Abstract A086: Phase Ib study of a novel MDM2 inhibitor APG-115, in combination with pembrolizumab in patients with metastatic solid tumors in U.S.
Authors: Tolcher Anthony W , Karim Raghad , Tang Yuefen , Ji Jiao , Wang Hengbang , Meng Lichuang , Kaiser Angela , Coe Jennifer , Liang Eric , Rosas Christina , Yang Dajun , Zhai Yifan 
Published: March 2020

Abstract
Keywords: MDM2; Immuno-oncology; PD-1 Background APG-115 is an orally active small-molecule MDM2 inhibitor that potently binds MDM2 protein, restores TP53 function, and 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. Retrospective clinical analyses suggested that MDM2 amplification is associated with hyper-progression in the patients treated with check point inhibitors. Keywords: MDM2; Immuno-oncology; PD-1 In general, by targeting MDM2-p53 pathway, APG-115 in combination with PD-1/PD-L1 blockade may provide a novel strategy to reverse immunosuppression and/or enhance antitumor immunity in the cancer patients who were either failed to standard therapies or resistant to IO therapies. Methods This dose escalation study (NCT03611868) combines APG-115 with pembrolizumab for the treatment of patients with metastatic solid tumors. Four dose levels of APG-115 have been tested: 50, 100, 150, and 200mg. APG-115 is administrated orally every other day (QOD) for consecutive 2 weeks of a 21-day-cycle with pembrolizumab at 200mg IV on day1 of a 21-day-cycle. Results Through June 15, 2019, a total of 14 patients have been treated in 4 cohorts of APG-115 in combination with pembrolizumab IV q3weeks. No cycle 1 DLTs have been observed up to and including 200 mg APG-115 at total doses of APG115 that are equivalent to the single agent MTD of APG-115 alone. Eleven patients experienced at least 1 TEAE. The most common TRAEs (≥10%) were nausea (42.9%), neutrophil count decreased (21.4%), vomiting (14.3%), decreased appetite (14.3%), diarrhea (14.3%), platelet count decreased (14.3%), white blood cell count decreased (14.3%), and fatigue (14.3%). Four patients experienced at least 1 grade 3 or higher TRAE beyond course 1 including neutrophil count decreased (21.4%). Five SAEs occurred in 3 patients, but only one grade 3 febrile neutropenia was treatment related. One patient with advanced ovarian cancer with a germline ATM mutation, refractory to 6 prior lines of therapy, has a sustained “confirmed CR” that continues beyond 12 cycles at the 100mg cohort. A patient with advanced NSCLC in 100mg cohort has received “confirmed PR” (still ongoing) after failed prior 5 lines of therapies including 3 months’ nivolumab treatment; 5 patients had SD after two cycle treatments, 2 of them ongoing. PK analyses indicates an approximately dose proportional increase in exposure across dose levels from 50 to 100 mg with plasma concentrations that exceed those that portend MDM2 inhibition. Preliminary pharmacodynamic (PD) results showed that the serum macrophage inhibitory cytokine-1 (MIC-1) levels are elevated in the APG-115 treated patients, suggesting a potential p53 activation in patients. Conclusion APG-115 in combination with pembrolizumab is well tolerated. The MTD has not been exceeded at full doses of APG-115. Promising anti-tumor effects have been seen in several tumor types when in combination with pembrolizumab. Expansion cohorts in molecularly selected patients is planned.
Citation Format: Anthony W Tolcher, Raghad Karim, Yuefen Tang, Jiao Ji, Hengbang Wang, Lichuang Meng, Angela Kaiser, Jennifer Coe, Eric Liang, Christina Rosas, Dajun Yang, Yifan Zhai. Phase Ib study of a novel MDM2 inhibitor APG-115, in combination with pembrolizumab in patients with metastatic solid tumors in U.S. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A086. doi:10.1158/1535-7163.TARG-19-A086