Abstract CT120: A phase 1 study of BGB-24714, a second mitochondrial-derived activator of caspases (SMAC) mimetic, as monotherapy or in combination with chemotherapy or concurrent chemoradiotherapy in solid tumors

Abstract Background: Apoptosis modulation may enhance the efficacy of standard-of-care chemotherapy (CT) and concurrent chemoradiotherapy (cCRT) in solid tumors. BGB-24714, a selective SMAC mimetic that antagonizes Inhibitor of Apoptosis Proteins (IAPs), has demonstrated promising preclinical antitumor activity. This open-label, multicenter, first-in-human Phase (Ph) 1 study evaluated BGB-24714 as monotherapy or in combination with CT or cCRT in patients (pts) with advanced or metastatic solid tumors (NCT05381909). Methods: The study included dose-escalation (1a) and -expansion (1b) Phs. Ph1a Part A assessed BGB-24714 monotherapy; Part B: BGB-24714 + weekly paclitaxel; Parts C/D: BGB-24714 + cCRT in NSCLC and esophageal squamous cell carcinoma (ESCC), respectively. Ph1b enrolled pts with second-line or later metastatic NSCLC and platinum-resistant ovarian cancer (PROC) to receive BGB-24714 + docetaxel or paclitaxel, respectively. Primary endpoints were safety/tolerability (Ph1a) and preliminary antitumor activity (Ph1b). Results: As of July 25, 2025, 157 pts were enrolled and treated (132 in Ph1a; 25 in Ph1b 11 NSCLC; 14 PROC). 9 dose levels (DLs; 30 mg to 900 mg QD) of BGB-24714 were assessed (n=68) in Ph1a Part A and 7 DLs (60 mg to 650 mg QD) in Ph1a Parts B to D (n=64). No MTD was reached in Ph1a monotherapy or combination dose escalation. The most common BGB-24714-related TEAEs varied by study part and were predominantly low grade: nausea (33. 8%) in Ph1a Part A, diarrhea (25%) in Part B, neutrophil count decreased (43. 8%) in Parts C/D, diarrhea and fatigue (45. 5% each) in Ph1b-NSCLC, and stomatitis, ALT/AST increased (28. 6% each) in Ph1b-PROC. The most common Grade ≥3 BGB-24714-related TEAEs were ALT increased (5. 9%) in Ph1a Part A, lipase increased and fatigue (6. 3% each) in Part B, neutrophil count decreased (31. 3%) in Parts C/D, anemia (27. 3%) in Ph1b-NSCLC, and neutrophil count decreased (28. 6%) in Ph1b-PROC. The most common serious BGB-24714-related TEAEs (≥5%) were pneumonitis (6. 3%) in Ph1a Part B, diarrhea (18. 2%) in Ph1b-NSCLC, and febrile neutropenia and fatigue (7. 1% each) in Ph1b-PROC. Treatment discontinuation due to BGB-24714-related TEAEs occurred in 12. 1% of Ph1a and 24. 0% of Ph1b pts. Confirmed ORRs in Ph1a were 0% (Part A), 12. 8% (Part B), 54. 5% (Part C), and 66. 7% (Part D) ; DCRs were 40. 0%, 59. 6%, 81. 8%, and 100. 0%, respectively. In Ph1b, confirmed ORRs were 0% in NSCLC and 28. 6% in PROC; DCRs were 70. 0% and 85. 7%, respectively; median PFS was 162 days for both NSCLC and PROC. Pharmacodynamics showed rapid and sustained cIAP1 degradation in a dose-dependent manner, demonstrating strong target engagement in apoptosis regulatory pathway. Conclusion: BGB-24714 demonstrated antitumor activity with a manageable safety profile in pts with advanced or metastatic solid tumors. Citation Format: Andreas Varkaris, Erika Hamilton, Jermaine Coward, Rafael Santana-Davila, Jinming Yu, Byoung Chul Cho, Jung Yun Lee, Yongsheng Li, Sanjeev Deva, Youngjoo Lee, Huai Liu, Yuping Sun, Zhe Yang, Wen Xu, Sook Ryun Park, Se-Hoon Lee, Andrew Z. Wang, Hui Shao, Jinhui Zhang, Zhaoyin Zhu, Runzhe Chen, Hua-Xin Gao, Judy S. Wang. A phase 1 study of BGB-24714, a second mitochondrial-derived activator of caspases (SMAC) mimetic, as monotherapy or in combination with chemotherapy or concurrent chemoradiotherapy in solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT120.