A phase Ib/II study of APG-115 in combination with pembrolizumab in patients with unresectable or metastatic melanomas or advanced solid tumors
Authors: A.W. Tolcher, D.D. Fang, Y. Li, Y. Tang, J. Ji, H. Wang, R. Karim, C. Rosas, Y. Huang, Y. Zhai
Journal: Annals of Oncology (2019)

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. Binding to MDM2 protein, APG-115 restores p53 expression, activates p53 - mediated apoptosis in tumor cells retaining wild-type p53. Preclinical studies demonstrated that APG-115 promoted the production of proinflammatory cytokines in T cells, enhanced CD4+ T cell activation, and increased PD-L1 expression on tumor cells. Enhanced antitumor activity was demonstrated in syngeneic tumor models after APG-115 combined with PD-1 blockade. Methods: APG-115 has been evaluated as a single agent in a Phase I study in US (NCT02935907). In this study, total six dose levels (10 mg, 20 mg, 50 mg, 100 mg, 200 mg and 300 mg) have been tested. The preliminary results suggested a favorable safety and tolerability profile. APG-115 exhibited an approximately dose proportional increase in exposure in PK analyses. A Phase Ib/II study of APG-115 in combination with pembrolizumab for treatment of patients with metastatic solid tumor is ongoing. Pembrolizumab is administrated as a fixed dose of 200mg IV on d1 of a 21-d cycle. Safety, tolerability, and determination of the MTD and RP2D are primary objectives of phase Ib. Results: The second cohort (APG 115 at 100 mg) has enrolled, no DLT was observed, and evidence of antitumor activity has been observed. Biomarker studies are ongoing to identify potential selection criteria. Updated clinical data will be presented. Conclusions: This represents one of the first clinical trials to evaluate MDM2-mediated resistance to immunotherapy. Clinical trial identification: NCT03611868. Legal entity responsible for the study: Ascentage Pharma Group Corp Limited. Funding: Ascentage Pharma Group Corp Limited. Disclosure: A.W. Tolcher: Research funding: AbbVie, ADC Therapeutics, Adagene, Aminex, Acentage, Asana, Birdie, C Stone, Arrys, GlaxoSmithKline, Inhibrx, Innate, Kiromic, NatureWise, NextCure, Nitto BioPharma, Pfizer, Pieris, Deciphera, Syndax, Symphogen, Tizona, Mersana, Zymeworks; Consultancy (includes travel funding): AbbVie, Adagene, ADC Therapeutics, Agenus, Ascentage, AxImmune, Bayer, Bioinvent, Birdie, Boston Biomedical (Syneos), EMD Serono, Forbius (Formerly Formation Biologics), Gilde Healthcare Partners, HBM Partners, Ignyta, Immunome, ImmunoMet, Innate, Jazz Pharmaceuticals, Mekanistic, Nanobiotix, NBE Therapeutics, Nuvalent, Pelican, Pierre Fabre, Ridgeway, Scitemex, Sesen (formerly EBIO), Seattle Genetics, Symphogen, Syneos. D.D. Fang, Y. Li, Y. Tang, J. Ji, H. Wang, Y. Huang, Y. Zhai: Employee of Affiliates of Ascentage Pharma Group Corp Limited ("Ascentage Pharma"); Stock ownership: Ascentage Pharma. All other authors have declared no conflicts of interest.