(P 26) PHASE 1 STUDY OF IDRX-42 IN PATIENTS WITH ADVANCED GASTROINTESTINAL STROMAL TUMORS RESISTANT TO PRIOR SYSTEMIC THERAPY: EARLY RESULTS

Objective: IDRX-42 is a potent, highly selective, oral inhibitor of multiple mutant variants of the KIT tyrosine kinase, targeting a range of clinically relevant resistance mutations in KIT as oncogenic drivers of gastrointestinal stromal tumor (GIST). In preclinical studies, IDRX-42 demonstrated superior antitumor activity compared to imatinib in human xenograft models of GIST expressing mutations in KIT exons 9 and 11. In xenograft models expressing secondary resistance mutations in KIT exon 13, IDRX-42 treatment resulted in potent and dose-dependent antitumor activity superior to the second-line standard of care agent, sunitinib (De Sutter 2023). Similar results were seen in a xenograft model expressing secondary resistance mutations in KIT exon 17. We present preliminary results of the ongoing phase 1 first-in-human study evaluating IDRX-42 in patients (pts) with metastatic, surgically unresectable GIST after failure of imatinib or other approved drugs.

Methods: This open-label, phase 1/1b study evaluates the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of orally administered IDRX-42 in adult pts with GIST and documented KIT mutations. The dose escalation phase focuses on establishing the maximum tolerated dose (MTD) of IDRX-42. In the planned phase 1b part of the study, three exploratory cohorts of pts progressing on a defined number of prior lines of systemic therapies at the selected recommended phase 1b dose(s) will be studied to assess antitumor effects and further characterize the safety profile of IDRX-42. The phase 1b portion of the trial will include a second line cohort.

Results: As of October 5, 2023, 33 pts have received IDRX-42 in the ongoing dose escalation portion of the study. Median age was 60 years, median number of lines of prior systemic therapy was 4, 70% of pts had any KIT exon 11 mutation, and 33% of patients had any KIT exon 9 mutation. With the starting dose of 120 mg QD, 4 dose levels (120, 240, 400 and 600 mg QD) were cleared by the Safety Review Committee and a 400 mg BID cohort is currently under evaluation. The majority of treatment-related adverse events were CTCAE version 5.0 grade 1, the most common (>25%) being diarrhea (70%), nausea (52%), and vomiting (27%). Two events were graded as dose limiting toxicities, one at 600 mg QD (syncope) and one at 400 mg BID (vomiting); both pts chose to proceed with dose reduction and continue on IDRX-42 for more than 5 and 2 months, respectively. Twenty-eight of 33 pts were evaluable for objective response (completed ≥1 response assessment). MTD has not been reached. The disease control rate (partial response [PR] or stable disease ≥ 16 weeks) to date is 67.9% (19 of 28 evaluable pts). Four pts exhibited confirmed PRs per modified RECIST (mRECIST): 1 pt at 120 mg, 1 pt at 400 mg, and 2 pts at the 600 mg dose levels. Tumor shrinkage and confirmed PRs were observed across all KIT mutants treated, including both primary driver and resistance mutations (exons 9, 11, 13, and 17), consistent with the potent multi-mutant KIT inhibitory profile of IDRX-42 (Figure 1). FDG-PET scans indicated early metabolic responses in GIST with IDRX-42, and 23 pts (70%) remain on IDRX-42 with 10 pts discontinued due to GIST progression after a median follow-up of 4 months. No pts discontinued for toxicity. Longitudinal analyses of ctDNA show reductions across all mutation variants in all KIT exons identified. IDRX-42 demonstrated a dose-dependent increase in plasma exposure with a long half-life (~125 hours) and a 5-8 fold accumulation at steady state.

Conclusion: IDRX-42 demonstrates promising antitumor activity and a favorable safety profile in a pre-treated group of pts with advanced/metastatic GISTs. IDRX-42 has a broad and potent KIT inhibitory profile including primary driver and resistance mutations. Phase 1b will evaluate IDRX-42 in pts after failure of first-line imatinib as well as after failure of later lines of therapy.

Figure 1: