BGB-24714 (SMAC mimetic/IAP antagonist) shows no MTD; adds cCRT response signal but chemo-combo activity mixed

BGB-24714 is a selective SMAC mimetic that antagonizes inhibitor-of-apoptosis proteins (IAPs), aiming to restore apoptosis and potentially sensitize tumors to chemotherapy or concurrent chemoradiotherapy (cCRT). In this open-label, multicenter first-in-human Phase 1 dose-escalation/expansion study (NCT05381909), 157 patients with advanced/metastatic solid tumors were treated as of July 25, 2025 (Ph1a n=132 across monotherapy, weekly paclitaxel, and cCRT in NSCLC/ESCC; Ph1b n=25 in later-line metastatic NSCLC [BGB-24714+docetaxel, n=11] and platinum-resistant ovarian cancer [PROC; BGB-24714+paclitaxel, n=14]); no MTD was reached up to 900mg QD (mono) and 650mg QD (combos). Discontinuation due to BGB-24714-related TEAEs was 12.1% (Ph1a) and 24.0% (Ph1b), with notable Grade ≥3 events including neutrophil count decreased in the cCRT cohorts (31.3%) and anemia in Ph1b-NSCLC (27.3%); serious related TEAEs included pneumonitis (6.3%) with weekly paclitaxel and febrile neutropenia (7.1%) in PROC. Efficacy was highly regimen/setting-dependent: confirmed ORR was 0% with monotherapy, 12.8% with weekly paclitaxel, 54.5% in the cCRT NSCLC cohort, and 66.7% in the cCRT ESCC cohort (Ph1a), while in Ph1b confirmed ORR was 0% in NSCLC and 28.6% in PROC with median PFS 162 days (5.3mo) for both—broadly in the range of typical single-agent taxane activity in PROC (22% ORR historically; and PFS often ~3–5 months depending on regimen/patient mix), while the NSCLC +docetaxel signal here looks weaker than historical docetaxel second-line activity (generally modest but non-zero response rates). Pharmacodynamics showed dose-dependent, rapid and sustained cIAP1 degradation, supporting on-mechanism target engagement.