Abstract 5886: In vitro profiling of IDRX-42 and NB003 against secondary and tertiary (AP/AL) mutations found in TKI-resistant GIST

Abstract Approximately 70-75% of Gastrointestinal stromal tumor (GIST) harbor a KIT mutation and patients with KIT-mutant GIST have durable responses to front-line imatinib (IM). Over time, clinical resistance emerges due to secondary IM-resistance mutations. These secondary mutations are restricted to two regions of the KIT protein: the drug/ATP binding pocket (AP, exons 13 and 14) and the activation loop (AL, exons 17 and 18). Although additional TKI drugs are now approved for 2L-4L+ treatment these agents lack activity against the entire spectrum of known resistance mutations. For example, sunitinib (SU) is potent against AP mutations (V654A, T670I), but has minimal activity against AL mutations. Conversely, ripretinib (RIP) has minimal activity against AP mutations. Neither SU nor RIP has activity against KIT-mutant GIST with both AP and AL mutation paired with the original primary KIT mutation (AP/AL). Recently, two new agents, IDRX-42 and NB-003 have been tested in phase 1 studies of patients with TKI-resistant GIST and are initiating randomized phase 3 studies in the second- and third-line, respectively. However, the cellular potency of IDRX-42 and NB-003 against different primary, secondary, and AP/AL KIT mutations has not been comprehensively described. We assessed the biochemical potency of IDX-42 and NB-003 against cell lines with relevant primary, secondary, and AP/AL KIT mutations. To assess relative potency, we also profiled IM in the same cell line model. IM was potent against primary K11 mutations (K11 exon 11 deletion and K11 V560D) but was much less potent against K11 + secondary mutations, KIT exon 9 (K9) primary mutations, and K9 + secondary mutations. IDRX-42 was active against K11, K11 + V654A, K11 + AL, K9 primary, K9 + AP, K9 +AL mutations. IDRX-42 lacked potency against K9 or K11 with T670I mutations. NB003 was active against K11, K11 + AP, K11 + AL, and K11 + V654A + A829 P (AP/AL), K9 primary, K9 + AP, K9 +AL mutations. Notably, none of these drugs had activity against K11 + AP/AL or K9 + AP/AL mutant kinases. IDRX-42 and NB003 have superior biochemical potency against a panel of primary and secondary KIT mutations compared with IM. NB003 may lack potency against certain K9 + secondary mutations. Neither IDRX-42 or NB003 have activity against K9 + AP/AL or K11 + AP/AL mutations. Ideally, future development of these newer agents should focus on earlier lines of therapy, prior to the development of AP+ AL mutations. The pan-resistance of AP/AL mutations to existing TKIs indicates the need to develop new drugs to target these resistance mutations. Citation Format: Michael C. Heinrich, Ajia Town, Marcelina Roberti, Sebastian Bauer. In vitro profiling of IDRX-42 and NB003 against secondary and tertiary (AP/AL) mutations found in TKI-resistant GIST abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5886.