Victoria: A multicentric, randomized, open-label, phase I/II of mTOR inhibitor (VISTUSERTIB) combined with anastrozole in patients with hormone receptor-positive advanced/metastatic endometrial cancer—A CLIPP program INCA in collaboration with GINECO group.
Authors: Heudel Pierre-Etienne , Frenel Jean-Sebastien , Dalban Cécile , Bazan Fernando , Joly Florence , Arnaud Antoine , Abdeddaim Cyril , Chevalier Annick , Augereau Paule , Pautier Patricia , Chakiba Camille , You Benoit , Lancry Lecomte Laurence , Garin Gwenaelle , MArcel Virginie , Diaz Jean-Jacques , Treilleux Isabelle , Pérol David , Fabbro Michel , Ray-Coquard Isabelle Laure 
Published: June 2021

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Background: Endometrial carcinoma is generally hormone dependent and aromatase inhibitors are used in routine practice before or after 1st line chemotherapy (CT) for HR positive patients. Deregulation of the Pi3K-Akt-mTOR signaling pathway is observed in many tumor types including endometroid carcinoma driven oncogenesis and hormonal resistance. Vistusertib (V) is a small-molecule ATP competitive inhibitor of both mTORC1 and mTORC2 complexes. Methods: Adult patients (pts) with recurrent oestrogen or progesterone (ER and/or PR) positive advanced/metastatic endometrial carcinoma, one previous line of chemotherapy (CT) allowed, with ECOG PS 0/1, were randomised (2:1, stratification according to prior CT line: 0 vs 1) to receive V (125 mg bid/2 days/week, orally) + Anastrozole (A, 1 mg/d, orally) or A alone. Treatments were given until progression, intolerable toxicity or patient willingness. Following a safety run in phase, a Simon’s 2-stage design was employed to explore the 8-week progression free rate (PFR-8W) according to central review (p1: 60%, p0: 40%, type I error rate of 5%, power of 80%). At the end of Stage II, if ≥24/46 evaluable pts are progression free at 8w in Arm A+V, the combination will be considered of interest for further investigation. Overall response rate (ORR) by RECIST v1.1, safety and progression-free survival (PFS) were key secondary endpoints. Results: Out of 75 patients (pts) enrolled, 73 were randomised and treated (Arm V+A: 49; Arm A: 24; median age: 69.5 y [36.8; 87.8]), BMI ≥30 kg/m²: 45%). PS ECOG was 0 (48%) and 44% of randomised pts were chemotherapy naïve; 12% previously received hormonal therapy. At the end of the safety run-in, no major safety concerns were reported. At the end of Simon’ Stage II, centrally assessed PFR-8W was 67.3% (33/49 [95% CI unilateral: 54.7; -]) for A + V arm and 39.1% (9/23 [[95% CI unilateral: 22.2; -[) for arm A. Median PFS was 5.2 months (95% CI: 3.4-8.9) and 1.9 months (95% CI: 1.6-8.9) for A+V and A arms, respectively. One complete response and 11 partial responses (PR) were observed (ORR: 24.5 % (CI 95% [13.3 – 38/9%]) in the combination arm and 4 PR in arm A (ORR: 17.4% [CI 95%: 5-38.8%]). Fatigue, lymphopenia, hyperglycaemia and diarrhoea were the main (≥10%) Grade ≥2 adverse events related to V. Overall survival and translational research are ongoing. Conclusions: The A+V combination demonstrated clinically and meaningful improvement in 8w-PFR and median PFS with manageable toxicity. PI3K pathway remains a key target for new therapies in endometrial cancer and translational research must help to better select pts benefiting from these targeted therapies. Clinical trial information: NCT02730923.