Abstract A105: Credentialing the concept of “co-clinical trials”: Utility of lung cancer PDX models derived from patients on AZD9291 clinical trials

Abstract

Abstract Background: The EGFR T790M mutation is the most common mechanism of acquired drug resistance to currently approved EGFR inhibitors gefitinib, erlotinib, and afatinib. AZD9291 is a mutant-selective EGFR inhibitor effective against both EGFR activating and T790M mutations while sparing wild type EGFR. AZD9291 is highly active in patients with lung cancer with the EGFR T790M mutation, with a response rate of 61% and progression free survival of ∼10 months. However, as resistance to AZD9291 is beginning to emerge, we aimed to develop patient derived xenografts (PDXs) using pre-treatment biopsies obtained from patients with acquired resistance to first-line EGFR inhibitors enrolling on clinical trials with AZD9291. These clinically annotated PDX models allow direct correlation with the clinical efficacy of AZD9291 in patients and may be useful in studying mechanisms of acquired resistance to AZD9291 and refine strategies for treatments. Methods: Pre-AZD9291 treatment tumor biopsies (core needle biopsies or pleural effusions) were implanted into the flank or sub-renal capsule of NSG mice. Tumors were serially passed in NSG mice for up to 3 generations. Successfully established models were expanded and treated with AZD9291. The efficacy in the PDX model was compared to the clinical efficacy of AZD9291 in the patient from whom the model was derived. Results: 33 patients underwent a pre-AZD9291 treatment biopsy (26 core needle; 7 pleural effusions). 26/33 patients enrolled in the AURA AZD9291 clinical trial for patients with acquired resistance to first-line EGFR inhibitors. From these patients, 10 PDX models have been successfully developed so far and confirmed by ddPCR to maintain fidelity to the original patient tumor's EGFR mutation status. These models include 6 with EGFR T790M and 4 with EGFR non-T790M mechanisms of resistance to erlotinib. Among the 10 patients used to develop PDX models, the best clinical response to AZD9291 included 5 partial responses, 3 progressive diseases, 1 stable disease and 1 acquired resistance. A subset of these PDX models were further tested for their sensitivity to AZD9291 and the data was consistent with the clinical responses of the patients. Two models, DFCI 243 and DFCI 217 (both with EGFR T790M; both patients with PR > 9 months) were treated with gefitinib (6.25mg/kg) or AZD9291 (25 mg/kg). Both models were confirmed to maintain EGFR T790M and had a dramatic response to AZD9291 but not to gefitinib treatment. However, tumors rapidly regrew upon cessation of AZD9291 treatment. DFCI 306 PDX model established from a patient with acquired resistance to monotherapy with AZD9291, showed AZD9291 resistance in vivo. AZD9291 treatment of DFCI 284, a model with EGFR T790M derived from a patient with primary resistance to AZD9291, is underway. Conclusion: We have developed PDXs from patients with erlotinib resistance who were treated with AZD9291. The PDX platform is currently being utilized in studies to refine strategies to: a) improve durability of responses to AZD9291 in EGFR T790M mutation positive patients and b) identify combinations in EGFR T790M mutation positive or negative patients who have de novo or acquired resistance to AZD9291. Citation Format: Sangeetha S. Palakurthi, Man Xu, Amanda Redig, Michael Dills, Prafulla Gokhale, Jihyun Choi, Atsuko Ogino, Yanan Kuang, Nora Feeney, Cloud Paweletz, Paul Kirschmeier, Jessie English, Darren Cross, Pasi A. Janne. Credentialing the concept of “co-clinical trials”: Utility of lung cancer PDX models derived from patients on AZD9291 clinical trials. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A105.