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MINI 09 - Drug Resistance (ID 107)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
MINI09.04 - Identification of Effective Drug Combinations to Prevent or Delay Resistance to the EGFR Mutant Selective Inhibitor Rociletinib (CO-1686) (ID 3010)
16:45 - 18:15 | Author(s): A. Simmons
Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) that has demonstrated efficacy against the activating mutations (L858R and del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type (WT) EGFR. Although rociletinib has generated compelling objective responses in heavily-pretreated T790M positive and negative NSCLC patients, acquired resistance to rociletinib monotherapy has also been observed. We are currently exploring preclinical combinations to delay or prevent resistance to rociletinib.
To study acquired resistance in an unbiased fashion, rociletinib resistant populations and clones were generated from the EGFR mutant NSCLC cell lines PC-9 (del19 EGFR), HCC827 (del19 EGFR), and NCI-H1975 (L858R/T790M EGFR) by chronic in vitro and/or in vivo exposure of rociletinib. Compound library screening was performed with rociletinib resistant cell lines to identify drug combinations that could restore rociletinib sensitivity. In vitro and in vivo validation, mechanism of action, and combination studies were performed to evaluate the potency of these combinations in rociletinib sensitive and resistant preclinical models. In addition, combination studies with therapies commonly used in NSCLC, including radiotherapy (RT), an anti-EGFR antibody, and anti-PD-1/L1 antibodies were also explored.
Multiple mechanisms of resistance were observed in rociletinib resistant cell lines, including MET amplification and an epithelial-mesenchymal transition (EMT). In a PC-9 resistant population (designated 2A10) generated by in vitro and in vivo selection, multiple agents including the aurora kinase inhibitor MLN8237, the MEK inhibitor trametinib, and an anti-EGFR antibody restored rociletinib sensitivity in cell viability assays. Western blot analysis demonstrated that the levels of p-ERK in the parental PC-9 cell line were comparable to p-ERK levels in 2A10 cells grown in the presence of 1 mM rociletinib. The combination of rociletinib and trametinib in the 2A10 cell line suppressed p-ERK signaling, concomitant with increased levels of apoptotic markers such as PARP cleavage. The combination of rociletinib and trametinib also demonstrated potent in vivo activity in the 2A10 xenograft model. In vitro and in vivo studies performed with additional cell lines and combinations are ongoing and will also be presented.
Resistance to all 3[rd] generation EGFR inhibitors is likely to be observed, and identifying tolerable and effective combinations to delay or prevent resistance is critical in extending the clinical benefit of these therapies. In vitro and in vivo studies reported here highlight multiple combinations that restore the activity of rociletinib in rociletinib resistant models. In particular, the combination of trametinib and rociletinib restored MAPK pathway suppression and anti-tumor activity in the rociletinib resistant 2A10 model. These nonclinical data support the ongoing Phase 1/2 evaluation of the combination of trametinib and rociletinib.
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