StrateGIST 1: A first-in-human (FIH), phase 1 study of IDRX-42 in patients with metastatic gastrointestinal stromal tumors resistant to prior treatment with tyrosine kinase inhibitors (TKIs).
Authors: Schöffski Patrick , Heinrich Michael C. , Trent Jonathan C. , Serrano Cesar , Bauer Sebastian , von Mehren Margaret , Somaiah Neeta , Reichardt Peter , Demetri George D. , Lydon Nick , Verweij Jaap , Kadambi Vivek , Christo Jessica , Kim Sean , Johnson Debbie , Shao James , George Suzanne 
Published: June 2024

11501 Background: Resistance to kinase inhibitors in gastrointestinal stromal tumors (GIST) is mainly driven by secondary mutations in KIT, and currently available TKIs fail to inhibit the full spectrum of secondary KIT mutations.IDRX-42 is an oral, potent, and highly selective inhibitor of the KIT tyrosine kinase, active against multiple primary and secondary resistance mutations in KIT-driven GIST. We present data from the ongoing FIH phase (ph) 1 study evaluating IDRX-42 in patients (pts) with metastatic GIST in 2nd or later lines of therapy after failure of imatinib and other drugs. Methods: This ph 1 study evaluates the safety, tolerability, pharmacokinetics, and antitumor activity of oral IDRX-42 in adult pts with KIT-mutant GIST in dose escalation (ph1a) and defines the recommended dose for continued development (ph 1b). Ph 1b comprises 4 cohorts including pts without prior exposure to TKIs (1st line), pts treated with prior imatinib only (2nd line) and later line treatment cohorts. Correlative studies include sequential circulating tumor DNA (ctDNA) analyses and metabolic imaging using 18FDG-PET. Results: As of January 2, 2024, 42 pts received IDRX-42 in the ph 1a portion of the study with median treatment duration of 19+ (range 2-73+) weeks, with 30 pts remaining on treatment as of data cutoff. The median number of prior TKI therapy lines was 4 (range 1-6). Primary driver mutations were in KIT exon (ex) 11 (n = 27), ex 9 (n = 13) and ex 8 (n = 2). To date, five dose levels (120, 240, 400 and 600 mg QD; 400 mg BID) have been deemed safe to continue escalation. MTD has not been reached. A total of 39/42 pts are evaluable for efficacy; 9 achieved objective partial response (PR) per mRECIST (5 confirmed, 4 pending) across all doses studied. Three of 6 patients receiving IDRX-42 as 2nd line therapy have confirmed PRs at 120 mg QD, 400 mg QD, and 400 mg BID respectively. The clinical benefit rate (mRECIST PR or stable disease ≥16 weeks) is 71% overall and 100% in 2nd line. Sequential analyses of ctDNA show reductions across all primary and secondary KITmutations. Treatment-related adverse events (TRAE, CTCAE v5.0) were mainly low grade. The most frequently reported TRAE (≥25%) were gastrointestinal symptoms (diarrhea, nausea, vomiting, decreased appetite, dysgeusia) and fatigue. Eight of 42 pts reported Grade 3/4 TRAEs including gastrointestinal symptoms, fatigue and anemia. Two events qualified as DLT, 1 at 600 mg QD (syncope) and 1 at 400 mg BID (vomiting); after dose reduction both pts continued IDRX-42 for more than 8 and 5 months, respectively. Only two patients discontinued treatment due to TRAEs. Conclusions: IDRX-42 demonstrates promising clinical activity and a favorable safety profile in patients with advanced GIST following resistance to prior TKIs. Dose finding continues, and additional cohorts are ongoing. Clinical trial information: NCT05489237 .