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

B Basu, M G Krebs, R Sundar, R H Wilson, J Spicer, R Jones, M Brada, D C Talbot, N Steele, A H Ingles Garces, W Brugger, E A Harrington, J Evans, E Hall, H Tovey, F M de Oliveira, S Carreira, K Swales, R Ruddle, F I Raynaud, B Purchase, J C Dawes, M Parmar, A J Turner, N Tunariu, S Banerjee, J S de Bono, U Banerji, B Basu, M G Krebs, R Sundar, R H Wilson, J Spicer, R Jones, M Brada, D C Talbot, N Steele, A H Ingles Garces, W Brugger, E A Harrington, J Evans, E Hall, H Tovey, F M de Oliveira, S Carreira, K Swales, R Ruddle, F I Raynaud, B Purchase, J C Dawes, M Parmar, A J Turner, N Tunariu, S Banerjee, J S de Bono, U Banerji

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.

Figures

Figure 1.
Figure 1.
Pharmacodynamic profile of vistusertib at 50 mg bd 3/7. Phosphorylation of AKT (Ser473) in platelet-rich plasma was quantified using MSD electrochemiluminescent immunoassays and normalised to corresponding total AKT values. Baseline values were established prior to the start of treatment. On C1D1, only paclitaxel (80 mg/m2) was administered and a non-significant rise in p-ATK at 4 h following treatment was noted. On C1D4, a single dose of vistusertib was administered and non-significant reduction of p-AKT was seen. On C1D8, the combination of paclitaxel and vistusertib was administered, which caused a significant reduction of p-AKT compared with baseline. Points represent individual patients, orange line represents mean of up to N = 6 patients. Four samples were excluded because of haemolysis, which interfered with the assay (*P<0.05; paired t-test).
Figure 2.
Figure 2.
Clinical outcomes of patients in the ovarian cancer expansion treated at the R2PD for ovarian cancer. (A) Waterfall plot of 23/25 patients with ovarian cancer treated at the RP2D for ovarian cancer that were evaluable for response; two patients clinically progressed with bowel obstruction in the first cycle and did not have a repeat CT scan to assess response. A total of 19 of 25 (76%) patients showed a reduction in size of their tumour, with 13/25 (52%) achieving a partial response. (B) Mutations in tumour tissue or plasma of patients compared with clinical response. (C) Spider plots representing percentage change in measured sum of tumour dimensions of individual patients over time (each cycle is 7 weeks).
Figure 3.
Figure 3.
Clinical outcomes of patients in the squamous NSCLC expansion treated at the R2PD for squamous NSCLC. (A) Waterfall plot of 21/23 patients with sqNSCLC treated at RP2D of the combination; two patients clinically progressed within their first cycle and repeat radiological evaluation was not done. Eighteen of the 23 (78%) patients showed reduction in the size of their tumour with 8/23 (35%) achieving a partial response. (B) Mutations in tumour tissue or plasma of patients compared with clinical response. (C) Spider plots representing percentage change in measured sum of tumour dimensions of individual patients over the time (each cycle is 7 weeks).

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