bezuclastinib (PLX9486)

Despite the outstanding results of first-line imatinib in advanced GIST, resistance ultimately occurs mainly through secondary mutations in KIT/PDGFRA...However, it is now recognized that the situation is more intricate, with various factors interacting with KIT and PDGFRA, playing a crucial role in the response and resistance to treatments. Future strategies in the management of advanced GIST should integrate driver inhibition with the blockade of other molecules to enhance cell death and establish enduring responses in patients.

P2, N=40, Not yet recruiting, Sarcoma Alliance for Research through Collaboration

Patients with a history of prior TKI therapy (e.g., avapritinib, midostaurin) are permitted in the trial. Enrollment in Part 1 of the Apex trial is complete. Patients enrolled in Part 1 of the Apex trial are generally representative of the population of patients with AdvSM based on patient characteristics and markers of disease. Part 1 includes a small subset of patients with prior use of TKIs.

There are currently no approved therapies for patients with NonAdvSM. Data from the Summit study will support further development of bezuclastinib in SM.

Patients with a history of prior TKI therapy (e.g., avapritinib, midostaurin) are permitted in the study. Early data suggest that bezuclastinib is well-tolerated and is associated with encouraging early signs of clinical activity as demonstrated by meaningful reductions in serum tryptase, MC burden, and KIT D816V VAF. Enrollment is currently ongoing. Updated safety and clinical activity as well as initial clinical objective response data will be presented.

There remains a high unmet need for more effective and better tolerated second- and later-line treatments for patients with GIST. Phase 1/2 bezuclastinib data in advanced solid tumors, including GIST, were encouraging and support further clinical investigation of co-targeting the complementary conformational states of the same kinase with bezuclastinib and sunitinib. The Peak Study aims to assess the efficacy and safety of bezuclastinib in combination with sunitinib as second-line treatment in adult patients with imatinib-resistant, or intolerant, GIST.

Data from this study will support development of bezuclastinib in SM

Part 1 of the Apex study aims to determine the optimal dose to further evaluate in Part 2. Early insights into the safety and tolerability profile and biomarker data will further inform clinical development of bezuclastinib in AdvSM.

Second-line sunitinib is active against exon 13/14 mutations but not A-loop mutations and identifying inhibitors that target the spectrum of possible mutations without incurring off-target toxicities related to broad-spectrum kinase inhibition has been challenging. This attractive selectivity and nonclinical safety profile, combined with early clinical data in advanced solid tumors, supports the potential for a best-in-class KIT inhibitor. Bezuclastinib is currently under clinical investigation in advanced SM (Phase 2, Apex NCT04996875), non-advanced SM (Phase 2, Summit), and imatinib-resistant GIST (Phase 3, Peak).

P3, N=388, Recruiting, Cogent Biosciences, Inc. | Not yet recruiting --> Recruiting

P3, N=388, Not yet recruiting, Cogent Biosciences, Inc.

This attractive selectivity and nonclinical safety profile, combined with early clinical data in advanced solid tumors (Trent et al, 2020), supports the potential for a best-in-class KIT inhibitor. Bezuclastinib is currently under clinical investigation in advanced SM with additional clinical studies planned in non-advanced SM and imatinib-resistant GIST.

The study will enroll approximately 138 subjects. Data from this study will support further development of bezuclastinib in SM.

Data from this study will support continued development of bezuclastinib in SM including Non-Advanced SM. This study opened in June 2021.