Coquard  1   2   3
Affiliations
Clinical Trial

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

Pierre Heudel et al. JAMA Oncol. .

Abstract

Importance: Endometrial 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 participants: The 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 measures: The 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.

Results: Of 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 ≥2) adverse events associated with vistusertib.

Conclusions and relevance: This 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.

Trial registration: ClinicalTrials.gov Identifier: NCT02730923.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Heudel reported personal fees from Seagen, Novartis, and AstraZeneca, and nonfinancial support from Lilly, Pfizer, and Roche outside the submitted work. Dr Frenel reported personal fees from AstraZeneca during the conduct of the study and personal fees from Pfizer, Lilly, Novartis, AstraZeneca, Clovis Oncology, GlaxoSmithKline, Daiichi-Sankyo, and Roche outside the submitted work. Dr Bazan reported personal fees from Roche, Novartis, Pierre-Fabre, AstraZeneca, Clovis Oncology, Daiichi-Sankyo, Seagen, and Pfizer outside the submitted work. Dr Joly reported personal fees from GlaxoSmithKline for the scientific board and coordination of an international study in endometrial cancer, and from the scientific board of Merck Sharp & Dohme/Eisai, both outside the submitted work. Dr Abdeddaim reported personal fees from GlaxoSmithKline outside the submitted work. Dr Augereau reported nonfinancial support from AstraZeneca, GlaxoSmithKline, Clovis, Novartis, and Pfizer outside the submitted work. Dr Pautier reported grants from PharmaMar, Merck Sharp & Dohme, and personal fees from AstraZeneca and GlaxoSmithKline outside the submitted work. Dr You reported consulting fees from Merck Sharp & Dohme, AstraZeneca, GlaxoSmithKline−Tesaro, Bayer, Roche-Genentech, ECS Progastrine, Novartis, Lek, Amgen, Clovis Oncology, Merck Serono, Bristol Myers Squibb, Seagen, and Myriad outside the submitted work. Dr Pérol reported grants from the National Cancer Institute, France, during the conduct of the study; and honoraria and consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Ipsen, Janssen, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Pfizer, Roche, and Takeda outside the submitted work. Dr Fabbro reported serving on the boards of AstraZeneca and GlaxoSmithKline outside the submitted work. Dr Ray-Coquard reported personal fees from PharmaMar, Immunogen, Genmab, Bristol Myers Squibb, Deciphera, Mersana, Clovis, AstraZeneca, Agenus, Novartis, Roche, Macrogenics, GlaxoSmithKline, and grants from Merck Sharp & Dohme, all outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram of Study Participants
aOne patient was deemed not evaluable. BICR denotes a blinded independent central review; and 8wk-PFR, the 8-week progression-free rate.
Figure 2.
Figure 2.. Waterfall Plots by Treatment Allocation, Vistusertib Plus Anastrozole Arm vs Anastrozole Alone Arm
Two patients had 0% change from baseline of target lesion. CR indicates complete response; PD, progressive disease; PR, partial response; and SD, stable disease.
Figure 3.
Figure 3.. Progression-Free Survival (PFS) for Vistusertib Plus Anastrozole Arm vs Anastrozole Alone Arm for Treatment of Endometrial Cancer
See this image and copyright information in PMC

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