On December 2, 2016 Ignyta, Inc. (Nasdaq: RXDX), a biotechnology company focused on precision medicine in oncology, reported data examining the combination of entrectinib and trametinib in overcoming resistance to TRK inhibition during a late-breaking oral plenary presentation (during the Exceptional Response and Expected Resistance Session) at the 2016 EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) (ENA) Molecular Targets and Cancer Therapeutics Symposium in Munich, Germany (Press release, Ignyta, DEC 2, 2016, View Source [SID1234516880]). Entrectinib is the company’s orally available, CNS-penetrant tyrosine kinase inhibitor, targeting tumors that harbor TRK, ROS1 or ALK fusions, and is currently in a registration-enabling Phase 2 clinical trial known as STARTRK-2.
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"This presentation is a great example of the successful translation of preclinical observations into clinical practice for the benefit of patients," said Alexander Drilon, M.D., of Memorial Sloan Kettering Cancer Center, who presented the data on behalf of the abstract authors at ENA. "The patient experience described in today’s presentation highlights the ability of entrectinib, in combination with a MEK inhibitor, to overcome potential treatment resistance that has been described for TRK inhibitors."
Data presented describe results from a single patient protocol designed to allow co-administration of entrectinib and trametinib, a commercially-approved MEK inhibitor. The patient, diagnosed with mammary analog secretory carcinoma (or MASC) with an NTRK3 fusion—~90-100% of MASC cases have TRK fusions—and previously treated with multiple surgeries, radiation, vinorelbine, carboplatin/paclitaxel, doxorubicin and crizotinib, experienced a rapid and confirmed partial response (89% reduction) with single-agent entrectinib treatment and remained on therapy for nine months. However, during the course of therapy, the patient’s tumor developed a solvent front point mutation, the predicted mechanism of resistance to first generation TRK inhibitors and analogous to a common mechanism of resistance for other TKIs against other fusion targets.
Based on both in vitro and in vivo data developed by Ignyta, indicating that entrectinib plus a MEK inhibitor could overcome such TRK inhibitor resistance, a single patient protocol was created, reviewed by the FDA and implemented to allow for dose escalation of entrectinib in combination with trametinib. While on the combination, all drug-related adverse events (AEs) were grade 1 or 2, and no new AEs specific to the combination were encountered. The patient achieved a 22% reduction in tumor volume and remained on the combination regimen for nearly seven months.
"This single-patient protocol is an excellent example of our vision at Ignyta, leveraging the molecular alterations responsible for cancer’s growth to design rational treatment strategies for patients in their fight against cancer," said Jonathan Lim, M.D., Chairman and CEO of Ignyta. "In addition to STARTRK-2, our global Phase 2 basket trial of entrectinib in multiple tumor histologies and STARTRK-NG, our Phase 1/1b trial of entrectinib in pediatric patients with solid tumors, we look forward to further exploration of entrectinib in combination with a MEK inhibitor in a Phase 1/1b clinical trial anticipated to initiate in the second half of 2017."