Abstract
Abstract
MET-amplification has been identified as a resistance mechanism in >5% of patients with non-small cell lung cancer (NSCLC) and 25% of those that progress on 1st/2nd or 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). There are no approved therapies specifically indicated to treat EGFR mutation-positive (EGFRm)/MET amplified NSCLC patients. We report preclinical data of savolitinib (AZD6094, HMPL-504, volitinib, a potent and selective MET inhibitor) plus osimertinib (3rd generation, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFR sensitizing mutation and EGFR T790M) in an EGFRm/MET amplified model.
Combination efficacy of savolitinib and osimertinib was tested in an EGFRm (L858R) and MET-amplified LG1208 PDX model, resistant to osimertinib. As single agents, and at doses that deliver clinically relevant exposures, osimertinib (10 mg/kg) and savolitinib (15 mg/kg) showed minimal (32% tumor growth inhibition [TGI]) and moderate (81% TGI) anti-tumor activity, respectively. Upon combination, at a fixed dose of osimertinib (10 mg/kg), anti-tumor activity increased with savolitinib dose, ranging from 1 mg/kg (99.8 % TGI) to 15 mg/kg (77.9% regression). Pharmacokinetic-pharmacodynamic (PKPD) modelling was also conducted linking exposure of savolitinib to inhibition of phosphorylated MET (pMET), and osimertinib to inhibition of pEGFR. A combination effect on pEGFR was observed whereby the maximum inhibition of pEGFR increased from approximately 50% with no savolitinib to approximately 90% with 15 mg/kg of savolitinib. The exposure-dependent effect of savolitinib on pEGFR was accounted for in the PKPD model by incorporating an interaction term such that the inhibition of pEGFR is modelled as a function of savolitinib and osimertinib exposure. This PKPD model was successfully used to link to the anti-tumor activity and provide biomarker-led rationale for the combination benefit seen for efficacy in this model.
Overall, the PKPD analysis describes the biomarker changes linking to efficacy and provides supporting insight into the exposure requirements for combination dosing in the clinic. Savolitinib plus osimertinib was tested in the TATTON study (NCT02143466) where patients with EGFRm, MET-amplified NSCLC with prior progression on EGFR-TKIs had encouraging responses to this combination therapy. A phase 2 trial, SAVANNAH (NCT03778229), is testing the combination of osimertinib and savolitinib in patients with EGFRm, MET-amplified NSCLC with prior progression on osimertinib only.
Citation Format: Rhys Jones, Awlin Schuller, Klas Petersson, Ghada Ahmed, Stein Schalkwijk, Areya Tabatabai, Andrew Mortlock, Rana Anjum. Using a pharmacodynamic biomarker led approach to explore and quantify the combination effect of savolitinib and osimertinib in the LG1208 NSCLC PDX model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3017.