FDA Grants Orphan Drug Designation to Novel KIT Inhibitor for Advanced GIST

The FDA has granted orphan drug designation to the small molecule oral pan-variant KIT inhibitor, THE-630, for the treatment of patients with advanced gastrointestinal stromal tumors (GIST), according to a press release by Theseus Pharmaceuticals, Inc.1

The currently FDA approved treatments for advanced GIST include imatinib (Gleevec) in the frontline setting, sunitinib (Sutent) in the second line, regorafenib (Stivarga) in the third line, and ripretinib (Qinlock) in the fourth line. The objective response rates (ORRs) for the FDA-approved agents range from 9% to 51.4%, according to a presentation given during the American Association for Cancer Research Annual Meeting 2021. The median progression-free survival (PFS) observed with these agents ranges from 4.5 months to 18.9 months.2

However, an unmet need in the treatment of GIST remains for a fifth-line option, as well as better options for earlier lines of treatment. Considering that about 80% of relapse cases are driven by secondary resistance mutations in KIT, a KIT inhibitor like THE-630 in the treatment landscape is warranted.

"We are pleased to have received [orphan drug designation] for THE-630 so quickly after the initiation of the first-in-human trial. This designation from the FDA emphasizes the need to bring better therapeutic options to patients with advanced GIST," said David Kerstein, MD, chief medical officer, Theseus, in a press release. "For patients living with GIST, progression through standard lines of therapy is often associated with the emergence of resistance mutations in KIT. We look forward to evaluating the clinical potential of THE-630 to inhibit these resistance mutations in patients who've exhausted available therapies and when used in earlier lines of therapy."

In the phase 1/2 study of THE-630 in advanced GIST, approximately 160 patients will be enrolled. The study will include a dose-escalation phase (phase 1) and then patients will be evaluated in 4 expansion cohorts (phase 2). The coprimary end points of phase 1 include the number of patients with dose-limiting toxicities, determination of the recommended phase 2 dose, and determination of the maximum-tolerated dose. The phase 2 primary end point is objective response rate (ORR).

The study will also explore multiple secondary end points including confirmed ORR in the dose-escalation phase, the number of treatment-emergent adverse events, Cmax, Tmax, area under the curve from time zero to 24 hours to metabolite, best overall response, time to response, duration of response, disease control rate, clinical benefit rate, PFS, and overall survival.

To be included, patients must be 18 years of age or older with histologically or cytologically confirmed unresectable or metastatic GIST, at least 1 measurable lesion per modified RECIST v1.1, new or archival tissue for biopsy, an ECOG performance status of 0-2, adequate renal, hepatic, and bone marrow function, and be able to use contraception during the study. Patients are actively being recruited at Dana-Farber Cancer Institute in Boston, Massachusetts.


1. Theseus Pharmaceuticals receives U.S. FDA orphan drug designation for THE-630 for the treatment of advanced gastrointestinal stromal tumors (GIST). News release. Theseus Pharmaceuticals. February 2, 2022. Accessed February 2, 2022. https://bit.ly/3rnDCVp

2. Rivera VM, Huang W, Lu M, et al. Preclinical characterization of THE-630, a next-generation inhibitor for KIT-mutant gastrointestinal stromal tumors (GIST). Can Res. 2021;81(13). doi: 10.1158/1538-7445.AM2021-1292

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