Abstract B28: Overcoming drug resistance to Trk inhibition by rational combination of entrectinib and trametinib: from bench to bedside
Authors: Wei Ge , Maneval Edna Chow , Esquibel Vanessa , Berger Michael F. , Haque Sofia , Patel Roopal , Walsh Colin , Hornby Zachary , Multani Pratik , Li Gary 
Published: December 2017

Abstract
Abnormal expression and constitutive activation of TrkA, TrkB and TrkC due to gene fusions are oncogenic drivers in many cancer types. Entrectinib, a potent, brain-penetrant Trk inhibitor, has demonstrated rapid, deep, and sustained clinical responses in patients with advanced or metastatic Trk-fusion-positive solid tumors across multiple histologies.
For tyrosine kinase inhibitors, point mutations that disrupt the binding between the inhibitor and kinase domain of the target are a common mechanism of resistance. By design, entrectinib retains its potency against gatekeeper mutations in Trk, ROS1 and ALK. On the other hand, solvent front mutations, G595R in TrkA or G623R in TrkC (analogous to ROS1 G2032R and ALK G1202R), have been identified as resistance mutations in a clinical setting. Preclinically, upregulation of the MAPK pathway was observed following the introduction of such mutation in Trk-fusion-positive cancer cell lines. In vitro combination screening and in vivo efficacy study further demonstrated the potential for entrectinib-trametinib (a MEK inhibitor) combination to overcome the drug resistance mediated by solvent front mutations.
In the clinic, a 34-year-old female patient with ETV6-NTRK3 positive mammary analog secretory carcinoma (MASC) who progressed despite multiple courses of prior multi-modal therapy, including crizotinib, experienced a rapid confirmed partial response (PR: 89% reduction at nadir) with entrectinib treatment. Seven months later, asymptomatic progressive disease (PD) was detected at a solitary tumor site, a biopsy of which showed a G623R solvent front mutation. After three more months on entrectinib, the patient experienced generalized progression and was in need of additional therapy. She was then treated with another Trk inhibitor with no clinical benefit. She then received palliative radiation therapy to symptomatic pleural/chest wall metastases. Supported by the preclinical data on combination therapy, a single patient protocol was subsequently developed to allow co-administration of entrectinib and trametinib. Significant tumor regression was achieved within the first eight weeks, including sustained resolution of tumor-associated pain and hypertrophic osteoarthropathy.
In conclusion, we have identified a mitigation strategy, utilizing an approved agent combined with a well-characterized clinical stage agent, to overcome acquired Trk-inhibitor resistance, presumably by overcoming solvent front mutation-driven MAPK activation. The successful translation of a preclinical observation made at the bench to clinical practice at the bedside has greatly extended the duration of tumor regression and provided continued care to a Trk-fusion positive patient even after the emergence of resistance. This clinical observation will be further explored in a dedicated Phase 1/1b combination study.
Citation Format: Ge Wei, Edna Chow Maneval, Vanessa Esquibel, Michael F. Berger, Sofia Haque, Roopal Patel, Colin Walsh, Zachary Hornby, Pratik Multani, Gary Li. Overcoming drug resistance to Trk inhibition by rational combination of entrectinib and trametinib: from bench to bedside [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B28.