KIT Program for GIST

We are developing a targeted therapy for gastrointestinal stromal tumors (GIST) that are designed to address treatment resistance.

About GIST
Our goal is to develop a truly pan-variant inhibitor that can address the limitations of current therapies by simultaneously addressing all clinically relevant KIT mutations with a single agent.

GIST is the most common sarcoma of the gastrointestinal tract with an estimated 4,000 to 6,000 new cases diagnosed in the United States each year. Approximately 80% of GIST cases are driven by mutations in KIT, and the disease remains KIT-dependent through successive lines of therapy. Most patients who receive first-line imatinib as a treatment for GIST later experience disease progression due to the emergence of other KIT mutations rendering subsequent lines of targeted therapy significantly less effective.

We believe that the broad inhibitory profile of THE-630 has the potential to generate robust and durable responses in advanced GIST across the spectrum of previously-treated patient populations.

About THE-630
Our lead candidate, THE-630, is a single molecule pan-variant inhibitor of the receptor tyrosine kinase KIT designed for patients with advanced GIST whose cancer has developed resistance to earlier lines of targeted therapy.

Theseus’ predictive resistance assay (PRA) compared the activity of THE-630 to current standard-of-care KIT inhibitors against all major classes of known KIT mutations and found that only THE-630 successfully inhibited KIT in the face of both cancer-causing and resistance mutations. THE-630 is predicted to achieve pan-inhibition of cancer-causing mutations (exons 9 and 11) and resistance mutations (exons 13-14 and 17-18) in a single agent. Current standards of care have shown to address some, but not all, of these mutations, opening the door for treatment resistance and the proliferation of heterogeneous clonal tumors that inevitably develop in KIT-driven GIST.

THE-630 will initially be under clinical evaluation for advanced KIT-driven GIST in the fifth-line where no standard therpies exist. It will also be clinically evaluated in second-line GIST, where a pan-KIT inihibitor with activity against all major classes of cancer-causing and resistance mutations has the potential to deliver meaningful clinical benefit over the current standard of care.

We are currently evaluating THE-630 in a Phase 1/2 dose escalation and dose expansion trial. The Phase 1 portion of the trial is enrolling patients with resistance to imatinib and at least one other TKI. We plan to evaluate multiple expansion cohorts in the Phase 2 portion of the trial.

For more information visit (NCT05160168).