Abstract
BackgroundWe 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 methodsIn dose escalation, weekly paclitaxel (80mg/m2) was given 6/7weeks 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 (3/7days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7days). 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. ResultsThe 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 80mg/m2 paclitaxel with 50mg vistusertib bd 3/7days for 6/7weeks. 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 5.8months (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 25mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8months (95% CI: 2.76–21.25). DiscussionIn 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 registrationClinicialTrials.gov identifier: CNCT02193633
Highlights
We have previously studied cancer cells isolated from serous effusions and shown raised p-S6K to be associated with chemoresistance and poor clinical outcome in ovarian and lung cancers, respectively [1, 2]
We report the first study of the combination of weekly paclitaxel with the dual m-TORC1/2 inhibitor, vistusertib, establishing a safe dose and schedule and preliminary evidence of efficacy in HGSOC and SqNSCLC
We chose to investigate the m-TORC1/2 inhibitor in the context of weekly paclitaxel, as this regimen is often used in the setting of platinum-resistant ovarian cancer [9], and taxanes are commonly used in the treatment of platinumresistant NSCLC [10, 11]
Summary
We have previously studied cancer cells isolated from serous effusions and shown raised p-S6K to be associated with chemoresistance and poor clinical outcome in ovarian and lung cancers, respectively [1, 2]. This led us to hypothesise that inhibition of m-TOR signalling, in combination with chemotherapy, could improve treatment outcomes in these tumour types. 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
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