Abstract 5192: Utilizing NSCLC PDXs derived from patients on osimertinib (AZD9291) clinical trials to further refine therapeutic strategies
Authors: Palakurthi Sangeetha , Xu Man , Redig Amanda J. , Dills Michael , Gokhale Prafulla , Choi Jinyun , Ogino Atsuko , Kuang Yanan , Feeney Nora , Paweletz Cloud , Kirscmeier Paul , English Jessie , Cross Darren , Jänne Pasi 
Published: July 2016

Background: Osimertinib (AZD9291)is a mutant-selective EGFR tyrosine kinase inhibitor (TKI) effective against EGFR activating and the T790M acquired resistance mutations.Osimertinib has been approved by the US FDA for patients with EGFR T790M positive NSCLC with resistance to first line EGFR TKIs. However, as acquired resistance to osimertinib is now emerging, we aimed to develop PDXs from patients with: a) acquired resistance to first-line EGFR TKIs prior to enrolling on osimertinib trials and b) post-osimertinib resistance.

Methods: Pre- and post-osimertinib tumor biopsies were implanted into the flank or sub-renal capsule of NSG mice. Successfully established PDXs were expanded and confirmed by ddPCR and NGS to maintain molecular fidelity to the original patient tumor. The osimertinib efficacy in a subset of PDX models was tested and compared to clinical osimertinib response in the patients from whom the PDXs were derived. Acquired osimertinib resistance models were further treated with a panel of novel targeted agent combinations, matching the potential mechanism of osimertinib resistance.

Results: 46 patients underwent a pre-osimertinib or post-osimertinib biopsy. 26 biopsies were from the AURA trial for patients with acquired resistance to first-line EGFR TKIs; 5 biopsies were from the TATTON trial for patients without a T790M mutation; and 7 biopsies were from patients with acquired resistance to osimertinib. A platform of 16 PDX models have been successfully developed and shown to exhibit diverse mechanisms of TKI resistance as confirmed by NGS. These models include: 6 with EGFR T790M; 4 with EGFR non-T790M resistance to erlotinib; and 4 with acquired resistance to osimertinib. In the drug efficacy studies, PDX sensitivity to osimertinib is shown to be comparable to the corresponding patient's clinical response. In the DFCI-243 model (patient: EGFR T790M+, PR 8.9 months), tumors showed regression during the dosing phase and rapidly regrew upon cessation of osimertinib treatment. In contrast, in the DFCI-217 model (patient EGFR T790M+, PR &gt;24 months), tumors showed sustained regression even after osimertinib treatment cessation. In the DFCI-284, a potential model of primary AZD9291 resistance tumors showed no regressions with osimertinib treatment. PDX models have also been used to refine treatment approaches for acquired resistance to osimertinib. DFCI-306 model established from a patient who developed an acquired BRAF mutation while on osimertinib has been shown to respond to either selumetinib or the selumetinib/osimertinib combination.

Conclusion: We have developed a platform of NSCLC PDXs from patients with acquired resistance to first-line EGFR TKIs and the newly approved third-generation inhibitor osimertinib. These models can be used to refine treatment strategies in patients with acquired resistance to first-line EGFR TKIs with primary or acquired resistance to osimertinib.

Citation Format: Sangeetha Palakurthi, Man Xu, Amanda J. Redig, Michael Dills, Prafulla Gokhale, Jinyun Choi, Atsuko Ogino, Yanan Kuang, Nora Feeney, Cloud Paweletz, Paul Kirscmeier, Jessie English, Darren Cross, Pasi Jänne. Utilizing NSCLC PDXs derived from patients on osimertinib (AZD9291) clinical trials to further refine therapeutic strategies. [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 5192.