AL101

P1, N=14, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2025 --> Dec 2028 | Trial primary completion date: Dec 2025 --> Dec 2028

Emerging breakthroughs in targeted therapies warrant attention, including antisense oligonucleotides targeting MYB-NFIB fusion genes, clinical trial data of NOTCH inhibitors (e.g., AL101), and PARP inhibitor-based combinatorial regimens leveraging DNA damage repair mechanisms. By integrating fundamental research and clinical translational evidence, this review provides a theoretical framework for optimizing LGACC diagnosis and treatment paradigms.

NOTCH inhibitors demonstrate activity in NOTCH-activated ACC, surpassing the efficacy of observation or prior systemic therapies. However, limited PFS and progression of nontarget lesions suggest the potential need for combination therapy to address ACC heterogeneity.

Here we report the cryo-electron microscopy structures of human γ-secretase bound individually to five clinically tested GSIs (RO4929097, crenigacestat, BMS906024, nirogacestat and MK-0752) at overall resolutions of 2.4-3.0 Å. The size and shape of the binding pocket are induced by the bound GSI. Analysis of these structural features suggest strategies for modification of the GSI with improved inhibition potency.

P1, N=14, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P1, N=14, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P2, N=18, Terminated, Ayala Pharmaceuticals, Inc, | N=67 --> 18 | Active, not recruiting --> Terminated; Sponsor's decision

P2, N=87, Completed, Ayala Pharmaceuticals, Inc, | Active, not recruiting --> Completed

Ni included AL101, a gamma-secretase inhibitor, or OMP-52M51, an antibody targeting N1...The efficacy of Ni compares favorably with efficacy of systemic therapies administered prior to Ni. The limited PFS and high rate of tumor progression on non-target lesions suggests Ni combination therapy may be necessary to address ACC heterogeneity.

*Inverse variance method, no transformation, 0.5 continuity correction. ORR: CR + PR; DCR: CR + PR + SD Conclusions AL101 showed acceptable safety and tolerability in ACC pts with Notchmut and a response rate comparable to pooled estimates for available therapies in pts regardless of Notch status.

Here, we describe the antitumor activity of AL101 using ACC cell lines, organoids, and patient-derived xenograft models. Specifically, we find that AL101 has potent antitumor effects in in vitro and in vivo models of ACC with activating NOTCH1 mutations and constitutively upregulated NOTCH signaling pathway, providing a strong rationale for evaluation of AL101 in clinical trials for patients with NOTCH-driven relapsed/refractory ACC.

P2, N=67, Active, not recruiting, Ayala Pharmaceuticals, Inc, | Recruiting --> Active, not recruiting