A phase Ib/II study of APG-115 in combination with pembrolizumab in patients with unresectable or metastatic melanomas or advanced solid tumors
Open accessAbstract
Background: Emerging evidence suggests that p53 participates in the regulation of tumor immunity. TP53 activation in the myeloid linage suppresses alternative (M2) macrophage polarization and attenuates tumor development and invasion. Retrospective clinical analyses suggested that MDM2 amplification is associated with hyper-progression. Targeting MDM2-p53 pathway may represent a novel strategy for reversing immunosuppression and enhancing antitumor immunity of PD-1/PD-L1 blockade. APG-115 is a potent and orally active small-molecule MDM2 protein inhibitor.
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APG-115 has significant activity, which is more than 10 times that of SAR-405838, and can overcome the chronic isomerization of SAR-405838.
“APG-115 has significant activity, which is more than 10 times that of SAR-405838, and can overcome the chronic isomerization of SAR-405838.404,405”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [404]
Phase I trials showed that APG-115 had good tolerance, controllable adverse reactions and good anti-tumor activity.
“Phase I trials showed that APG-115 had good tolerance, controllable adverse reactions and good anti-tumor activity [48] and demonstrated the potential to mediate drug resistance in immunotherapy [49, 50].”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [49]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
Zhu, H., Gao, H., Ji, Y., Zhou, Q., Du, Z., Tian, L., Jiang, Y., Yao, K., & Zhou, Z. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01314-3 · Cited by 223 · see citing works
- Authors
- Tolcher, A. W., Fang, D. D., Li, Y., Tang, Y., Ji, J., Wang, H., Karim, R., Rosas, C., Huang, Y., & Zhai, Y.
- Affiliations
- Ascentage Pharma Group Inc. (United States) (US)
- Venue
- Annals of Oncology
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 30
- Pages
- i2
- ISSN
- 0923-7534 (ISSN-L)
- OpenAlex
- W2917550972
- Cited by
- 13
- References
- 0
- Citations by year
- 2024: 4 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 1
- FWCI
- 0.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Annals of Oncology (publishedVersion, cc-by-nc-nd)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- MDM2 inhibitors, pembrolizumab, melanoma, metastatic melanoma, advanced solid tumors, PD-1/PD-L1 blockade, p53, MDM2 amplification, tumor immunosuppression, M2 macrophage polarization, combination immunotherapy
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