Final Results Of The Pharmacodynamic (Pd) Data Of Pqr309-001 A First-In-Human Trial Of A Combined Pi3k/Mtor Inhibitor In Advanced Solid Tumors

Abstract Background: PQR309 is a novel, oral, balanced pan-class 1 PI3K, mTORC1 and mTORC2 inhibitor. PQR309-001 was a first-in-man dose escalation study evaluating PQR309 in patients with advanced solid tumours. The primary objective of the study was to establish the maximum tolerated dose (MTD) of PQR309, its safety and tolerability. Secondary objectives included characterization of PQR309 pharmacokinetics (PK) and pharmacodynamics (PD). Methods: We investigated PQR309 treatment-induced PD, including changes of 16 PI3K-mTOR and MAPK associated phospho-proteins, and 84 mRNAs in serial tumor biopsies obtained from patients enrolled in study PQR309-001. 13 patients were eligible for PD analysis after histologic evaluation of fresh-frozen tissue. A solid-phase assay with phospho-specific antibodies was used for the investigation of PI3K/mTOR and MAPK signalling. RNA analysis was performed with an RTK/PI3K-specific RNA array. Results: Under treatment with PQR309, phospho-Akt (p_T308 and p_S473), phospho-mTOR and phospho-S6 were significantly downregulated compared to baseline (p<0.05, Wilcoxon signed-rank test). Moreover, patients with radiographic tumor shrinkage (n = 7) had significantly stronger phospho-Akt (p_T308), phospho-mTOR and phospho-S6 reduction than patients whose tumor was growing (n = 6) (p<0.05, Mann-Whitney test). Importantly, ERK1/2 phosphorylation, as the readout of MAPK activity, was decreased overall with no statistically significant difference between shrinking and growing tumors. The analysis of mRNAs showed a trend towards upregulation of PDGFRA (3.2 times, not statistically significant) after 21 days of therapy with PQR309. Intriguingly, no consistent changes of other PI3K-related RNAs was observed. Conclusion: PD assessments in tumour tissue samples from patients treated with PQR309 demonstrated a reduction of phosphorylation of direct targets for PQR309 (PI3K and mTOR) as well as downstream effectors of mTOR. Furthermore, the data indicate that downregulation of phospho-Akt (p_T308) and mTORC1 activity may be predictive of tumor shrinkage while upregulation of PDGFRA may represent a mechanism of resistance against PI3K/mTOR inhibition. Citation Format: Andreas Wicki, Vincent Prêtre, Reto Ritschard, Nicholas Brown, Vincent Bize, Thomas Fabbro, Natasa Cmiljanovic, Sasa Dimitrijevic, Deborah Schmitz, Michael Stumm, Rebecca Kristeleit. Final results of the pharmacodynamic (PD) data of PQR309-001, a first-in-human trial of a combined PI3K/mTOR inhibitor in advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2287.