Hiroyuki Iida (1), Ryu Fujikawa (1), Ryohei Kozaki (1), Tomoya Ohno (1)
(1) Ono Pharmaceutical Co., Ltd., Osaka, Japan
Objectives: Oncogenic rearrangements of neurotrophic tyrosine receptor kinase (NTRK) encode chimeric proteins with constitutive kinase activity, which promote tumour cell growth and survival. Patients with NTRK fusion-positive cancers well responded to treatment with tropomyosin receptor kinase (Trk) inhibitors in clinical studies [1]. ONO-7579 is a highly potent and selective oral pan-Trk inhibitor which selectively inhibits Trk autophosphorylation, associated with the down-stream signalling [2]. The objective of this work is to define relationship between phosphorylated TrkA (pTrKA) and antitumour effect in KM12 xenografted model mice with PK/PD modelling approach in order to contribute to determination of recommended dose with biomarker in early clinical development.
Methods: KM12 cells were transplanted subcutaneously into female BALBnu/CrlCrlj mice. A single dose of ONO-7579 was orally administered at doses of 0.06 and 0.6 mg/kg to evaluate the time-course of ONO-7579 concentration and pTrkA level in tumour. On the other hand, repeated doses of ONO-7579 were orally administered once daily for 12 days at 0.06, 0.2, and 0.6 mg/kg to evaluate the time-course of tumour volume. Plasma and tumour concentrations of ONO-7579 and pTrkA level in tumour were obtained from both studies. The resulting data were integrated and empirical model analyses were performed with NONMEM 7.1.2. Plasma PK model, tumour PK model, tumour PK/pTrkA model and pTrkA/tumour volume model were developed in a sequential manner. The relationship between tumour growth rate and pTrkA inhibition in the tumour was predicted by using the developed model.
Results: Plasma concentration of ONO-7579 was well described with oral 1-compartment model. Tumour concentration of ONO-7579 was higher than plasma concentration, and tumour compartment was added on the plasma compartment. Though delay in distribution from plasma to tumour was observed, tumour concentration of ONO-7579 and pTrkA level in tumour were well described with direct Emax model. Time-course of tumour volume were well described with first-order growth/death model, with the pTrkA inhibition effect included as a sigmoid Emax model on tumour growth rate. Though ONO-7579 hardly exerts antitumour effect at pTrkA inhibition rate ≤ 60%, ONO-7579 starts to sharply increase the tumour growth inhibition at pTrkA inhibition rate > 60%. It turned out that pTrkA inhibition rate ≥ 91.5% was required in order to reduce tumour volume. The result indicates that there is a threshold of pTrkA inhibition rate where antitumour effect is exerted. Also, dosage and administration where, for example, pTrkA continues to be fully inhibited at trough concentration can be proposed so that ONO-7579 will be effective in clinical studies.
Conclusions: PK/PD/Efficacy model has identified “switch-like” relationship between pTrkA inhibition rate and antitumour effect in KM12 xenografted model mice, and demonstrated that pTrkA in tumour can be an effective biomarker to consider dosing regimen of ONO-7579 in clinical studies.
References:
[1] Cocco E., et al., NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol, (2018) 15: 731-747.
[2] Kawamoto M., et al., The novel selective pan-TRK inhibitor ONO-7579 exhibits antitumor efficacy against human gallbladder cancer in vitro. Anticancer Res, (2018) 38: 1979-1986.
Reference: PAGE 28 (2019) Abstr 8883 [www.page-meeting.org/?abstract=8883]
Poster: Drug/Disease Modelling - Oncology