APG-2449

P1, N=150, Recruiting, Ascentage Pharma Group Inc.

Three tested ALK-TKIs including APG-2449, brigatinib and alectinib effectively and preferentially inhibited Akt/mTOR as well as MEK/ERK signaling and decreased cell survival in ALK-mutant (ALKm) NSCLC cells with induction of apoptosis. Hence, it appears that ALK-TKIs downregulate DR4 expression in ALKm NSCLC cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression. Our findings thus warrant further investigation of the biological significance of DR4 downregulation in ALK-targeted cancer therapy.

When combined with inhibitors against mitogen-activated protein kinase kinase (MEK) [trametinib and selumetinib], mammalian target of rapamycin (mTOR) [rapamycin], focal adhesion kinase (FAK) [defactinib and Ascentage’s APG-2449, which targets FAK/ALK/ROS1], and MEK/rapidly accelerated fibrosarcoma [RAF] [VS-6766], alrizomadlin demonstrated enhanced antiproliferative activity. Combining MEK and FAK inhibitors also markedly augmented caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1) cleavage (apoptosis hallmarks) and enhanced observed antitumor effects. In conclusion, our results demonstrate the potential utility of combining alrizomadlin with MAPK pathway inhibitors to treat patients with UM.

Taken together, our studies demonstrate that APG-2449 exerts potent and durable antitumor activity in human NSCLC and ovarian tumor models when administered alone or in combination with other therapies. A phase 1 clinical trial has been initiated to evaluate the safety and preliminary efficacy of APG-2449 in patients with advanced solid tumors, including ALK NSCLC refractory to earlier-generation ALK inhibitors.

Another pt with the G1202R mutation following alectinib treatment had tumor shrinkage of 27.9%. APG-2449 has a favorable safety and PK profile and was well tolerated in 84 subjects. Preliminary efficacy was observed in pts whose disease was resistant to second-generation TKIs, especially among those with brain metastases, and in TKI-naïve pts. Biomarker data indicated potential target engagement on FAK and immunomodulatory effects of APG-2449.

P1, N=150, Recruiting, Ascentage Pharma Group Inc. | N=100 --> 150 | Trial completion date: May 2023 --> Feb 2025 | Trial primary completion date: May 2022 --> Jan 2025

The synergistic effects are evidently mediated by induced autophagy and enhanced cellular senescence. This preclinical study lays a foundation for future clinical development of APG-2449 combined with CDK4/6 inhibitors for mesothelioma.

In ESCC xenotransplantation models, single therapy with either ibrutinib or APG-2449 was equivalent in delaying tumor growth, while the combination therapy suppressed tumor growth more significantly. Our data strongly suggest that the combination therapy of APG-2449 and ibrutinib can provide an effective therapeutic strategy for ESCC patients, which deserved further clinical investigation.