(P 423) ZIFTOMENIB IN COMBINATION WITH IMATINIB IN ADVANCED GASTROINTESTINAL STROMAL TUMORS (GIST) AFTER IMATINIB FAILURE: PHASE 1A/B STUDY OF SAFETY, PHARMACOKINETICS, AND ANTITUMOR ACTIVITY

Objective: GIST, the most common digestive tract mesenchymal neoplasm, is mainly driven by KIT gain-of-function oncogenic mutations. Patients (pts) with GIST are typically treated with anti-KIT tyrosine kinase inhibitors (TKIs) like imatinib, but few achieve complete response and most eventually progress due to secondary KIT alterations that cause resistance. Other TKIs are approved in later lines with only moderate clinical outcomes and additional therapies are needed. The menin-KMT2A complex epigenetically upregulates KIT expression in GIST cells in preclinical studies. Ziftomenib is a potent and highly selective menin inhibitor that disrupts menin-KMT2A complex formation. Ziftomenib + imatinib has shown synergistic antitumor activity in imatinib-sensitive and -resistant GIST models, with reduced KIT protein levels and downstream oncogenic signaling observed in imatinib-resistant GIST pt-derived xenografts. Ziftomenib + imatinib may enhance KIT recycling while reducing KIT transcription.

Methods: KOMET-015 (NCT06655246) is a phase 1a/b, open-label study to determine safety, tolerability, recommended phase 2 dose (RP2D), and preliminary antitumor activity of ziftomenib + imatinib 400 mg in advanced/metastatic GIST. KOMET-015 includes dose escalation, RP2D-determination, and dose expansion parts. Eligible pts: ≥18 yrs, biopsy-proven diagnosis of advanced/metastatic KIT-mutant GIST (T670X excluded) that progressed on imatinib at any point (dose escalation, RP2D determination), ECOG PS ≤2, measurable disease (mRECIST). Dose escalation (i3 + 3 design) will evaluate safety and tolerability of up to 4 dose levels (DL) of ziftomenib combined with imatinib. Based on escalation, up to 2 DL will be compared to determine the RP2D. Dose expansion will examine toxicity and preliminary clinical activity of the RP2D: Cohort A: progressed on imatinib as immediate prior therapy; Cohort B: failed imatinib and received ≥2 lines of therapy; Cohort C: imatinib-naive. Tumor response to be assessed (mRECIST). All adverse events to be recorded, monitored, and graded (CTCAE v5.0). This trial is open and actively recruiting in the United States.

Results: n/a

Conclusion: n/a