Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer

Basu, B. et al. (2018) Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer. Annals of Oncology, 29(9), pp. 1918-1925. (doi: 10.1093/annonc/mdy245) (PMID:30016392) (PMCID:PMC6158767)

Abstract

Background: We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients. Patients and methods: In dose escalation, weekly paclitaxel (80 mg/m2) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively. Results: The dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m2 paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28–18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76–21.25). Discussion: In this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC. Clinical trial registration: ClinicialTrials.gov identifier: CNCT02193633.

• Item Type: Articles
• Additional Information: This work was supported by AstraZeneca through Cancer Research UK’s Experimental Cancer Medicine Centre (ECMC) Combinations’ Alliance. All sites acknowledge funding from ECMC awards. In addition, The Institute of Cancer Research and The Royal Marsden, Cambridge University Hospitals NHS Foundation Trust, King’s College London, and The Christie NHS Foundation Trust, Manchester, acknowledge infrastructural funding from the National Institute for Health Research Biomedical Research Centre (NIHR BRC) and Clinical Research Facility grants. RS was supported by a fellowship from the National Medical Research Council, Singapore. U Banerji is a recipient of an NIHR Research Professorship Award [grant number RP-2016-07-028].
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Evans, Professor Jeff and Wilson, Professor Richard
• Authors: Basu, B., Krebs, M.G., Sundar, R., Wilson, R. H., Spicer, J., Jones, R., Brada, M., Talbot, D.C., Steele, N., Ingles Garces, A.H., Brugger, W., Harrington, E.A., Evans, J., Hall, E., Tovey, H., de Oliveira, F.M., Carreira, S., Swales, K., Ruddle, R., Raynaud, F.I., Purchase, B., Dawes, J.C., Parmar, M., Turner, A.J., Tunariu, N., Banerjee, S., de Bono, J.S., and Banerji, U.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Annals of Oncology
• Publisher: Oxford University Press
• ISSN: 0923-7534
• ISSN (Online): 1569-8041
• Published Online: 17 July 2018
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Annals of Oncology 19(9): 1918-1925
• Publisher Policy: Reproduced under a Creative Commons License